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Folic acid functionalized nanoparticles as pharmaceutical carriers in drug delivery systems

May 2019
Drug Development Research 80(4)

May 2019
80(4)

DOI:10.1002/ddr.21545

Authors:

Parvaneh Darkhor

Asghar Narmani

University of Tehran

Bagher Farhood

Kashan University of Medical Sciences and Health Services

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photon upconversion where two or more photons are absorbed by a material and a single photon of shorter wavelength (anti-Stokes shift) is subsequently emitted (Rinkel, Nordman, Raj, & Haase, 2014; Narmani, Farhood, Haghi-Aminjan, et al., 2018; Han, Deng, Xie, & Liu,

…

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OVERVIEW

Folic acid functionalized nanoparticles as pharmaceutical

carriers in drug delivery systems

Asghar Narmani

| Melina Rezvani

| Bagher Farhood

| Parvaneh Darkhor

Javad Mohammadnejad

| Bahram Amini

| Soheila Refahi

Nouraddin Abdi Goushbolagh

Department of Life Science Engineering,

Faculty of New Sciences and Technologies,

University of Tehran, Tehran, Iran

Department of Biology, Faculty of Sciences,

Payame Noor University, Tehran, Iran

Department of Medical Physics and Radiology,

Faculty of Paramedical Sciences, Kashan

University of Medical Sciences, Kashan, Iran

Department of Medical Physics, Tabriz

University of Medical Sciences, Tabriz, Iran

Department of Biology, Science and Research

Branch, Islamic Azad University, Tehran, Iran

Department of Medical Physics, Faculty of

Medicine, Ardabil University of Medical

Sciences, Ardabil, Iran

Department of Medical Physics, Faculty of

Medicine, Shahid Sadoughi University of

Medical Sciences, Yazd, Iran

Correspondence

Javad Mohammadnejad, Department of Life

Science Engineering, Faculty of New Sciences

and Technologies, University of Tehran,

Tehran 1439957131, Iran.

Email: mohamadnejad@ut.ac.ir

Nouraddin Abdi Goushbolagh, Department of

Medical Physics, Faculty of Medicine, Shahid

Sadoughi University of Medical Sciences, Yazd,

Iran.

Email: noure_al_din@yahoo.com

Abstract

Conventional chemotherapeutic approaches in cancer therapy such as surgery, che-

motherapy, and radiotherapy have several disadvantages due to their nontargeted

distributions in the whole body. On the other hand, nanoparticles (NPs) based thera-

pies are remarkably progressing to solve several limitations of conventional drug

delivery systems (DDSs) including nonspecific biodistribution and targeting, poor

water solubility, weak bioavailability and biodegradability, low pharmacokinetic prop-

erties, and so forth. The enhanced permeability and retention effect escape from P-

glycoprotein trap in cancer cells as a passive targeting mechanism, and active

targeting strategies are also other most important advantages of NPs in cancer diag-

nosis and therapy. Folic acid (FA) is one of the biologic molecules which has been

targeted overexpressed-folic acid receptor (FR) on the surface of cancer cells. There-

fore, conjugation of FA to NPs most easily enhances the FR-mediated targeting deliv-

ery of therapeutic agents. Here, the recent works in FA which have been decorated

NPs-based DDSs are discussed and cancer therapy potency of these NPs in clinical

trials are presented.

KEYWORDS

cancer diagnosis and therapy, folic acid, nanoparticles, nanotechnology, targeted drug delivery

1|INTRODUCTION

Nowadays nanoparticles (NPs) based technologies are developed in

wide spectrum of prognosis, diagnosis, treatment, and prevention in

medicine. These technologies are related with practical applications of

different NPs including nano-polymers, nanofibers, nanomembranes,

nanosized chips, and nanomachines for protein, nucleic acid, peptide,

and therapeutic agent delivery or their applications in nanosensors-

based detection (Petros & De Simone, 2010; Barratt, 2000; Narmani,

Kamali, Amini, et al., 2018). The monodispersity, nanosize and shape,

Abbreviations: 5-FU, 5-fluorouracil; BO, borneol; BSA, bovine serum albumin; CAP, capsaicin; CS, chitosan; CT, computed tomography; Cur, curcumin; CD/5-FC, cytosine

deaminase/5-fluorocytosine; DDS, drug delivery system; DEX, dextran; DOX, doxorubicin; DTX, docetaxel; EPR, enhanced permeability and retention; ETB, erlotinib; FA, folic acid; FR, folic acid

receptor; GNP, gold nanoparticle; GO, graphene oxide; HA, hyaluronic acid; LD, monolayer lipid; Lf, lactoferrin; LS, liposome; MNP, magnetic nanoparticle; MRI, magnetic resonance imaging;

MTN, mitoxantrone; MTX, methotrexate; NIR, near-infrared; NP, nanoparticle; OA, oleic acid; OQLCS, octadecyl-quaternized lysine modified chitosan; PAMAM, polyamidoamine; PDT,

photodynamic therapy; PEG, polyethylene glycol; PEI, polyethyleneimine; PHis, poly(L-histidine); PLA, polylactic acid; PLGA, poly(lactide-co-glycolide); PLLA, poly(L-lactide)-b-poly(ethylene

glycol); PLS, polymeric liposome; PNIPAAm-co-OA, N-isopropylacrylamide-oleic acid; PTX, paclitaxel; QU, quercetin; RSV, resveratrol; siVEGFA, siRNA against vascular endothelial growth factor

A; Tf, transferrin; UCL, upconversion luminescence; UCNP, upconverting nanoparticle.

Received: 4 January 2019 Revised: 2 March 2019 Accepted: 7 May 2019

DOI: 10.1002/ddr.21545

good biocompatibility, high capacity of surface modification and func-

tionalization, great in vivo stability, excellent pharmacokinetic proper-

ties, and other specific aspects of NPs indicate great promise for their

application in the treatment of cancers (Hawker & Wooley, 2005;

Kesharwani, Jain, & Jain, 2014). These various physicochemical and

biocompatible features of NPs have made them as potent therapeutic

vehicle for cancer therapy. Furthermore, NPs have been led to

increase the circulation half-life of therapeutics and improve their

tumors accumulation in body (Jadidi-Niaragh et al., 2017).

On the other hand, conventional therapeutic anticancer agents,

due to their nontargeted distributions in the whole body, are typically

affected both normal and cancer cells. This general drug distribution

decreases the effective cytotoxic dose effect of anticancer on cancer-

ous cell and mostly indicates the growth inhibitory effect on normal

cells (Allen, 2002; Morgillo & Lee, 2005). This low dose effect on can-

cer cells is also eliminated via multidrug resistance process in these

cells and thereby, the remarkable toxic effects of anticancer agents

are threated the normal cells. Moreover, the intrusive processes in

cancer therapy such as surgery to remove the tumor that has been

followed by chemotherapy radiation, are accompanied with extreme

ailment in patient and lead to organ amputation and even patient

death in some cases (Stein & Skinner, 2006). In order to overcome

these nontargeted and invasive surgeries approaches, the targeted

(active) drug delivery is so crucial to affect cancer therapy. The active

targeting strategies can increase the intracellular concentration of

therapeutic agents in cancer cells while prevent the cytotoxic effects

in normal cells (Figure 1).

Folic acid (FA; Figure 2; Mr 38 kDa) is one of the cancer cell-

targeted biomolecules with high overexpressed receptor to avoid for-

midable membrane barrier of tumors with poorly formed vasculature

(Amini et al., 2019; Yoo & Park, 2004). As a kind of vitamin, FA is

essential for the biosynthesis of nucleotide bases and cell prolifera-

tion. The physiological FA is transported using the cell membrane-

associated proteins or folic acid receptor (FR) via receptor-mediated

endocytosis (Turk et al., 2002). FR has overexpression in various

human carcinomas including breast, ovary, kidney, lung, and so forth,

and it is considered as a tumor-specific target platform due to its

accessibility to intravenous drugs (Toffoli et al., 1997; Zhong et al.,

2017). FR-αand FR-βas glycosylphosphatidylinositol-anchored mem-

brane glycoproteins are common overexpressed receptors on the sur-

face of cancer cells. In comparison to FR-β, high affinity for the

circulating folic acid coenzyme (6S)-5-methyltetrahydrofolic acid and

physiologic FA are major properties of FR-α(Da Costa & Rothenberg,

1996; Narmani, Mohammadnejad, & Yavari, 2019). Other isoforms of

FR are FR-γand FR-γ0that are soluble forms of the human FR specific

for hematopoietic tissues and lymphoid cells. The affinities of these

receptors are K

0.1 , 1, and 0.4 nM for FR-α, FR-β, and FR-γ,

respectively (Bueno, Appasani, Mercer, Lester, & Sugarbaker, 2001;

Shen, Wu, Ross, Miller, & Ratnam, 1995; Wu, Gunning, & Ratnam,

1999). Also, there is a remarkable correlation between the degree of

FR-αexpression in cancer cells and their resistance to standard che-

motherapy. As high level of FR expression in cancers tissue has been

directly related to survive of cancer cells from standard chemotherapy

(Toffoli et al., 1998). FR-βexpression level is elevated in most of non-

epithelial origin malignancies such as myelogenous leukemias and sar-

comas (Reddy et al., 1999). On the other hand, FR-γand FR-γ0

expression high levels are also related to certain hematopoietic malig-

nancies (Ross et al., 1999). Thus, cancer selectivity of FA and FA con-

jugates can be considered as potent approach in NP-based targeted

delivery of anticancer therapeutic agents in cancer diagnosis and ther-

apy (Figure 3; Narmani, Yavari, & Mohammadnejad, 2017).

There are six FA-linked practical applications for targeting delivery

of therapeutic agents that have been tested in the clinic until now

FIGURE 1 Schematic representation

of NPs in drug delivery. The classification of

NP-based drug delivery and main roles of

NPs in targeted (passive and active) and

nontargeted drug delivery. FA, folic acid;

NP, nanoparticle

FIGURE 2 Molecular structure of folic acid

NARMANI ET AL.405

(Leamon et al., 2007). These practical cases are including, FA-targeted

protein toxins (such as use of FA-Pseudomonas exotoxin conjugate to

kill FR

cancer cells), FA-targeted chemotherapeutic agents (such as

FA-paclitaxel and FA-camptothecin in order to tumor inhibition), FA-

targeted immunotherapy (such as use of FA/anti-T cell receptor to

educate the immune system to recognize tumor activating mutations),

FA-targeted gene therapy (such as FA-nonviral gene therapy vectors),

FA-targeted antisense oligodeoxyribonucleotides (ODN) and small

interfering RNAs (siRNA) delivery (such as use of ODN or siRNA to

knockout or modulate gene expression), and design of FA-targeted

NPs in targeted cancer therapy (Leamon et al., 2007; Tranoy-

Opalinski, Fernandes, Thomas, Gesson, & Papot, 2008).

On the other hand, use of new and innovative protocols and

methods for the synthesis and functionalization of NPs has made excel-

lent scientific and clinic community between molecular-targeted drug

delivery and commercialization (Shi, Kantoff, Wooster, & Farokhzad,

2017). As, many more formulations of targeted NPs are annually pro-

gressing to clinical trials investigation (Phase I–IV) that liposomal and

polymeric formulations represent the biggest share of the targeted NPs

under clinical evaluation. Even several formulations of liposomal and

polymeric NPs earned the FDA-approved and introduced in the market

(Shi et al., 2017; Svenson, 2012). However, there are several key obsta-

cles and challenges which are related to the clinical and translational

development of targeted NPs in nanomedicine, such as lack of clear

regulatory guidelines that are specific to targeted NPs, limited under-

standing of the biological stability of targeted NPs in human body and

serum, and limited knowledge about NPs biocompatibility and biode-

gradability (Hua, De Matos, Metselaar, & Storm, 2018; Svenson, 2012).

On the other hand, there is some incoordination between members of

the investment community in conceptual understanding of the

nanomedicine and scientific research recognize that has very low

understanding about business expertise to develop commercial product

in nanomedicine.

Also, there are other studies that previously evaluated some other

properties of FA-functionalized NPs as delivery systems. In a work by

Bahrami et al. (2015), the general properties of FA-functionalized NPs

and their delivery behavior in preclinical experiments evaluated. Also,

their group just prepared some of the information about specific types

of NPs without complete classification and preparation methods of

nanocomplexes. However, in this work, most of the NPs classified first

and then different properties and synthetic methods of nanocomplexes

were reviewed in detail. In this work, many angels of FA-functionalized

NPs and their practical applications in preclinical cases were also evalu-

ated. Also, this study focused on recent studies. In another study by

Samadian, Hosseini-Nami, Kamrava, Ghaznavi, and Shakeri-Zadeh

(2016), some of the specific aspects of FA-functionalized gold NPs and

their applications in therapeutic and diagnostic delivery systems were

collected. However, this work is completely different from their work

because in this study, different types of FA-functionalized NPs (not just

gold NPs) were investigated and different characteristics of different

NPs were reviewed.

Several NPs, as drug delivery systems (DDSs), are the most impor-

tant applications in cancer prognosis, diagnosis, and therapy (Misra,

Acharya, & Sahoo, 2010; Rawat, Singh, & Saraf, 2006). These practical

NPs are including polymer-based (biopolymers and chemopolymers),

lipid-based (liposomes and micelles), oxide-based (iron oxide, graphene

oxide, etc.), and upconversion NPs (Tables 1 and 2). These NPs, due to

their specific properties, are excellent nanocarriers as long as implement

FIGURE 3 Schematic representation of FA-functionalized NPs in active targeting delivery. (a) Surface modification and functionalization of

NPs for improve their biocompatibility, drug-loading capacity, in vivo stability, and pharmacokinetic properties in order to enhance the

therapeutic potency of NPs. (b) Tumor targeting of NPs actively by FA-mediated internalization. Long-circulating therapeutic NPs accumulate

actively in solid tumor cells by the targeting FR on the surface of tumor cell. After internalization, the nano-complex compartments dissociated in

acidified condition of endosomes and therapeutic agents inhibits the cell growth. FA, folic acid; FR, folic acid receptor; NP, nanoparticle

406 NARMANI ET AL.

TABLE 1 Various bio- and chemo-polymer based nanocarriers reported in preclinical drug delivery studies

Nanocarriers

Bioactive

agents Characteristics Comments Kind of cell lines and tumors References

Bio-polymers

FA-SOCS NPs HCPT Core-shell micelle for

active delivery of

hydrophobic agent

In vitro and

in vivo

Bel-7402 hepatoma cell line and

Bel-7402 tumor-bearing nude

mice

Zhu, Cao, Cui, Qian,

and Gu (2013)

FA-(PNIPAAm-co-OA)-

g-CS NPs

ETB Self-assembled core-shell

micelle

In vitro OVCAR-3 ovarian carcinoma and

A549 human non-small-cell

lung cancer cell lines

Fathi et al. (2017)

FA-PLA-PEG NPs DOX Hybrid core-shell micelle

for active drug delivery

In vitro SKOV3 ovarian cancer cell line Hami, Amini, Ghazi-

Khansari, Rezayat,

and Gilani (2014)

FA-PLLA-PEG NPs DOX Self-assembled core-shell

micelle for codelivery

In vitro A2780 ovarian cancer cell line Kim, Lee, Oh, Gao, and

Bae (2008)

FA-Au-PLA-PEG NPs DOX Self-assembled micelle for

active delivery of

hydrophobic agent

In vitro 4T1 breast cancer cell line Prabaharan, Grailer,

Pilla, Steeber, and

Gong (2009)

FA-PLGA-PLS NPs DOX,

pEGFP

Self-assembled core-shell

micelle for codelivery

In vitro MDA-MB-231 breast cancer cell

line

(Wang, Zhao, Su, et al.,

2010)

FA-PLGA-Lf NPs Etoposide Co-targeted delivery In vitro U87MG glioma cells cell line Kuo and Chen (2015)

FA-PLGA-CS NPs Ins Globular electrostatic self-

assemble

In vitro and

in vivo

HT-29 colon cancer cell line and

diabetic rats

(Xu, Jiang, Yu, et al.,

2017)

FA-PEG-PLLA NPs Plasmid

DNA

Three-layered co-polymeric

micelle

In vitro and

in vivo

RAW264.7 macrophage cell line

and mice model

Mohammadi et al.

(2016)

FA-PEG–PLA NPs Cur Amphiphilic copolymeric

nanocarrier

In vitro MCF-7 breast cancer and

HepG2 liver cancer cell lines

(Yang, Chen, Zhao, et

al., 2014)

FA-DEX-BSA NPs DOX Self-assembled core-shell

micelle

In vitro and

in vivo

H22 hepatoma cell line and

murine ascites hepatoma H22

tumor-bearing mice

(Hao, Ma, Huang, He,

& Yao, 2013)

FA-DEX NPs RSV Core-shell micelle In vitro A549 human non-small-cell lung

cancer cell line

Zhao et al. (2017)

FA-HA-PHis NPs DOX pH sensitive self-assemble

micelle

In vitro MCF-7 breast cancer cell line Qiu et al. (2014)

FA-HA NPs PTX Dual-targeted self-

assemble micelle

In vitro MCF-7 breast cancer cell line Liu et al. (2011)

Chemo-polymers

FA-PAMAM/BO NPs DOX Dual-targeted delivery In vitro and

in vivo

C6 glioma cell line and glioma-

bearing rats

Xu et al. (2016)

FA-PAMAM-

PEG-

99m

Tc NPs

5-FU Theranostic targeted

codelivery

In vitro and

in vivo

MCF-7 breast cancer and C2C12

cell lines and 4T1 tumor

bearing BALB/C mice

Narmani et al. (2017)

FA-PAMAM NPs siVEGFA Localized FR-αmediated

gene delivery

In vitro and

in vivo

HN12 and HN12-YFP cell lines

and athymic nude mice

(Xu, Yeudall, & Yang,

2017)

FA-PEG-b-(CL-g-PEI)-b-

CL NPs

DOX, P-gp

siRNA

Amphiphilic core-shell

polymer-based micelle

for codelivery

In vitro and

in vivo

MCF-7 breast cancer and MCF

7/ADR cell lines and athymic

nude mice

Wu et al. (2016)

FA-C60-PEI NPs DTX Amphiphilic core-shell

micelle

In vitro and

in vivo

PC3 prostate cancer cell line and

S180 prostate tumor models

Shi et al. (2013)

FA-PEI-OA NPs LOR-2501 Amphiphilic carriers for

targeted delivery

In vitro HeLa cervical cancer and SK-

HEP-1 human cell lines

Yang et al. (2015)

FA-PEG-PEI NPs pCD/5-FC,

pTRAIL

Hydrophilic globular carrier

for delivery

In vitro and

in vivo

C6 glioma cell line and glioma-

bearing rats

Liang et al. (2009)

Abbreviations: 5-FU, 5-fluorouracil; BO, borneol; BSA, bovine serum albumin; CS, chitosan; Cur, curcumin; DEX, dextran; DOX, doxorubicin; ETB, erlotinib;

FA-SOCS, FA-fuctionalized N-succinyl-N0-octyl CS; HA, hyaluronic acid; HCPT, hydroxycamptothecin; Lf, lactoferrin; NP, nanoparticle; OA, oleic acid;

PAMAM, polyamidoamine; PEG, polyethylene glycol; PEI, polyethyleneimine; PHis, poly(L-histidine); PLA, polylactic acid; PLGA, poly(lactide-co-glycolide);

PLLA, poly(L-lactide)-b-poly(ethylene glycol); PLS, polymeric liposome; PNIPAAm-co-OA, N-isopropylacrylamide-oleic acid; PTX, paclitaxel; RSV, resveratrol.

NARMANI ET AL.407

TABLE 2 Various lipid-, metal-, and nonmetal-based nanocarriers reported in preclinical drug delivery studies

Nanocarriers

Bioactive

agents Characteristics Comments Kind of cell lines and tumors References

Bilayer lipid NPs

FA-LS-Tf NPs DOX Dual-targeted LS for

targeted delivery

In vitro and

in vivo

HeLa cervical and A2780-ADR

ovarian cell lines and

athymic nude mice

Sriraman, Salzano,

Sarisozen, and

Torchilin (2016)

FA-LS-PEG NPs CAP Amphiphilic globular LS for

targeted delivery

In vitro and

in vivo

SKOV-3 ovarian cell line

ovarian tumor bearing rats

Lv et al. (2017)

FA-PEG-LS-PLGA

NPs

DTX Amphiphilic functionalized-

LS for targeted delivery

In vitro MCF7 breast cancer and NIH/

3T3 fibroblast cell lines

Liu, Li, Pan, Liu, and Feng

(2010)

Monolayer lipid NPs

FA-PEG-LD-PLGA

NPs

PTX Self-assembled core-shell

micelles

In vitro and

in vivo

HeLa cervical and A549 human

non-small-cell lung cancer

cell lines and cervical tumor

bearing SCID mice

Zhao et al. (2012)

FA-LD-PLGA NPs MTX Self-assembled amphiphilic

hybrid micelles

In vitro MDA-MB-231 breast cancer,

PC3 prostate, and HT29

colon cell lines

Tahir et al. (2017)

FA-LD-FA NPs MTN Self-assembled amphiphilic

block or graft

copolymers

In vitro HeLa cervical cancer cell line Chen et al. (2013)

FA-PEG-PPO-PEG

NPs

DOX, QU Amphiphilic core-shell

micelles for targeted

codelivery

In vitro HeLa cervical cancer cell line Hassanzadeh, Feng,

Pettersson, and

Hakkarainen (2015)

Iron oxide NPs

FA-DEX-MNPs DOX Hydrophilic biocompatible

core-shell NPs for dual-

targeted imaging and

therapy

In vitro MCF-7 and MDA-MB-468

breast cancer cell lines

Varshosaz, Sadeghi-

Aliabadi, Ghasemi, and

Behdadfar (2013)

FA-BSA-MNPs DOX Hydrophilic core-shell NPs

for active therapy

In vitro and

in vivo

KB human nasopharyngeal

epidermal carcinoma cell line

and KB tumor bearing

BALB/c nude mice

(Yang, An, Miao, et al.,

2014)

FA-PEG-FITC-PEI-

MNPs

Hydrophilic core-shell NPs

for MRI

In vitro and

in vivo

KB human nasopharyngeal

epidermal carcinoma cell line

and KB tumor bearing

BALB/c nude mice

Li et al. (2013)

FA-PEG-PEI-MNPs DOX,

Co-targeted hydrophilic

core-shell NPs for

codelivery

In vitro and

in vivo

MCF7 breast cancer cell line

and MCF7 tumor bearing

cell BABB/c mice

Huang, Mao, Zhang, and

Zhao (2017)

FA-S/ZnO-MNPs Cur, Fe

Hydrophilic core-shell NPs

for codelivery

In vitro HepG2 liver cancer and MCF7

breast cancer cell lines

Saikia, Das, Ramteke, and

Maji (2017)

FA-PEG-CMNPs Fe

Dual-targeted core-shell

NPs magnetic

hyperthermia

In vitro Normal human fibroblasts and

HeLa cervical cancer cell

lines

Sadhasivam, Savitha, Wu,

Lin, and Stobinski

(2015)

Graphene oxide NPs

FA-BSA-GO NPs DOX Nano-hybrid sheets for

targeted delivery

In vitro MCF-7 human breast cancer

and A549 human non-small-

cell lung cancer cell lines

Ma et al. (2017)

FA-MNP-GO NPs DOX Dual-targeted core-shell

NPs for delivery

_ _ (Wang, Zhou, Xia, et al.,

2013)

FA-PVP-GO NPs DOX Targeted chemo-

photothermal therapy

In vitro HeLa cervical cancer and A549

human non-small-cell lung

cancer cell lines

Qin et al. (2013)

(Continues)

408 NARMANI ET AL.

such intelligence vehicle in cancer targeting that is possible via their

surface functionalization with FA as cancer-targeted agent. In the fol-

lowing summary of significant applications of FA-decorated NPs in

active delivery of therapeutic agents and their importance will state.

2|POLYMER-BASED NPS IN DRUG

DELIVERY

2.1 |Biopolymers in drug delivery

2.1.1 |Chitosan NPs

Targeted nanoscaled chitosan (CS)-based DDSs are the subject of

interest as targeted carriers of therapeutics and diagnostics agents to

cancer cells, which have improved systemic performance in cancer

detection and therapy (Figure 4; Chen et al., 2008; Park et al., 2004).

The CS, as natural biopolymer, has excellent biocompatibility, biode-

gradability, great bioavailability, hydrophilicity, and low toxicity, and it

has also practical application in different forms including nanomicelles,

NPs, microspheres, hydrogels, biofilms, and tablets (Rege, Garmise, &

Block, 2003; Rezvani, Mohammadnejad, Narmani, & Bidaki, 2018).

Furthermore, functional surface hydroxyl and amine groups facilitate

their chemical modification to surface engineering in the CS backbone

(Zhang, Ding, Yu, & Ping, 2007).

Also, CS as N-deacetylated derivative of chitin is a copolymer of

glucosamine and N-acetyl-D-glucosamine. The micelle form of CS-

based nanostructures (amphiphilic block copolymers) has shown broad

spectrum of potency in anticancer agent delivery that are following by

several research studies. In a work, Zhu, Cao, Cui, Qian, and Gu (2013)

used the FA-functionalized N-succinyl-N0-octyl CS (FA-SOCS) micelle,

as hydrophobic–hydrophilic core–shell, for targeted delivery system

of 10-hydroxycamptothecin (HCPT) anticancer agent to targeted

delivery. Average diameter size of these NPs was 122–145 nm. HCPT

due to its insolubility in water, short half-life, and high toxicity to nor-

mal tissue cells needs to active delivery. Also, HCPT undergoes lactone

ring-opening hydrolysis to inactive carboxylate form in physiological

conditions and it is instable in body serum (Wang, Shang, Li, & Jiang

2009; Watanabe, Kawano, Toma, Hattori, & Maitani, 2008). Therefore,

TABLE 2 (Continued)

Nanocarriers

Bioactive

agents Characteristics Comments Kind of cell lines and tumors References

Gold NPs

FA-GNPs DOX Targeted NPs for imaging

and therapy

In vitro Human dermal fibroblasts

(HDF) and HepG2 human

liver cancer cell lines

Cheng, Gu, Cheng, and

Wong (2013)

FA-PEG-siRNA-

GNPs

si-RNA Dual-targeted NPs for

silencing and imaging

In vitro and

in vivo

HeLa cervical cancer cell line

and HeLa bearing nude mice

(Wang, Zheng, Peng,

Shen, Shi, & Zhang,

2013)

FA-FITC-PEG-PEI-

GNPs

Targeted core-shell NPs for

CT imaging

In vitro and

in vivo

KB cell line and KB tumor-

bearing BALB/c nude mice

Zhou et al. (2016)

FA-BSA-GNPs Au

Targeted core-shell NPs for

cancer cell detection

In vitro HeLa cervical cancer cell line Li, Cheng, Liu, and Chen

(2016)

Upconversion NPs

FA-Tm-UCNPs Tm

Targeted surface modified

NPs for imaging

In vitro and

in vivo

KB human nasopharyngeal

epidermal carcinoma cell line

and KB tumor-bearing

BALB/c nude mice

Cao et al. (2011)

FA-Fe

-NaYF

Yb/Er UCNPs

,Er

Targeted core-shell NPs for

theranostic codelivery

In vitro and

in vivo

MCF-7 human breast cancer

and HeLa cervical cancer cell

lines and MCF-7 tumor-

bearing nude mice

Zeng et al. (2015)

FA-SiO2-LaF3:Yb,

Tm,Ho,Er UCNPs

,Tm

,Ho

Targeted core-shell NPs for

dual-modality imaging of

UCL and X-ray CT

In vitro and

in vivo

MGC-803 and GES-1 human

gastric cancer cell lines and

MGC-803 tumor-bearing

nude mice

Ma et al. (2012)

FA-PEG-NaYF

:Yb/

Er UCNPs

,Er

DOX

Targeted core-shell NPs for

theranostic codelivery

In vitro KB human nasopharyngeal

epidermal carcinoma and

HeLa cervical cancer cell

lines

Wang, Cheng, and Liu

(2011)

Abbreviations: BSA, bovine serum albumin; CAP, capsaicin; DEX, dextran; DOX, doxorubicin; DTX, docetaxel; FA, folic acid; GNP, GNP, gold nanoparticle;

GO, graphene oxide; LD, monolayer lipid; LS, liposome; MTN, mitoxantrone; MTX, methotrexate; NP, nanoparticle; PEG, polyethylene glycol; PEI,

polyethyleneimine; PLGA, poly(lactide-co-glycolide); PTX, paclitaxel; PVP, polyvinylpyrrolidone; QU, quercetin; Tf, transferrin; UCNP, upconverting

nanoparticle.

NARMANI ET AL.409

Zhu, Cao, Cui, Qian, and Gu (Zhu et al., 2013) applied the FA-targeted

CS micelles to solve the water insolubility, provide sustained release

and mainly improve the active delivery of this drug. Moreover, FITC-

labeled FA-SOCS micelle remarkably evidenced the high internalization

in in vitro and in vivo, while no HCPT signal was observed in free FA

micelle uptake study. The outer hydrophilic layer of micelles is so cru-

cial for improving the prolong circulation, escaping the immune clear-

ance, and substantial accumulation in cancer site (Huo et al., 2010;

Zhang, Huang, & Li, 2014). The pharmacokinetic behavior of the free

HCPT, HCPT/SOC, and HCPT/folic acid-SOC micelles were investi-

gated in the rats via I.V. administration. The total body clearance rates

of free HCPT were about sevenfold faster than those HCPT/folic acid-

SOC micelles, which have been shown translational development of

targeted NPs in clinical applications. Also, plasma concentration rate of

targeted micelles was more than four times in respect to nontargeted

ones. On the other hand, tumor targeting potency of targeted micelles

was investigated in Bel-7402 tumor-bearing mice by means of near

infrared dye. As, targeted micelles were sharply detectable in the tumor

site just 6 hr post-injection, it was 24 hr for nontargeted micelles.

Moreover, it was revealed that NPs above 200 nm can be rapidly elimi-

nated from the vascular pathway by macrophages and particles below

10 nm can be easily filtered by the kidney (Zhu et al., 2013).

In a research by Fathi et al. (2017), the maleic anhydride moieties

were conjugated to hydroxyl sites of CS to produce the hydro-

phobic/hydrophilic nanomicelles. In order to this, sodium dodecyl sul-

fate/CS complex (SCCS) has been used for solubilizing CS in common

organic solvents and dissolved in maleic anhydride to produce CS

(O-maleoyl-SCCS) nanocomplex. Then, this organosoluble complex

dissolved in N-isopropylacrylamide/oleic acid as hydrophilic/hydro-

phobic moieties to formation of N-isopropylacrylamide-oleic acid

(PNIPAAm-co-OA)-g-CS micelles with free amino groups (mean

particle size 100 nm). These intact amino groups are site of FA conju-

gation. Subsequently, erlotinib (ETB), as hydrophobic agent was

physically encapsulated into micelles for treatment of metastatic

advanced non-small cell lung and pancreatic cancers (Fathi et al., 2017).

Eventually, it was concluded that the (Fluorescein isothiocyanate)-

modified micelles can be delivered rapidly and effectively (more than

six times internalization in comparison to nontargeted NPs) into the

targeted cancer cells, significantly (Fathi et al., 2017). On the other

hand, hemolysis assay was carried out to evaluate hemocompatibility of

folic acid-modified micelles. As, the hemolytic ratio of the targeted

micelles was less than 3%, that was in accordance with the guidelines

of ISO/TR 7406 (Fathi et al., 2017).

In the amphiphilic polymers, hydrophobic core region serves as a

reservoir for hydrophobic drugs, while hydrophobic core stabilization,

polymers water-solubility of polymer is the fundamental role of hydro-

philic shell (Adams, Lavasanifar, & Kwon, 2003). On the other hand, the

various amphiphilic polymers can be formed micelles or self-aggregates

nanocomplex in isotropic aqueous solution which is extended by intra-

and intermolecular association between hydrophobic segments, primar-

ily to minimize interfacial free energy (Mortensen, 2001). The rheologi-

cal feature, small hydrodynamic radius, and thermodynamic stability are

unique properties of polymeric micelles.

2.1.2 |PLGA NPs and PLA NPs

Currently, the most important therapy approaches to circumvent side

effects of chemotherapy and Multi drug resistance (MDR) are the use of

biocompatible and biodegradable nano-biopolymers such as PLGA

poly(lactide-co-glycolide), PLA (polylactic acid), and so forth in chemo-

therapeutic anticancer delivery (Figure 4; Hami et al., 2014; Kim et al.,

2008). The PLGA is approved by FDA and it is classified safe for clinical

use, as pharmaceutical excipients. Also, the great drug release behavior,

excellent ability associate, and good ability of penetration the

transmucosal are the main properties of PLGA NPs (Prabaharan et al.,

2009; Zhou, Patel, Michael, Bertram, & Saltzman, 2012). On the other

FIGURE 4 Schematic representation of different types of biopolymers in drug delivery systems. PLGA, poly(lactide-co-glycolide)

410 NARMANI ET AL.

hand, the negative surface charge of PLGA makes it as suitable carrier in

surface functionalization and drug conjugation and limits its interaction

in normal cells.

In a research by (Wang, Zhao, Su, et al., 2010), the self-assemble

cationic PLGA/FA which had been coated PEGlated polymeric lipo-

some (PLS) core–shell NPs (FA-PLGA-PLS NPs) was developed to

codelivery of pEGFP as a model of DNA and doxorubicin (DOX), as a

model drug. So DOX was encapsulated and pEGFP was bound to the

FA-PLGA-PLS NPs. In order to these syntheses, the cationic PEGlated

amphiphilic octadecyl-quaternized lysine modified chitosan (PEG-

OQLCS), cationic folic acid conjugated amphiphilic octadecyl-

quarternized lysine modified chitosan (FA-OQLCS), and cholesterol

(weight ratio 1/1/1, total lipids 30 mg) were dissolved in chloroform

to create the organic phase. Cholesterol helps to maintain the struc-

tural stability of lipid shell. Then, chloroform was separated and thin

film of lipid bilayer was obtained. Subsequently, the lipid film was dis-

persed in PLGA nanospheres solution and it was stirred to produce

self-assemble micelles with maximum particle size 100 nm. The roles

of PEG-OQLCS as protective coat and FA-OQLCS as targeted part

are promoting the in vivo stability and monodispersity, and enhancing

tumor accumulation and reducing the systemic toxicity, respectively

(Wang, Zhao, Su, et al., 2010). Drug release (more than 50%) time of

this NP was happened at first 6 hr. Codelivery efficiency of PLGA/FPL

NPs was by 46.6%, while it was by 5.78 and 15.06% for free PLGA

and FA-PLGA-PLS NPs, respectively, that it has been shown the FA-

induced targeted delivery effects (Wang, Zhao, Su, et al., 2010). On

the other hand, internalization efficiency was demonstrated about

more than 50-fold for targeted micelles; as the bright red and green

fluorescences were considerably observed in the cytoplasm around

the nuclei which were indicated suitable codelivery of drug and gene.

These results were demonstrated excellent potency of FA-based

targeted therapy in clinical application.

In a report by Kuo and Chen (2015), the lactoferrin (Lf)- and FA-

grafted PLGA NPs (Lf/FA/PLGA NPs; 181.9 ± 4.5 nm particle size with

positive surface charge) were developed for targeted delivery of

etoposide to inhibit the Glioblastoma (GBM) growth and penetrate in

monolayer of human brain-microvascular endothelial cells (HBMECs).

The Lf has been applied to permeate an in vitro blood–brain barrier

(BBB) via receptor-mediated transcytosis (RMT) (Huang et al., 2007).

Moreover, Lf can mediate the trigger the RMT pathway and accelerates

the transportation of Lf/FA/PLGA NPs to HBMECs and makes a crucial

role in delivering etoposide across the BBB by docking it. The sustained

release was recorded for more than 50% of etoposide at first 7 days.

On the other hand, the uptake of Lf/FA/PLGA NPs by U87MG cells

was revealed the delivery of antitumor etoposide to brain cancer cells

that was strongly related to FA (Kuo & Chen, 2015). Also, Lf could

improve the uptake of Lf/FA/PLGA NPs by U87MG cells via binding to

low-density lipoprotein receptor. Furthermore, the tiny NPs can be

penetrate from BBB, however effective penetration was obtained via

mediating specific blood proteins, including transferrin, leptin, insulin-

like growth factors, and specifically Lf (Lf showed more effective pene-

tration potency than others). Moreover, the other same work was car-

ried out by (Xu, Jiang, Yu, et al., 2017) in order to active delivery of

insulin in diabetic (as lethal disease) models. As specified, the subcuta-

neous needle injection of insulin is concomitant with lethal pain in

patients. In order to overcome this disadvantage, FA-modified Ins-

PLGA/CS NPs with 252.4 ± 4.6 nm in diameters were fabricated via

electrostatic self-assembly approach by Xu et al. research work. The

sustained release of insulin was about 35% at first 6 hr for globular

positive-charge Ins-PLGA/FA-CS NPs. Furthermore, the serum which

had been sustained release of insulin was significantly demonstrated

that serum insulin level was maintained at 40 μIU/mL for long period

time and subsequently it was decreased the percentage of initial blood

glucose levels to half of maximum levels (100%; Xu, Jiang, Yu, et al.,

2017). On the other hand, the enzyme inhibition test was performed to

investigate the stability of insulin. Insulin is easy to damage in the pres-

ence of pepsin or pancreatin in gastrointestinal fluid. It was shown that

about 10% of free insulin can be remained for 30 min in simulated gas-

tric fluid after incubation and simulated intestinal fluid, while more than

80% of insulin can be remained after encapsulation of insulin into

nanocarriers. Subsequently, many values of the insulin have been

degraded for the free insulin by increasing the incubation time, while it

was less than 40% for Ins-PLGA/FA-CS. Also, pharmacokinetics investi-

gation of this micelle has been shown that oral delivery of insulin solu-

tion has no hypoglycemic effect, while blood glucose level has been

reduced significantly after subcutaneous injection of 5 IU/kg insulin

solution. Eventually, it was indicated that high hypoglycemic efficacy of

the Ins-PLGA/FA-CS in the diabetic rats is related to the following fea-

tures: the nanocomplex serves as an efficient tool for protection of

insulin in acidify environment of the stomach, and the nanocomplex

might increase the cellular permeability of the insulin and improve cellu-

lar uptake of Ins-PLGA/FA-CS nanocomplex (Xu, Jiang, Yu, et al., 2017).

In order to suppress the inappropriate activated macrophages,

Mohammadi et al. (2016) were applied triblock copolymers FA-poly(L-

lactide)-b-poly(ethylene glycol) (FA-PEG-PLLA), poly(L-lactide)-poly-

ethylenimine-poly(L-lactide) (PLLA-PEI-PLLA), and PLLA-poly(ethylene

glycol)-PLLA (PLLA-PEG-PLLA), as three-layered micelle to target FR-

βthat has high expression in this macrophages. FR-αhas negligible

accessibility to circulate folic acid-targeted drugs, because of its

expression on the apical side of healthy tissues, while FR-βhas great

accessibility for activated macrophages. The three-layered micelle was

optimized for the encapsulation of plasmid DNA at N/P ratio of 12.

Subsequently, the transfection efficiency of micelle containing plasmid

GFP-DNA was ascertained via isolation of spleen macrophages. The

in vitro and in vivo FITC-labeled micelles high fluorescence intensity

of FITC was quantified and a shift to higher fluorescence indicates the

expression of FR in activated macrophages (more than 10 times in

comparison to resting macrophages). Also, Green fluorescent protein

(GFP) expression was shown more than three times to evaluate the

transgene expression and results of gene expression in activated mac-

rophages in comparison to resting macrophages. Gene release was

determined with hydrogel retardation assay and no gene release was

observed in physiologic pH condition, however about 15.3% DNA

were released after 144 hr incubation in acidic pH (Mohammadi

et al., 2016).

NARMANI ET AL.411

These amphiphilic micelles have excellent advantages such as good

solubility of hydrophobic drugs, high loading capacity, great biocompatibil-

ity and biodegradability, reducing the nonspecific uptake by the reticuloen-

dothelial system (RES), enhancing circulation time in blood, optimizing the

anticancer efficiency of drug, overcoming the drug's drawbacks through

minimizing its toxicity, overcoming the development of drug resistances,

and siting specific targeting delivery (Hu et al., 2008; Ortiz et al., 2012;

Xiao et al., 2012). In order to increase the drug's anti-angiogenic efficacy

and enhance the antitumor efficacy, the curcumin-loaded copolymer FA-

PEG-PLA, as amphiphilic micelles, were synthesized by (Yang, Chen, Zhao,

et al., 2014). This nanocarrier was prepared by thin-film hydration method

with mPEG2000-PLA2000 and Folate-PEG3000-PLA2000 (with 9:1

weight ratio) with average size of 70 nm. The drug loading and encapsulat-

ing efficiency of curcumin were by 4.84% ± 0.01% and 80.73% ± 0.16%.

Moreover, the pharmacokinetic investigations in rats demonstrated that a

three times enhancement in the half-life was achieved for Cur-loaded

micelle formulations which were relative to solubilized Cur (Yang, Chen,

Zhao, et al., 2014). Also, internalization studies were shown more than five

times enhancement in cellular uptake.

2.1.3 |Dextran NPs and hyaluronic acid NPs

Dextran (DEX), as biodegradable and biocompatible nanosize biomole-

cule, is a complex branched polysaccharide which has been made of

many glucose molecules and has chains of varying lengths from

3 to 2,000 kD that straight chain consists of α-1,6 glycosidic linkages

between glucose molecules (Figure 4). The saccharide-based nano-

carriers are developed in order to improve the high anticancer efficacy,

decrease the drug side effects, and prolong the drug circulation time in

bloodstream, and so forth (Takara et al., 2012; Zhang et al., 2012). In a

research by Hao, Ma, Huang, He, & Yao (2013), the bovine serum

albumin-dextran-doxorubicin-FA (DOX/BSA-DEX-FA) conjugate was

prepared by an esterification reaction between FA and dextran that

fallowed by Maillard reaction between the DEX-FA and BSA to obtain

BSA-DEX-FA with 90 nm in size. BSA has some advantages for NPs

including reduced plasma protein adsorption on the particle surface,

ease of NP purification, low cost, and unusual ligand-binding properties

(Elzoghby, Samy, & Elgindy, 2012; Mohanta, Madras, & Patil, 2012).

Also, BSA NPs were used in multilayer thin film via layer-by-layer self-

assembly for targeting delivery. DOX loading amount and loading effi-

ciency of the NPs are larger than 14 and 90%, respectively. Further-

more, drug release investigation was indicated more than fourfold

sustained release versus free drug release. In this work, pH adjusting

and heating process was applied to modulate the electrostatic and

hydrophobic interactions between DOX and BSA, induce the self-

aggregation of DOX and the denaturation/aggregation/gelation of

BSA. On the other hand, the in vivo antitumor results were shown

about three times survivability in DOX/BSA-DEX-FA treated animal

models which were relative to nontargeted sample treatments (Hao

et al., 2013). As, the tumor inhibition and survivability efficacies of

DOX/BSA-DEX-FA nanocomplex were evaluated on H22 tumor-

bearing mice. The results were shown that tumors inhibition rates

(n= 5 per every group) of the DOX which has been loaded

nanocomplex are nearly same in comparison to free DOX at the same

dose of 5 mg/kg. However, the groups treated with the nanocomplex

increase their body weights considerably, while the free DOX group

decreases the body weight extremely. Also, increasing the dose of

nanocomplex led to enhance the tumor inhibition rate, whereas it was

toxic to mice body for free DOX. These results suggest that the toxicity

of targeted nanocomplex is so lower than the toxicity of free DOX and

even DOX/BSA-DEX nanocomplex. Hao et al. (2013) were also investi-

gated the nanocomplexes which have been produced by heating for

30 and 70 min. The results indicate that the nanocomplexes produced

by heating for 30 min have better antitumor activity in comparison to

other ones that it can be due to longer heat treatment and decomposi-

tion of the FA during the heat treatment.

In the other DEX-based DDS by Zhao et al. (2017), the resveratrol

(RSV) as polyphenol was developed to cancer growth inhibition with

antioxidant and antimutagen aspects. RSV can inhibit the cancers via

activating the mitochondrial apoptotic pathway with induces apoptosis

to inhibit cancerous cell proliferation and improves the sensitivity of

drug resistant cancer cells (Mattarei et al., 2013). FA-DEX-RSV (mean

particle size 140 nm) as polymeric micelle, has several great properties,

including better stability compared to surfactant micelles, enhanced sol-

ubilizing power, longer circulating time which is owing to outer hydro-

philic shell, small size, and targeting capability. The free RSV

demonstrated around 20% of apoptotic fractions while FA-DEX-RSV

indicated a threefold higher apoptosis. Moreover, drug release of FA-

DEX-RSV nanomicelle was observed by 40 and 30% after 24 hr at

acidic and normal pHs. Also, the cellular internalization of FA-DEX-RSV

was more than eightfold in comparison to free RSV (Zhao et al., 2017). It

was revealed that RSV-DF is associated with the higher expression of

p53, caspase-3, and BCL2 associated X gene, apoptosis regulator (BAX)

than the free RSV and higher level of BAX and caspase-3 was further

demonstrated the involvement of mitochondria-dependent apoptosis in

the anticancer efficacy ofFA-DEX-RSV micelle (Zhao et al., 2017).

In recent decade, hyaluronic acid (HA) has also been widely evalu-

ated for use in tumor-targeted DDS due to its ability in specifically bind

to various cancer cells (Jing, Zhang, Zhou, Liu, & Zhang, 2013). HA, as

anionic glycosaminoglycan, is a main component of the extracellular

matrix that has major roles in cell proliferation and migration. Also, HA

is a biodegradable, biocompatible, nontoxic, nonimmunogenic, and bio-

available polysaccharide. This polysaccharide is a ligand of CD44

hyaluronan receptors, which are overexpressed in a variety of tumor

types including prostate and breast cancers (Choi et al., 2012; Jin et al.,

2012). Furthermore, the self-assembled small size in aqueous condi-

tions and enhance the enhanced permeability and retention (EPR)

effects are other properties of this nanosized polymeric micelles. In a

study by Qiu et al. (2014), the FA and poly(L-histidine) conjugated HA

(FA-HA-PHis) micelle, as pH-responsive amphiphilic copolymer was

developed for acid-triggered rapid release of DOX in cancer cells. The

results were revealed that, FA-HA-PHis micelles (154.8 ± 1.6 nm in

diameter) can selectively uptake via CD44 receptor-mediated endocyto-

sis and rapidly disassemble in early endosomes which are owing to pH-

induced protonation of PHis and hyaluronidase action. However, after

endocytosis inhibition experiments, it was observed that FA-HA-PHis

412 NARMANI ET AL.

micelles were mainly internalized via clathrin-mediated endocytosis and

DOX was delivered to lysosomes in this conditions (Qiu et al., 2014).

On the other hand, the effect of the macropinocytosis pathway on the

uptake of micelles was evaluated using colchicine (macropinocytosis

pathway inhibitor) and the results were indicated reduction in the inter-

nalization (reduce to 3%) of targeted nanocomplex that imply mac-

ropinocytosis has main role in targeted-cell uptake. Self-assembled

hydrophobized polysaccharide polymeric micelles are significantly

exhibited high water-solubility for hydrophobic drug carrier, excellent

solubilization capacity and stability, sustained drug release, prolonged

circulation, and tumor localization aspects (Lee, Lee, & Park, 2008).

Moreover, Liu et al. (2011) were synthesized dual targeting paclitaxel-

loaded FA-HA-C18 micelles (FA-HA-PTX; 191.9 ± 8.7 nm in diameter)

with drug encapsulation efficiency of 97.3% and drug release by

55.2% at 192 hr. Substantially, five endocytic pathways were known

for surplus values of micelle internalization: FA-mediated endocytosis,

clathrin-mediated endocytosis, caveolae-mediated endocytosis, mac-

ropinocytosis, and clathrin- and caveolae-independent endocytosis.

These results were obtained by employing nanomolar dosages of sev-

eral endocytic inhibitors such as hypertonic sucrose solution to dissoci-

ate of the clathrin, indometacin to inhibit the caveolae-mediated

endocytosis, and chlorpromazine to dissociate the complex of clathrin

and AP2 protein. However, FA- and clathrin-mediated endocytosis

were considered as the most prominent mechanism for the micelle

internalization (Liu et al., 2011).

2.2 |Chemopolymers in drug delivery

2.2.1 |Polyamidoamine NPs

Dendritic architecture is one of the most general topologies which has

been observed in biological systems. Polyamidoamine (PAMAM) is one

of the most studied dendrimers as the DDS (Figure 5). PAMAM NPs

are nanosized (1–10 nm), three-dimensional, highly branched macro-

molecules which are consisting of three distinct components: a core, a

hyperbranched mantle, and terminal functional groups (Narmani et al.,

2017). These NPs are extremely soluble in water with many reactive

end amine groups that make it as excellent nanocarrier for diagnostic

and therapeutic goals (Narmani, Kamali, Amini, Salimi, & Panahi, 2018;

Xie et al., 2014). In a research by Xu et al. (2016), FA and borneol (BO),

well-known safe materials, which had been derived from traditional

Chinese medicine, were applied for targeting delivery of DOX to glioma

treatment. BO facilitates the BBB permeability and reduces the cyto-

toxic effects of PAMAM. On the other hand, the coupling BO on the

surface of FA-PAMAM/DOX (167 nm in diameter) has several advan-

tages for nanocomplex including increase its transportation from BBB

(more than twofold), enhance its distribution agents in brain, prolong its

circulation half-life time, improve DOX accumulation in brain tumor.

Also, FA was improved the internalization efficiency until fourfold in

cancer cell. Drug loading and entrapment efficiency of nanocomplexes

were by 6.64% ± 0.09% and 64.58% ± 0.85%, and drug release of

nanocomplex was by 28.2 and 48.8% over 24 hr at pH 7.4 and 5.5,

respectively (Xu et al., 2016). For preclinical evaluation, the DOX

plasma concentrations after intravenous injection of DOX, BO-

PAMAM/DOX, and FA-BO-PAMAM/DOX were investigated via

I.V. administration in rats (n= 5 per every group). As, DOX-loaded BO-

PAMAM and FA-BO-PAMAM nanocomplexes were increased the area

under the concentration-time curve (AUC0-inf) by 11.24- and

11.71-fold for BO-PAMAM/DOX and FA-BO-PAMAM/DOX, respec-

tively. Furthermore, elimination half-life time (T1/2β) and mean resi-

dence time (MRT) of FA-BO-PAMAM were equal to 12.60 and

16.58 hr, while they were equal to 11.66 and 16.31 hr for BO-

PAMAM, respectively. These results significantly support the extended

FIGURE 5 Schematic representation of different types of chemopolymers in drug delivery systems. FR, folic acid receptor

NARMANI ET AL.413

residence time and control release profile of encapsulated drug in

PAMAM as compared to free DOX in body (Xu et al., 2016). In another

study, Narmani, Yavari, and Mohammadnejad (Narmani et al., 2017)

were developed FA-PAMAM-PEG-5FU-

99m

Tc in order to imaging and

therapeutic goals. In the in vivo study, their synthetic nanocomplex was

effectively targeted breast cancer cells (fourfold better than non-

targeted complex) in tumor bearing mice (n= 3 per every group). More-

over, their targeted nanocomplex could be accumulated in tumor site

after 4 hr and tumor accompanied with liver were absorbed more than

75% of nanocomplex.

In the last decade, RNAs as anticancer agents have also been

developed to target cell signaling intermediates to cancer cell inhibi-

tion. RNA-mediated therapeutic approaches can be selectively down-

regulated molecular targets in signaling pathways that are responsible

for cell proliferation and significantly reduced multidrug resistance in

comparison to drugs (Lo et al., 2010). Xu, Yeudall, & Yang, (2017) pre-

pared FA-PAMAM NPs for active delivery of siRNA against vascular

endothelial growth factor A (siVEGFA) in head and neck squamous cell

carcinomas. The VEGFA is a main regulator of angiogenesis and pro-

motes tumor development in tumor tissues, so that its knockdown

has been shown to be effective in inhibiting tumor growth. FA-

PAMAM-siVEGFA was exhibited FR-αmediated tumor uptake as

excellent nanocomplex for local delivery of siRNAs and sustained

retention properties. As it was considered, the very low systemic tox-

icity, sustained local drug release, high drug bioavailability, and excel-

lent chemotherapeutic efficacy were advantages of this localized

targeted delivery.

2.2.2 |Polyethyleneimine NPs

Polyethyleneimines (PEIs) as cationic polymers have been applied as

nucleic acids and drugs delivery carriers both in vitro and in vivo

(Figure 5). Their surface positive charge, high drug loading, and good

conjugation efficiency make them be able to combine with the thera-

peutic anticancer agents via electrostatic interactions (Benjaminsen,

Mattebjerg, Henriksen, Moghimi, & Andresen, 2013). In a research by

Wu, Zhang, Zhang, Sun, Wu, and Tang (2016), the PEG-b-(CL-g-PEI)-

b-CL triblock copolymer (core–shell micelle) was applied for codelivery

of P-glycoprotein (P-gp) siRNA and doxorubicin (DOX) to reverse

MDR in breast cancer. The fabricated nanocomplex can effectively

prevent renal clearance, RNase degradation and aggregation in circu-

lation, minimize opsonization during circulation bloodstream, and pro-

tect micelles from mononuclear phagocytic system in circulation.

After internalization, proton sponge effect of the branched PEI in the

endosome help to endosomal elude of nanocomplex (Wu et al., 2016).

The apoptosis levels of nanocomplex were measured by flow

cytometric that they were obtained by 85.3, 41.3, and 15.7% for

micelleplexes (PEG-DOX-b-(CL-g-PEI)-b-CL-siRNA), PEG-DOX-b-(CL-

g-PEI)-b-CL, and free DOX, respectively. This high therapeutic effi-

ciency of PEG-DOX-b-(CL-g-PEI)-b-CL-siRNA owes to overcome the

drug efflux pump-mediated drug resistance. On the other hand, the

histological analysis of tumor sections which has been stained with

H&E was shown minimal residual cancer cells for micelleplexeses in

comparison to free DOX. These results were indicated that

micelleplexeses could considerably codeliver targeted nanocomplex to

tumor tissues and subsequently produce more severe cancer cell apo-

ptosis and tumor necrosis (Wu et al., 2016). Ultimately, the excellent

internalization and effective tumor growth inhibition were observed

in tumor bearing mice.

In other work by Shi et al. (2013), C60-PEI-FA nanocomplex was

synthesized for targeting delivery of docetaxel (N-debenzoyl-N-tert-

butoxy-carbonyl-10-deacetyl taxol, DTX) as a new class of hydrophobic

taxane drugs with higher patient response rates and fewer side effects.

DTX can inhibit the microtubule depolymerization to free tubulin in

cancer cell. Fullerene (C60), as the third allotrope of carbon, is nanosize

carbon material with unique photo-, electro-chemical, and physical

properties which has excellent potency in delivery of hydrophobic ther-

apeutic agents. This nanocomplex (140 ± 2.7 nm size in diameter) was

indicated the prolonged blood circulation more than threefold tumor

growth inhibition and apoptosis and 7.5-fold higher DTX uptake of

tumor. Furthermore, the high tumor absorption through FR, which has

been mediated internalization and EPR effect with low kidney clear-

ance, was obtained in pharmacokinetic investigations (Shi et al., 2013).

On the other hand, oligodeoxynucleotide delivery into cancer cells is a

critical challenge in the cancer therapy. PEI NPs have been significantly

developed to delivery of oligodeoxynucleotide vectors with high effi-

ciency and low toxicity. In a study, Yang et al. (2015) were developed

OA modified and FA decorated PEI NPs (FA-PEI-OA NPs) for delivery

of LOR-2501 as antisense oligonucleotide against ribonucleotide reduc-

tase R1 subunit. OA could significantly improve the delivery efficacy of

oligodeoxynucleotide. FA-PEI-OA-LOR-2501 nanocomplex was

remarkably induced the downregulation of R1 mRNA and R1 protein.

The higher cellular uptake was observed with PEI-OA/LOR-2501 at

N/P ratio of 6. After inhibition of clathrin-mediated uptake in cancer

cells, the clathrin-mediated uptake process was inhibited by 80.5% that

demonstrated the clathrin-mediated internalization of nanocomplex

(Yang et al., 2015). Also, the same results were obtained in cytosine

deaminase/5-fluorocytosine (CD/5-FC) and TNF-related apoptosis-

inducing ligand (TRAIL) genes delivery to glioma cells and rats via FA-

PEG-PEI nanocomplex (N/P ratio of 15) that was reported by Liang

et al. (2009). This research group was developed combined therapy of

CD/5-FC with TRAIL genes against rat C6 glioma models. According to

this study, average tumor size for the Phosphate-buffered saline (PBS)-

control groups was equal to 172.52 ± 8.02 mm

, while 53.13

±3.72mm

noted for the combined therapy against glioma tumor

(Liang et al., 2009). The cross-sensitization between TRAIL gene and

5-FC chemotherapeutic in this nanocomplex could induce apoptotic

pathway through caspase activation and might be an effective thera-

peutic strategy for C6 gliomas.

3|LIPID-BASED NPS IN DRUG DELIVERY

3.1 |Bilayer lipid NPs

Lipid-based NPs (e.g., solid lipid NPs and/or liposomes [LS]), as DDS,

have been approved by US FDA for clinical use such as cancer

414 NARMANI ET AL.

biomarkers detection and its therapy. LS NPs with bilayer lipid archi-

tecture are spherical vesicles which have been formed by single or

multiple lipid bilayers (Figure 6). These NPs provided better drug load-

ing, excellent biodegradability, good stability characteristics, long cir-

culation half-life, and easy surface functionalization (Huo et al., 2015;

Nogueira, Gomes, Preto, & Cavaco-Paulo, 2015). Furthermore, capa-

bility to entrap both hydrophilic and hydrophobic drugs, nontoxic and

lack of immune system activation are other advantages of LS NPs in

DDSs (Huo et al., 2015). In a research by Sriraman, Salzano, Sarisozen,

and Torchilin (2016), the PEGylated doxorubicin-loaded LSs targeted

with FA, transferrin (Tf; FA-LS-DOX-Tf; with size 165 ± 33 nm in

diameter and −21 ± 1.5 mV surface charge) were developed to cancer

growth inhibition. The egg phosphatidylcholine, cholesterol, cholesteryl

hemisuccinate, and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine

were the main components of LS micelles. The dual-targeted LS

micelles demonstrated sevenfold increase in cell accumulation com-

pared to single ligand targeted ones. In clinical investigation, 6- to

8-week-old female athymic nude mice (n=5)wereinoculatedonthe

righthind-flankwith4.5×10

HeLa cells in 100 μLof50%v/vmatrigel

in serum-free Roswell park memorial institute culture medium (RPMI

media). After 11th day, the mice were injected (I.V. administration) with

a cumulative targeted nanocomplex and DOX dose of 4 mg/kg (100-μL

injection volume for per day in five times). Tumor growth inhibition

potency of targeted NPs was showed about 75, 79, and 34% for FA-

targeted, dual-targeted micelles, and free DOX, respectively (Sriraman

et al., 2016). The caspase-dependent apoptosis and topoisomerase II

inhibition are DOX effects on cancer cells.

In other study by Lv et al. (2017), the capsaicin (CAP), as apoptosis

inducer that could be instigate the intrinsic mitochondrial pathway and

extrinsic death receptor pathways through caspase cascade in cancer

cells, was loaded in 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-

[methoxy (polyethylene glycol)-2000] (DSPE-PEG) FA-based lipid NP

(with size 108.5 nm in diameter) as novel DDS. CAP with an increase in

thep21anddecreaseincyclinElevel, induce the cell cycle arrest, and

cell death in G0/G1 phase of cell cycle. The higher cancer cell apoptosis

(about 39%) with more than threefold internalization efficiency in com-

parison to nontargeted LS was exhibited in this research work (Zhang

et al., 2008). Also, LS NPs which are owing to their high biocompatibility,

favorable pharmacokinetic profile, high delivery efficiency, and ease of

surface modification have been widely application in DDS for better clini-

cal and translational development of targeted NPs in nanomedicine.

However, some limitations of LS NPs such as insufficient drug loading,

fast drug release, and instability in storage led to use hybrid NPs to over-

come these disadvantages. Two methods including mix the polymeric

NPs with liposomes to form the lipid-shell and polymer-core, and com-

bines the nanoprecipitation method and the self-assembly technique are

main approaches in synthesis of hybrid NPs (Zhang et al., 2008). Such

hybrid NPs were synthesized by Liu, Li, Pan, Liu, and Feng (2010). They

were developed PLGA-LS hybrid nanocomplex for targeted delivery of

DTX as anticancer agent. Lipid layer was fabricated from three distinct

functional components including (a) 1,2-dilauroylphosphatidylocholine, a

phospholipid of an appropriate hydrophilic–lipophilic balance value as

stabilizer of nanocomplex in the aqueous phase; (b) PEG modified

1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) to facilitate

stealth NPs formulation to escape from recognition by the RES and sub-

sequently increase the systemic circulation time of nanocomplex; and

(iii) FA-functionalized 1,2-distearoyl-snglycero-3-phosphoethanolamine.

This nanocomplex with size equal to 66.88 ± 0.67 nm in hydrodynamic

diameter and surface charge of −20.74 ± 1.21 mV has been significantly

shown better FR-βmediated cellular uptake respect to nontargeted

nanocomplex (Liu et al., 2010).

3.2 |Monolayer lipid NPs

In last decade, several lipid drug formulations have been approved for

clinical use. However, some disadvantages of lipid-based NPs such as

low drug loading, fast drug release, and low stability in storage led to

use of monolayer lipid (LD) NPs (Figure 6) in combine with other NPs

FIGURE 6 Schematic representation of different types of lipid-based NPs in drug delivery systems. NP, nanoparticle

NARMANI ET AL.415

like polymers as core/shell micelles (Cho, Wang, Nie, Chen, & Shin,

2008). This mixed nanocomposite could be developed to combine the

advantages and meanwhile overcome the disadvantages of both NPs.

The PLGA, PLA, modified CS and PCL, PEG, and other bio-

nanoparticles are very favorable NPs in combine with monolayer lipid

NP due to their excellent biocompatibility and biodegradability, very

good solubility both in water and organic solvents and high solubility

and stability in aqueous solutions, desired pharmacokinetics, and pro-

longed blood circulation time (Cho et al., 2008; Jain, 2000). In a

research by Zhao et al. (2012), the FA which has been functionalized

PLGA and PEGylated octadecyl-quaternized lysine modified chitosan

(FA-LD-PLGA-PEG) as core–shell micelles was synthesized for active

delivery of PTX. PTX promotes the assembly and stabilization of

microtubules and subsequently interferes with essential cellular func-

tions including mitosis, cell transport, and cell motility. Subsequently,

the particles size, surface charge, encapsulation efficiency, and loading

efficiency of core–shell NPs were determined by 194 ± 7 nm, 22

± 4 mV, 87% ± 2%, and 13% ± 1%, respectively. On the other hand,

the core–shell NP was significantly shown controlled PTX release

behavior (about two times sustained release respect to PLGA NPs and

lipid NPs) with more than threefold tumor growth inhibition effects

on tumor bearing animal models in comparison to pure PTX injection

(Zhao et al., 2012). For the animal phase, 5- to 6-week-old severe

combined immunodeficiency (SCID) female mice (18 ± 2 g, n= 9) were

supplied in free access to sterilized FA-free food and inoculating

human HeLa cells (1 ×10

) were injected into the left flank of the

mice for bearing cervix tumors. After treatment of mice via non-

targeted and targeted nanocomplexes, by 22% mice were alive in

PTX-LD-PLGA-PEG treated mice, whereas by 78% mice were alive in

FA-PTX-LD-PLGA-PEG treated mice after 50 days treatment. Also,

the biodistribution of nanocomplexes was investigated at 2 hr after

tail intravenous injection of 10 mg/kg dose of nanocomplexes and

results shown that drug concentration in tumor for FA-PTX-LD-

PLGA-PEG was approximately equal to 3.70-, 1.85-, and 1.68-fold

compared to that of PTX injection, PLGA NPs, and PTX-LD-PLGA-

PEG, respectively (Zhao et al., 2012).

This kind of micelles comprise three distinct components including

inner most polymeric core, lipid layer surrounding the polymeric core,

and outer most PEGylated lipid covering which provides the good

mechanical integrity, better penetration, excellent biocompatibility and

in vivo stability, optimized drug entrapment, improve multiple drugs

loading, and so forth. The carbodiimide click chemistry or thiol-

maleimide approaches are main methods in surface modification of

these micelles (Jain, 2000; Mandal, Mittal, Balabathula, Thoma, &

Wood, 2016). In a study by Tahir et al. (2017), the methotrexate (MTX)

which has been loaded lipid-polymer (PLGA/Lipoid S100) hybrid NPs

was fabricated by employing a single-step modified nanoprecipitation

method combined with self-assembly. The particles size and surface

charges of different formulations varied between 308 and 176 nm, and

equal to −21.2 ± 2.1 to −13.1 ± 3.1 mV, respectively, which increased

with increasing polymer concentration. Furthermore, the in vitro drug

release was also determined in range of 70.34–91.95% (Tahir et al.,

2017). Also, the confocal fluorescence imaging was applied to

determine the size of FITC-incorporated spherical NPs that was

exhibited the particles with size less than 200 nm. In other work, Chen

et al. (2013) were developed self-assembled FA-poly(ethylene glycol)-

distearoyl-phosphatidyl-ethanolamine (PEG-DSPE) micelles in order to

target delivery of mitoxantrone (MTN). The MTN and also dexametha-

sone or estrogen antagonist tamoxifen could be manipulated FR-α

expression upregulation that induce the FR expression and significantly

enhance the efficacy of targeted delivery via FR-α. These micelles with

size about 40–60 nm were shown by 25.2% ± 2.2% encapsulation effi-

ciency for MTN that were suitable for enhanced penetration into solid

tumors. It was demonstrated that MTN which has been affected FR-α

upregulation could be extremely enhanced the FA-mediated endocyto-

sis efficiency of NPs (Chen et al., 2013). In another research by Has-

sanzadeh, Feng, Pettersson, and Hakkarainen (2015), the pluronic,

F127 and reverse pluronic, and 10R5 were molecularly modulated for

targeted codelivery of DOX and quercetin (QU) as hydrophilic agents.

The QU which was covalently anchored to 10R5 DOX was loaded in to

amphiphilic core–shell NPs (PEG-PPO-PEG, F127 and (PPO: poly pro-

pylene oxide) PPO-PEG-PPO, 10R5) with encapsulation capacity from

19 to 43%. Fundamentally, QU with interference on cell metabo-

lism, Glutathione S-transferase (GST) activity, cytoskeleton, and inva-

sive properties in tumor cells leads to improvement of DOX

interactions with tumor cells. Furthermore, stabilize the micelles and

decrease the critical micelle concentration (CMC) by adding a hydro-

phobic molecule to pluronic 10R5. The pluronics as bioavailable and

biocompatible molecules could inhibit P-gp and sensitize MDR cells as

a result of Adenosine triphosphate (ATP) depletion which subsequently

decrease drug resistance in the cancerous cells. Moreover, pluronics,

due to their high CMC, conjugated with PEG in order to enhance their

stability and decrease dilution in the blood after intravenous

administration.

4|METAL- AND NONMETAL-BASED NPS

IN DRUG DELIVERY

4.1 |Iron oxide NPs

Magnetic iron oxides (Fe

) NPs (MNP) are widely applied in biologi-

cal and biomedical fields due to their specific magnetic and tunable

physicochemical aspects (Ladj et al., 2013). These properties make

practical applications for MNPs in diagnostic and therapeutic fields

including cell labeling and targeting, active drug delivery, magnetic res-

onance imaging (MRI), hyperthermia, magnetofection, and so forth

(Figure 7). Furthermore, the good colloidal stability, biocompatibility,

and long blood circulation time are also other important properties of

MNPs (McBain, Yiu, & Dobson, 2008; Varshosaz et al., 2013). On the

other hand, the modification of hydrophilic and noncytotoxic polymers

such as dextran, dendrimers, CS, PEG, and PEI on the surface of MNPs

could effectively improve their colloidal stability and biocompatibility

of MNPs (Yang et al., 2014). In a study by Li et al. (2013), the PEI-

mediated approach was developed to synthesize FA-targeted MNPs

for in vivo MRI, as one of the powerful and noninvasive imaging tech-

niques because of its high spatial resolution and tomographic

416 NARMANI ET AL.

capabilities. As a matter of fact, PEI-coated MNPs were prepared by a

one-pot hydrothermal route and these aminated MNPs were subse-

quently decorated with FITC and FA-conjugated PEG (FA-PEG-FITC-

PEI-MNPs; with size equal to 288.7 ± 6.90 nm in hydrodynamic diame-

ter and equal to 16.3 ± 0.17 mV in surface charge). They were indi-

cated that the PEI-mediated approach along with the PEGylation

enables the generation of water-dispersible and stable multifunctional

MNPs. The in vitro investigations were also confirmed the

cytocompatibility, hemocompatibility, and cancer cell targeting of

nanocomplex. On the other hand, the spin–spin relaxation times

(T2) relaxivity measurements were indicated that FA-PEG-FITC-PEI-

MNPs have a higher r

value than the MNPs which have been coated

with polymer multilayers which is essential for them to be used as good

T2 negative contrast agent for sensitive MRI applications. For in vivo

experiments, the male 4- to 6-week-old BALB/c nude mice (15–20 g,

n= 5) were subcutaneously injected with 2 ×10

cells/mouse in the

left back and when the tumor nodules reached a volume of

0.8–1.4 cm

,theFe

-PEI-Ac-FI-PEG-FA NPs were administrated

into the nude mice. Subsequently, the T2-weighted MR images of the

xenografted (KERATIN-forming tumor cell line HeLa) KB tumor

obtained before injection, and 30 min, 1 hr, 2 hr, 4 hr, and 24 hr post-

injection and tumor MR signal of mice which has been treated with

targeted nanocomplex does not decrease with time post-injection

(Li et al., 2013). On the other hand, the Fe biodistribution analysis was

indicated that PEG-modified nanocomplex can help to the Fe particles

to escape from the reticuloendothelial system and deliver to the tumor

tissue.

In a research by Huang, Mao, Zhang, and Zhao (2017), MNPs co-

coated with PEG and PEI polymers were synthesized by an improved

polyol method in order to target delivery of DOX and imaging

(theranostics) with mean hydrodynamic diameters of 67 nm. Excellent

FA receptor-mediated endocytosis was implicated by means of

confocal laser scanning microscope. Also, drug-loading capacity and

drug-loading efficiency of theranostic nanocomplex (FA-PEG-PEI-DOX-

MNPs) were by 29.3 and 78.5%, respectively, that was indicated total

DOX released about 90% in PBS at pH 5.0 in 48 hr, which was signifi-

cantly higher than that at pH 7.4. Moreover, the external magnetic field

was enhanced about 6.9-fold of the accumulation of the injected dose

in tumor of the mice which has been treated with FA-PEG-PEI-DOX-

MNPs. Eventually, the nanocomplex was induced a higher inhibition in

tumor growth as compared to those treated with free DOX and MNP.

On the other hand, the T2 relaxivity of nanocomplexes were measured

by a 3.0T MRI system in order to evaluate the T2-weighted MR imaging

performance and results were shown that nanocomplex was negative

T2 contrast agent (Huang et al., 2017). Also, the in vivo investigation on

nude mice with MCF-7 xenograft (n= 5 per group) was demonstrated

that tumor sizes of the mice which have been treated with FA-PEG-

PEI-DOX-MNPs in the presence of external magnetic field are remark-

able reduction tendencies. Substantially, the polymers owing to good

biocompatibility, (laboratory-bred strain of the house mouse) drug

encapsulation, and controlled release can be considered as excellent

candidate for MNPs surface modifications (Huang et al., 2017). The

Saikia, Das, Ramteke, and Maji (2017) were developed the genipin

cross-linked aminated starch/ZnO nano-composite for surface modifi-

cation of MNPs to target delivery of Cur (FA-S/ZnO-Cur-MNPs). At

the lower pH, the positive charges generated on aminated starch cau-

sed by the protonation of the amine groups which have been facilitated

the repulsion between the polymer chains and thus increased the drug

release of nanocomplexes. They were found that NPs with 5% ZnO

(with size 31.2 nm) indicated highest cellular uptake among the ZnO

incorporated NPs. Furthermore, the reactive oxygen species (ROS) esti-

mation study was exhibited that with the increase in ZnO concentra-

tion, the generation of ROS increased in cancer cells. These results

were significantly shown the highest cellular uptake of nanocomplex

FIGURE 7 Schematic representation for different types of metal- and nonmetal-based NPs in drug delivery systems. NP, nanoparticle

NARMANI ET AL.417

(Saikia et al., 2017). In another study, Sadhasivam, Savitha, Wu, Lin, and

Stobinski (2015) were successfully prepared carbon encapsulated

MNPs (CMNP: carbon encapsulated-magnetic iron oxides

nanoparticles) (FA-PEG-CMNP) by carbon arc method for in vitro mag-

netic hyperthermia. These dual-targeted MNPs (with size 70–90 nm)

have generated quick heating (43–45C) upon exposure to an alternat-

ing magnetic field. In hyperthermia, as active cancer therapy, the certain

body tissues are exposed to the temperature range of 41–46Cto

damage and kill cancer cells. The magnetic hyperthermia efficiency was

evaluated by Lactic dehydrogenase (LDH) cytotoxic assay and the

MNPs were nontoxic to normal human cells under the alternating mag-

netic field (Sadhasivam et al., 2015).

4.2 |Graphene oxide NPs

Graphene oxide (GO), as a derivate of graphene, has many surface func-

tional groups such as carboxylic acid (on the sheet edges) and hydroxyl

groups (on the basal plane) (Figure 7; Liu, Robinson, Sun, & Dai, 2008).

The special structural characteristics, high physiological stability, excel-

lent biocompatibility, and nontoxicity make it as high potency NPs for

various biomedical applications including drug/gene delivery, biosensing,

photothermal therapy, and bioimaging (Ahadian et al., 2015; Liu et al.,

2008). Moreover, the GO NPs provide a large specific surface area for

the immobilization of anticancer agents (Hong, Compton, An, Eryazici, &

Nguyen, 2011). In a research by Ma et al. (2017), FA-grafted bovine

serum albumins (FA-BSA) were immobilized on GO NPs for delivery of

DOX as stabilizer and targeting agents. The FA-BSA was decorated on

the surface of GO NPs by the physical adsorption. Also, DOX was asso-

ciated with GO NPs through π–πand hydrogen-bond interactions,

resulting in high drug loading. The FA-BSA-DOX-GO nanocomplex was

exhibited pH responsive (high drug loading in acidic condition) and

sustained drug release. Furthermore, high drug loading was obtained in

3:1 mass ratio of DOX to FA-BSA/GO. The FA-BSA/GO, as biocompati-

ble and biodegradable nanocomplex, was shown less than 5% of hemo-

lysis ratio (Ma et al., 2017).

In another work, Wang et al. (2013) were employed dual-targeted

DDS using FA and MNPs bifunctionalized GO. The magnetic field as

external targeting strategy improves drug delivery efficiency affecting

the MNPs. They used CS as a bridge to combine FA with functional

GO, enhance the stability and biocompatibility of nanocomplex and

improve the encapsulation efficiency and control release of drug mol-

ecules. Moreover, pH-dependent drug release and drug-loading

capacity (0.98 mg/mg) were observed which are owing to the differ-

ent degree of hydrogen bonding interaction between DOX and the

FA-DOX-MNP-GO nanocomplex. Also, it was revealed that DOX

release may be related to the degradation of CS. On the other hand,

CS degradation is faster in acidic pH of 5.3 (Wang et al., 2013). In

another research by Qin et al. (2013), the FA and polyvinylpyrrolidone

(PVP) functionalized GO NPs (FA-PVP-GO NPs) were developed for

targeted near-infrared (NIR) photothermal therapy and DOX delivery

(with the loading ratio more than 100%). PVP was employed as a sta-

bilizing agent and dispersant in the synthesis of metal nanostructures.

Furthermore, PVP as a biocompatible stabilizer could improve the GO

NPs stability in physiological environment. On the other hand, NP-

based NIR photothermal therapy provides a promising treatment

strategy for efficient tumor ablation with minor injury to the sur-

rounding tissue. GO NPs, due to their strong absorbance in the NIR

region, have been employed to photothermal therapy. Moreover, GO

NPs indicated concentration-dependent and time-dependent temper-

ature increase in response to NIR irradiation and its extraordinary

photothermal energy conversion efficiency was remarkably demon-

strated. The FA-PVP-GO generated heat more efficiently (ΔT≈50C

at 10 μg/mL, 5 min) in the same conditions than PVP-GO (ΔT≈40C

at 10 μg/mL, 5 min; Qin et al., 2013). Both FR-mediated internaliza-

tion and mitochondrial accumulation, and cell surface attachment of

these NPs could enhance the sensitive of cells to NIR-mediated

photothermal damage. These effects lead to cytochrome c release and

subsequently cell apoptosis.

4.3 |Gold NPs

In the last decades, gold NPs (GNPs), due to their unique fluorescence,

low cost, and so forth have been developed extensively to establish

powerful optical methods for sensing and biomedical applications

(Figure 7; Narmani, Kamali, Amini, et al., 2018; Peng et al., 2012). Owing

to higher atomic number and electron density, GNP fundamentally has

a higher X-ray absorption coefficient that makes it as suitable candidate

for diagnostic and therapeutic applications. Also, GNPs are easy to mod-

ify the help to eliminate their low cytotoxicity and avoid removal activity

of RES after proper surface functionalization (Cheng et al., 2013). On

the other hand, tumor cell targeted GNPs can effectively induce the

DNA damage, cytokinesis arrest, and apoptosis (Cheng et al., 2013; Lu

et al., 2010). In a study by Wang, Zheng, Peng, Shen, Shi, and Zhang

(2013), the FA-modified polyamidoamine-entrapped GNPs (FA-

PAMAM-GNPs; with size 3.1 nm in diameter) as nanoprobes, were

employed for in vitro and in vivo targeted computed tomography

(CT) imaging. They were used amine-terminated generation 5 poly(-

amidoamine) dendrimers as platforms of covalently linked FA, followed

by an acetylation reaction to neutralize the remaining dendrimer surface

amines. Micro-CT images were indicated that cancer cells can be

detected under X-ray after intravenous and intraperitoneal administra-

tion of FA-PAMAM-GNPs. The nanocomplex was considerably pene-

trated in tumor vasculature through its leaky endothelium and

accumulated in solid tumors via the EPR. The silver enhancer staining

(using silver enhancement kit) and the FR immunohistochemistry

staining on xenografts SPC-A1 tumor cells were shown more than

10-fold of cellular uptake of FA-PAMAM-GNPs nanocomplex in tumor

cells and also the higher magnification images of Transmission electron

microscopy (TEM) were dominantly demonstrated the nanocomplex

accumulation in the lysosomes. For the FR immunohistochemistry

staining, the SPC-A1 cells which were growing on polylysine-coated

cover slips were prepared and fixed in 4% paraformaldehyde in 0.1 M

phosphate buffer. Then tumor tissue sections were boiled in 0.01 M cit-

rate buffer and they were cooled for FR immunohistochemistry. Subse-

quently, sections were blocked with 1% normal goat serum (blocking

buffer) and then incubated with primary polyclonal anti-FR antibody

418 NARMANI ET AL.

that fallowed with secondary biotinylated antibodies incubation. After

washing, sections were incubated with secondary biotinylated anti-

bodies and then images were captured using light microscope (Wang,

Zheng, Peng, Shen, Shi, & Zhang 2013). In addition, flow cytometry anal-

ysis was shown cell cycle and cell apoptosis followed the order of

G0-G1>G2-M>S>G2/G1. On the other hand, the biodistribution inves-

tigation was exhibited excellent tumor and spleen uptake and it was

indicated that nanocomplex can be cleared mainly through the

renal/urinary route and RES (Wang, Zheng, Peng, Shen, Shi, & Zhang

2013). Due to deep tissue penetration, better spatial and density resolu-

tion than other imaging modalities, CT has been considered as most

common imaging techniques in cancer diagnostic. On the other hand,

the intratumoral, intravenous, and intraperitoneal injection routes were

evaluated on animals to determine the best administration route for CT

imaging. Results were indicated that intravenous injection is the most

promising way to introduce its usage in clinical trials.

In another work, Zhou et al. (2016) were developed a cost-effective

contrast agent for tumor CT imaging. They were fabricated PEGylated

polyethylenimine-entrapped gold NPs which have been functionalized

with FA and FITC for active tumor CT imaging. PEGylation of PEI could

enhance the entrapment of GNPs within its interior (FA-FITC-PEG-PEI-

GNPs, with a mean diameter of 202.4 nm). Subsequently, the X-ray

attenuation property of FA-FITC-PEG-PEI-GNPs was indicated that all

three materials display which have been increased CT contrast

enhancement and nanocomplex have a great potential to be used for

CT imaging applications. Also, the flow cytometry and confocal micro-

scopic imaging data exhibited that FA can effectively increase the cellu-

lar uptake more than threefold in cancer cells of tumor (Zhou et al.,

2016). Furthermore, the tumor biodistribution investigation was rev-

ealed that the Au uptake in all the major organs started to decrease

after 72 hr post-injection, and Au uptake is just equal to 39.4, 37.5, and

15.6% in the liver, spleen, and lung, respectively. These evaluations

were demonstrated that the NPs can be effectively metabolized and

cleared out the body without exhibit any side effect in body normal

organs (Zhou et al., 2016). On the other hand, in a research by Li,

Cheng, Liu, and Chen (2016), the FA-BSA functionalized noble gold

nanoclusters (FA-BSA-GNP) were employed to imaging of FR which

has been overexpressed tumor cells. In this work, Li et al. were reported

a simple, cost-effective, turn on, and red fluorescent probe for FR over-

expressed tumor cells based on the recovery of fluorescence intensity

of FA-BSA-GNP nanocomplex. In this assay, first primary fluorescence

intensity of FA-BSA-GNP was quenched via FA-mediated the environ-

ment change of FA-BSA-GNP to produce negligible fluorescence back-

ground. Subsequently, primary fluorescence intensity of FA-BSA-GNP

turned on by FA desorbing from FA-BSA-GNP which is owing to spe-

cific affinity of FA and FR (Li et al., 2016).

5|UPCONVERSION NPS IN DRUG

DELIVERY

Upconverting NPs (UCNPs) are inorganic crystalline nanomaterials

that are able to convert low-energy NIR (photons with 980 or 808 nm

wavelength) excitation light into visible and ultraviolet emission light

(Figure 8; Zhou, Liu & Li 2012; Shen et al., 2013; Auzel, 2004). UCNPs

are promising for applications such as biological imaging and drug car-

riers in biology and medicine. Fundamentally, this photophysical phe-

nomenon is based on an anti-Stokes process and referred to as

photon upconversion where two or more photons are absorbed by a

material and a single photon of shorter wavelength (anti-Stokes shift)

is subsequently emitted (Rinkel, Nordman, Raj, & Haase, 2014;

Narmani, Farhood, Haghi-Aminjan, et al., 2018; Han, Deng, Xie, & Liu,

FIGURE 8 The mechanism and operating principle of the FA-functionalized UCNPs for photodynamic therapy (PDT) and imaging. It is shown

how NIR light upon 980 nm excitation get upconverted to visible light (red, green, and blue emission) in order to diagnosis and therapy. FA, folic

acid; NIR, near-infrared; NP, nanoparticle; UCNP, upconverting nanoparticle

NARMANI ET AL.419

2014; Boyer, Carling, Gates, & Branda, 2010). The excited state

absorption, energy transfer upconversion, and photon avalanche are

various mechanisms of upconversion emission (Zhou, Liu & Li 2012;

Wang et al. 2009). Furthermore, the uniform size and morphology,

narrow emission peaks, large anti-Stokes shifts, excellent photo-

stability, nonphotoblinking, long lifetimes, high crystallinity, good dis-

persibility in aqueous solution, and presence of suitable functional

surface groups are specific properties of UCNPs (Rinkel et al., 2014;

Wang et al., 2006). In a study by Cao et al. (2011), the FA which has

been functionalized rare-earth up conversion nano-phosphors, as

excellent luminescent labels, were developed for fluorescence bio-

imaging. They were synthesized high-quality water-soluble UCNPs

using a hydrothermal reaction assisted by binary cooperative ligands

by one-step synthetic strategy. Their research team used

6-aminohexanoic acid and oleate (as the chelating agent and surfac-

tant) to control nuclear generation and crystal growth of small NPs.

Moreover, these two compounds make UCNPs water-soluble to con-

jugate with FA. Eventually, the rare-earth activator ions including Er

, and Ho

were doped to nanomaterial to exhibit upconversion

luminescence (UCL) in imaging process that Tm

was sued in Cao

et al. (Cao et al., 2011) research. The clear UCL signal at 800 nm was

significantly detected at lymphatic and the removed axillary lymph

nodes were also indicated strong UCL in the ex vivo image due to spe-

cific FR targeting. The in vivo UCL imaging was performed for lym-

phatic mapping on mouse models. For this evaluation, two external

0–5 W adjustable CW (infrared laser) and 980 nm lasers were used as

the excitation sources. Then, the images of luminescent signals were

analyzed and UCL signals were subsequently collected at 800–12 nm.

For achieve to this evaluation, animals were placed in the prostrate

position while under pentobarbital anesthesia. Then, 20 mL (1 mg/mL)

of nanocomplex injected into the paw of the nude mice for 20 min

and eventually the UCL lymphatic imaging was performed (Cao et al.,

2011). Furthermore, lymphadenectomy was exhibited strong UCL in

the ex vivo image of removed axillary lymph nodes. These results

were indicated that detection of lymph nodes could help to clinical

lymph nodal excision surgery of tumor resection.

In a research, Zeng et al. (2015) were fabricated FA targeted, photo-

sensitizer (PS)-loaded Fe

-NaYF

:Yb/Er nanocomplex for in vivo

T2-weighted MRI and visualized photodynamic therapy (PDT) of breast

cancer. This nanocomplex (with size 175 nm in diameter, 12.5 mV in sur-

face charge) was indicated NIR-triggered PDT performance which is

owing to the production of singlet oxygen species. The UCL and singlet

oxygen species are important factors to investigate NIR-triggered PDT

of Er-doped UCL nanomaterials. On the other hand, the transverse MR

relaxivity of 63.79 mM/s (r

value) and in vivo MR imaging were

exhibited an excellent T2-weighted MRI. Also, the in vivo PDT perfor-

mance of nanocomplex was assessed on MCF-7 tumor-bearing nude

mice (n= 5), and change of relative tumor volume was evaluated

between 15-day treatments. As relative volume of MCF-7 tumors was

equal to 3.16, 2.46, and 2.89 for mice that treated with PBS, PBS + NIR,

and nontargeted nanocomplex, respectively, however it was equal to

0.16 in group of FA-NPs + NIR. Moreover, H&E staining for tissue sec-

tions of mice normal organs was not indicated fibrosis in the heart and

lung samples and inflammatory reaction in the liver section and also nor-

mal glomerular and tubular structures were exhibited for kidney (Zeng

et al., 2015). Furthermore, the Fe

-NaYF

:Yb/Er NPs were remarkably

accumulated in liver and tumor due to the extra uptake of Kupffer cells

in liver and FA-mediated internalization and EPR effect of nanocomplex

in tumor (Zeng et al., 2015). In another study by Ma et al. (2012), FA-

conjugated silica which has been modified LaF3:Yb, Tm, Ho, Er UCNPs

(FA-SiO

-UCNPs,withanaveragesizeof6.56±1.16nmindiameter

and −40.39 ± 3.22 mV in surface charge) with high La content were pre-

pared for simultaneously targeting dual-modality imaging of UCL and

X-ray CT. In this study, UCL properties of FA-SiO

-UCNPs were

codopedwithYb

and Er

/Tm

/Ho

. Substantially, nanocomplexes

were synthesized by a novel OA/ionic liquid two-phase system that sub-

sequently were functionalized via FA. The FA-SiO

-UCNPs were indi-

cated good stability, good biocompatibility, highly selective targeting,

great water solubility, excellent X-ray attenuation, and UCL emission

under excitation at 980 nm (Ma et al., 2012). On the other hand, Wang,

Cheng, and Liu (2011) were functionalized Yb

and Er

doped NaYF

UCNPs with a PEG-grafted amphiphilic polymer and FA (FA-PEG-NaYF

UCNPs) for intracellular active drug delivery and UCL imaging. UCNPs

are loaded with a DOX as chemotherapy molecule, by simple physical

adsorption via a supramolecular chemistry approach. The releasing of

DOX from UCNPs (with drug-loading efficiency of 8% w/w) was con-

trolled by varying pH and exhibited an increased drug dissociation rate

(more than twofold) in acidic environment (Wang et al., 2011).

6|CONCLUSION

In this review, we discussed various FA-functionalized NPs which have

been widely utilized for the development of active cancer diagnosis and

therapy. NPs-based active delivery systems hold excellent potential to

overcome some disadvantages of the conventional therapeutic and

diagnostic approaches. These systems have specific properties due to

their various advantages, including their nanosize range, great stability,

biocompatibility, bioavailability, biodegradability, nontoxicity, good

loading capacity, potential for active tumor accumulation, overcome to

problems of drug resistance in cancer cell, and excellent pharmacoki-

netic parameters. Furthermore, surface functionalized NPs can improve

the specific drug delivery into cancer cells and FA targeting shows con-

siderable promise for development of active cancer diagnosis and ther-

apy. Several studies against various tumors FR have tested for specific

drug delivery into tumor tissues. However, challenges still remain in

clinical trials for developing FR-targeted NPs against human cancer

cells. Moreover, an excellent understanding of FA-functionalized NPs in

clinical translations is needed to improve their performances for thera-

peutic and diagnostic practical applications. Actually, evaluation of

interaction between FA-functionalized NPs and complex biomolecules

in human body serum, determination of pharmacokinetic and pharma-

codynamic facts about FA-functionalized NPs, accurate evaluation of

FA-functionalized NPs biodistribution in human body, and probable

cytotoxic behavior and subcellular fate of FA-functionalized NPs are

the main challenges of FA-decorated NPs which need to more

420 NARMANI ET AL.

assessments in preclinical and clinical trials. On the other hand, there is

little understanding regarding the practical applications of FA-

functionalized NPs in human tumor models; however, we believe that

these NPs are most promising nanoplatforms for the future of targeted

DDSs. Therefore, it is necessary to design the comprehensive studies

regarding clinical trials in various cancer diseases to obtain more infor-

mation about the potency of FA-functionalized NPs in human cancer

diagnosis and therapy.

ORCID

Asghar Narmani https://orcid.org/0000-0001-9199-188X

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How to cite this article: Narmani A, Rezvani M, Farhood B,

et al. Folic acid functionalized nanoparticles as pharmaceutical

carriers in drug delivery systems. Drug Dev Res. 2019;80:

404–424. https://doi.org/10.1002/ddr.21545

424 NARMANI ET AL.

Biocompatible PLGA-PCL nanobeads for efficient delivery of curcumin to lung cancer

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Full-text available

Jun 2024

Lung cancer has been mentioned as the first and second most prevalent cancer among males and females worldwide, respectively since conventional approaches do not have enough efficiency in its suppression. Therefore, a biocompatible and efficient polylactic-co-glycolic acid (PLGA: P)- poly-ε-caprolactone (PCL: P) copolymer was fabricated for delivery of relatively insoluble curcumin (Cur) to A549 lung cancer cells. Next, the physicochemical aspects of the synthesized nanobeads were characterized by applying analytical sets, including FT-IR, DLS, TEM, and TGA as nano-metric size (20–45 nm) and 1.29% of Cur entrapment efficiency were determined for P-P-Cur nano-beads. Thereafter, a controlled (5% within 2 h at pH 7.4) and pH-sensitive (nearly 50% within 4 h at pH 5.0) drug release manner was observed for P-P-Cur nanobeads. Thereafter, biomedical assays were conducted for the cancer suppression ability of nanobeads. 41% cell viability after 24 h of treatment with 200 nM concentration and 7.55% cell cycle arrest at 5 h of post-treatment with 100 nM (IC50) concentration were attained for P-P-Cur. Also, 7-fold increase and 2-fold decrease in the expressions of Caspase-9 (apoptotic gene) and Bcl2 (anti-apoptotic gene) were observed which have further approved the cancer inhibition potency of the P-P-Cur sample. The cellular uptake results indicated 91% internalization in A549 cells while it was less than 1% for the pure Cur. These data have demonstrated that P-P-Cur can use as a biocompatible drug delivery system for Cur and treatment of lung cancer.

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Graphene has become a prominent material in cancer research in recent years. Graphene and its derivatives also attract attention as carriers in drug delivery systems. In this study, we designed a graphene oxide (GO)-based methotrexate (MTX)-loaded and folic acid (FA)-linked drug delivery system. MTX and FA were bound to GO synthesized from graphite. MTX/FA/GO drug delivery system and system components were characterized using Fourier transform infrared spectroscopy (FTIR), differential calorimetric analysis (DSC), scanning electron microscopy (SEM), transmission electron microscopy (TEM), zeta potential analysis, and dimension measurement (DLS) studies. SEM and TEM images confirmed the nanosheet structure of GO synthesized from graphite, and it was shown that MTX/FA binding to GO transformed the two-dimensional GO into a three-dimensional structure. FTIR and DSC graphs confirmed that oxygen atoms were bound to GO with the formation of carboxylic, hydroxyl, epoxide, and carbonyl groups as a result of the oxidation of graphite, and GO was successfully synthesized. Additionally, these analyses showed that MTX and FA bind physicochemically to the structure of GO. The in vitro Franz diffusion test was performed as a release kinetic test. The release kinetics mathematical model and correlation coefficient (R2) of MTX-loaded GO/FA nanomaterials were found to be the Higuchi model and 0.9785, respectively. Stiffness analyses showed that adding FA to this release system facilitated the entry of the drug into the cell by directing the system to target cells. As a result of the stiffness analyses, the stiffness values of the control cell group, free MTX, and MTX/FA/GO applied cells were measured as 2.34 kPa, 1.87 kPa, and 1.56 kPa, respectively. According to these results, it was seen that MTX/FA/GO weakened the cancer cells. Combined use of the MTX/FA/GO drug delivery system had a higher cytotoxic effect than free MTX on the MDA-MB-231 breast cancer cell line. The results showed that the synthesized MTX/FA/GO material has promising potential in cancer cell-specific targeted therapy for MTX as a drug delivery system.

Advancement of Nanoengineered Flavonoids for Chronic Metabolic Diseases

Chapter

Jun 2024

The increasing occurrence of chronic metabolic diseases (CMDs) presents a substantial public health challenge worldwide, necessitating the development of pioneering therapeutic approaches. Flavonoids, which are naturally occurring compounds, exert a broad spectrum of biological activities, encompassing their anti-inflammatory, anti-diabetic, and antioxidant properties, among others. Though they have a potential role in treating CMDs, they face challenges in their extraction and purification, poor gastrointestinal absorption, low solubility, and rapid metabolism, which impede their clinical applicability. Nanotherapeutics has been receiving significant attention as it aids in resolving these issues. Hence, the purpose of this chapter is to shed light on the advances in different nanoengineered.

459 13 Advancement of Nanoengineered Flavonoids for Chronic Metabolic Diseases

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Nigella sativa oil (NSO) and its essential oil (NSEO) have long been used in traditional treatment for various ailments. However, in practice, these substances are limited by their limited solubility in water, instability, and low bioavailability. Encapsulation has emerged as a promising solution for addressing these issues. This review is dedicated to the chemical composition of Nigella crude and essential oils, the exploration of their encapsulation system preparation methods, and a comprehensive examination of their potential applications across the food, cosmetics, and pharmaceutical industries. This exhaustive survey serves as an invaluable resource for researchers, professionals, and students with a keen interest in the encapsulation of N. sativa using cyclodextrins and liposomes.

Fullerene C60 Conjugate with Folic Acid and Polyvinylpyrrolidone for Targeted Delivery to Tumor Cells

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INT J MOL SCI

The use of targeted drug delivery systems, including those based on selective absorption by certain receptors on the surface of the target cell, can lead to a decrease in the minimum effective dose and the accompanying toxicity of the drug, as well as an increase in therapeutic efficacy. A fullerene C60 conjugate (FA-PVP-C60) with polyvinylpyrrolidone (PVP) as a biocompatible spacer and folic acid (FA) as a targeting ligand for tumor cells with increased expression of folate receptors (FR) was obtained. Using 13C NMR spectroscopy, FT-IR, UV-Vis spectrometry, fluorometry and thermal analysis, the formation of the conjugate was confirmed and the nature of the binding of its components was established. The average particle sizes of the conjugate in aqueous solutions and cell culture medium were determined using dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA). The FA-PVP-C60 showed antiradical activity against •DPPH, •OH and O2•−, but at the same time, it was shown to generate 1O2. It was found that the conjugate in the studied concentration range (up to 200 μg/mL) is non-toxic in vitro and does not affect the cell cycle. To confirm the ability of the conjugate to selectively accumulate through folate-mediated endocytosis, its uptake into cells was analyzed by flow cytometry and confocal microscopy. It was shown that the conjugate is less absorbed by A549 cells with low FR expression than by HeLa, which has a high level of expression of this receptor.

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Jun 2024
INT J BIOL MACROMOL

During the last decades, the ever-increasing incidence of diseases has led to high rates of mortality throughout the world. On the other hand, the inability and deficiencies of conventional approaches (such as chemotherapy) in the suppression of diseases remain challenging issues. As a result, there is a fundamental requirement to develop novel, biocompatible, bioavailable, and practical nanomaterials to prevent the incidence and mortality of diseases. Chitosan (CS) derivatives and their blends are outstandingly employed as promising drug delivery systems for disease therapy. These biopolymers are indicated more efficient performance against diseases compared with conventional modalities. The CS blends possess improved physicochemical properties, ease of preparation, high affordability, etc. characteristics compared with other biopolymers and even pure CS which result in efficient thermal, mechanical, biochemical, and biomedical features. Also, these blends can be administrated through different routes without a long-term treatment period. Due to the mentioned properties, numerous formulations of CS blends are developed for pharmaceutical sciences to treat diseases. This review article highlights the progressions in the development of CS-based blends as potential drug delivery systems against diseases.

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Breast cancer presents a significant global health challenge, ranking highest incidence rate among all types of cancers. Functionalised nanocarriers offer a promising solution for precise drug delivery by actively targeting cancer cells through specific receptors, notably folate receptors. By overcoming the limitations of passive targeting in conventional therapies, this approach holds the potential for enhanced treatment efficacy through combination therapy. Encouraging outcomes from studies like in vitro and in vivo, underscore the promise of this innovative approach. This review explores the therapeutic potential of FA (Folic acid) functionalised nanocarriers tailored for breast cancer management, discussing various chemical modification techniques for functionalization. It examines FA-conjugated nanocarriers containing chemotherapeutics to enhance treatment efficacy and addresses the pharmacokinetic aspect of these functionalised nanocarriers. Additionally, the review integrates active targeting via folic acid with theranostics, photothermal therapy, and photodynamic therapy, offering a comprehensive management strategy. Emphasising rigorous experimental validation for practical utility, the review underscores the need to bridge laboratory research to clinical application. While these functionalised nanocarriers show promise, their credibility and applicability in real-world settings necessitate thorough validation for effective clinical use.

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The use of nanotechnology in medicine has the potential to have a major impact on human health for the prevention, diagnosis, and treatment of diseases. One particular aspect of the nanomedicine field which has received a great deal of attention is the design and development of nanoparticulate nanomedicines (NNMs) for drug delivery (i.e., drug-containing nanoparticles). NNMs are intended to deliver drugs via various mechanisms: solubilization, passive targeting, active targeting, and triggered release. The NNM approach aims to increase therapeutic efficacy, decrease the therapeutically effective dose, and/or reduce the risk of systemic side effects. In order to move a NNM from the bench to the bedside, several experimental challenges need to be addressed. This review will discuss the current trends and challenges in the clinical translation of NNMs as well as the potential pathways for translational development and commercialization. Key issues related to the clinical development of NNMs will be covered, including biological challenges, large-scale manufacturing, biocompatibility and safety, intellectual property (IP), government regulations, and overall cost-effectiveness in comparison to current therapies. These factors can impose significant hurdles limiting the appearance of NNMs on the market, irrelevant of whether they are therapeutically beneficial or not.

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Ultrasensitive DNA based fluorescent assay is used for the determination of Vibrio cholera O1 OmpW gene. OmpW as a surface adherence protein plays a major role in virulence of bacteria with high gene expression. In the present study, two nanoparticles including gold nanoparticles (AuNPs) and magnetic nanoparticles (MNPs) were used. MNPs were functionalized with the first target-specific DNA probe1, which can recognize one end of the target DNA sequence (t DNA) and the AuNPs were functionalized with the second target-specific DNA FAM-probe 2 which can recognize the other end of the target gene. After hybridization of probes with the target DNA, the sandwich structure was formed as MNPs-probe1-target DNA-FAM-probe2-AuNPs by applying the magnetic field to separate the sandwich complex from no hybridized materials. Dithiothreitol (DTT) was used to decompose the sandwich structures and release the probes from target DNA and nanoparticles. Then, fluorescence emission of the released FAM probe 2 on surface AuNPs was detected by fluorescence spectrophotometry. The resulting nanomaterial system demonstrated excellent sensitivity (LOD=2.34ngmL⁻¹) with good linear relationship (R² =0.9989) between target DNA and great selectivity. In conclusion, the present method has a good potential as a rapid detector of bacteria and other infection.

Expression of folate binding protein as a prognostic factor for response to platinum‐containing chemotherapy and survival in human ovarian cancer

Article

Apr 1998
INT J CANCER

Overexpression of the folate binding protein (FBP) is a common feature in epithelial ovarian cancer, but its prognostic significance is not clearly understood. We investigated whether FBP in epithelial ovarian cancer specimens is a predictor of response to chemotherapy and survival. Between 1990 and 1995, 99 patients with epithelial ovarian cancer underwent primary surgery and were treated with chemotherapeutic regimens including platinum derivatives. First‐line chemotherapy was performed in 58 patients with residual disease and in 41 patients without residual disease after primary laparotomy. FBP expression level was determined in frozen specimens by cyto‐fluorimetric assay using the MOv 18 monoclonal antibody (MAb). Association of FBP fluorescence index (FI) with clinical characteristics, response to chemotherapy, and survival was studied by univariate and multivariate analysis. In the 58 patients with residual disease after primary surgery, failure to respond to chemotherapy (complete or partial remission) was about 15‐fold higher (95% confidence interval, 2.96–77.43) when tumors had FBP FI above the median value (FBP FI = 3.25). FBP FI was not a predictor of survival in the entire series of tumors (99 patients). However, in the subgroup of 58 patients with residual disease after primary surgery, survival analysis confirmed the disadvantage observed with respect to response to chemotherapy in patients expressing FBP FI above the median value (hazard ratio 2.01; 95% confidence interval 0.95–4.24). In conclusion, higher levels of FBP expression might be a predictor of chemotherapy response failure in ovarian cancer. In patients with residual disease after primary surgery, FBP FI could represent a valuable prognostic marker for survival. Int. J. Cancer (Pred Oncol) 79:121–126, 1998.© 1998 Wiley‐Liss, Inc.

Expression and Functional Characterization of the β-Isoform of the Folate Receptor on CD34+ Cells

Article

Jun 1999

We have investigated the expression and functional competence of folate receptor (FR) isoforms on human hematopoietic cells. Using immunofluorescence and reverse transcriptase-polymerase chain reaction (RT-PCR) methodology, we find that a substantial fraction of low-density mononuclear and CD34+ cells express both the β and γ isoforms of FR. The  isoform of FR (the form most commonly found on cancer cells) was surprisingly absent from all hematopoietic cells examined. Compared with KB cells (a human cell line known for its elevated expression of FR-), the abundance of FR-β on CD34+ cell surfaces was relatively low (≈8% of KB cell levels). Because many antifolates and folic acid-linked chemotherapeutic agents enter malignant cells at least partially via FR endocytosis, it was important to evaluate the ability of FR on CD34+ cells to bind folic acid (FA). Based on three FR binding assays, freshly isolated CD34+ cells were found to display no affinity for FA. Thus, regardless of whether steps were taken to remove endogenous folates before receptor binding assays, FR on primitive hematopoietic cells failed to bind 3H-FA, fluorescein isothiocyanate (FITC)-linked FA, or FA-derivatized liposomes. In contrast, analogous studies on KB cells showed high levels of receptor binding for all three FR probes. These studies show that although multipotent hematopoietic progenitor cells express FR, the receptor does not transport significant amounts of FA. Consequently, antifolates and FA-linked chemotherapeutic agents that can be engineered to enter malignant cells exclusively through the FR should not harm progenitor/stem cell function.

Synthesis and evaluation of polyethylene glycol- and folic acid-conjugated polyamidoamine G4 dendrimer as nanocarrier

Article

Feb 2019
J DRUG DELIV SCI TEC

Synthesis of folic-acid mediated targeting nanocarrier is one of the most important and effective approaches in drug delivery. In this study, firstly, the surface of polyamidoamine G4 (PAMAM G4) dendrimers was modified with polyethylene glycol (PEG) to reduce dendrimer toxicity and was engineered with folic acid (FA) to increase nanocomplex targeting of the mice myoblast C2C12 cell lines. Both these synthetic phases were characterized via fourier transform infrared spectroscopy (FT-IR), Proton nuclear magnetic resonance (¹H NMR), ultraviolet–visible spectrophotometry (UV–Vis), and differential scanning calorimetry (DSC) analysis. Secondly, 5-fluorouracil (5-FU), as a chemotherapeutic agent, was loaded in the nanocarrier to therapeutic goals and was characterized. In vitro drug release was also assessed and an excellent controlled release with good release efficiency was reported. The size, diameter, surface morphology, and surface charge of these synthesized nanocomplexes were ascertained with the scanning electron microscopy (SEM), dynamic light scattering (DLS) and zeta potential analyser, respectively, and PAMAM G4 positive charges eliminated. Finally, our nanocomplex was tested on the HT-29 human colorectal cancer and mice myoblast C2C12 normal cell lines and cell viability was evaluated with an 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. Good cancer cell inhibition and cell growth promotion effects of the nanocomplexes have been indicated in this research study.

Bio-barcode technology for detection of Staphylococcus aureus protein A based on gold and iron nanoparticles

Article

Nov 2018
INT J BIOL MACROMOL

S. aureus is one of important causes of disease, food poisoning in humans and animals. The generally methods for detection of S. aureus is time consuming. Therefore, a new method is necessary for rapid, sensitive and specific diagnosis of S. aureus. In the present study, two probes and a Bio-barcode DNA were designed for detection of S. aureus (Protein A). Firstly, magnetic nanoparticle (MNPs) and gold nanoparticle (AuNPs) were synthesized at 80 °C and 100 °C, respectively. The AuNPs and the MNPs were functionalized with probe1, Bio-barcode DNA and probe2, respectively. Target DNA was added into the nanomaterial's system containing bio-barcode DNA-AuNPs-probe1 and probe2-MNPs to formed bio-barcode DNA-AuNPs-probe1-target DNA-probe2-MNPs complex. The bio-barcode DNA-AuNPs-probe1-target DNA-probe2-MNPs complex was separated with magnetic field. Finally, the bio-barcode DNA was released from surface of complex using DTT (0.8 M) and there was isolated of nanoparticles by magnetic field and centrifuge. The fluorescence intensity of bio-barcode DNA was measured in different concentrations of S. aureus (10¹ to 10⁸ CFU mL⁻¹) by fluorescence spectrophotometry. The results showed that standard curve was linearly from 10² to 10⁷ CFU mL⁻¹. Limit of detection of bio-barcode assay for both PBS and real samples was 86 CFU mL⁻¹.

Synthesis and in vitro study of modified chitosan-polycaprolactam nanocomplex as delivery system

Article

Feb 2018
INT J BIOL MACROMOL

Targeting delivery of Oxaliplatin with smart PEG-modified PAMAM G4 to colorectal cell line: In vitro studies

Article

Feb 2018
PROCESS BIOCHEM

In this research, the anti-cancer efficacy of oxaliplatin (OX) was modulated using a nanocarrier system with enhanced targeting efficacy towards folic acid receptors (FAR) expressing colorectal cancer cells. Oxaliplatin was loaded into polyamidoamine dendrimers G4 (PAMAM) imprinted with polyethylene glycol (PEG) and folic acid (FA). The nano-complexes were characterized by FT-IR, ¹H NMR, DSC, TGA, SEM, TEM, DLS and Zeta potential analyzer. Drug loading efficiency (34%) and in vitro drug release studies of PEG-PAMAM-FA-OX nano-complex showed higher drug release at acidic pH. Furthermore, in vitro investigation of nano-complex was carried out using cellular uptake (84.67 ± 1.98% for colorectal cancer cell line), MTT assay, flow cytometry assay and acridine orange staining, to ascertain the cell internalization efficiency, cell viability, apoptotic phase and morphology of dead cell, respectively. Less value of cell viability (18.39 ± 1.91%) and more value of late apoptotic phase (81.8%) were obtained for PEG-PAMAM-FA-OX nano-complex as a final synthetic system.

Gadolinium nanoparticles as diagnostic and therapeutic agents: Their delivery systems in magnetic resonance imaging and neutron capture therapy

Article

Jan 2018
J DRUG DELIV SCI TEC

Gadolinium (Gd) chelates have been widely used as contrast agent in magnetic resonance imaging (MRI). In addition to using MRI, they are interesting, as a radiosensitizer, in neutron capture therapy (NCT). However, the poor selective tissue labeling and localization provided by conventional molecular Gd chelates have confined success in both MRI and NCT applications. To encapsulate Gd into nanoparticulate materials can be considered as a method to overcome these limitations. In this regard, developing various carrier systems have increased the sensitivity and improving the targetability of the contrast agents. In this review article, an overview of the delivery systems of Gd nanoparticles in the MRI and NCT would be mentioned.

Development and Optimization of Methotrexate-loaded Lipid-Polymer Hybrid Nanoparticles for Controlled Drug Delivery Applications

Article

Nov 2017

Lipid-polymer hybrid nanoparticles (LPHNPs) are emerging platforms for drug delivery applications. In the present study, methotrexate loaded LPHNPs consisted of PLGA and Lipoid S100 were fabricated by employing a single-step modified nanoprecipitation method combined with self-assembly. A three factor, three level Box Behnken design using Design-Expert® software was employed to access the influence of three independent variables on the particle size, drug entrapment and percent drug release. The optimized formulation was selected through numeric optimization approach. The results were supported with the ANOVA analysis, regression equations and response surface plots. Transmission electron microscope images indicated the nanosized and spherical shape of the LPHNPs with fair size distribution. The nanoparticles ranged from 176−308 nm, which increased with increased polymer concentration. The increase in polymer and lipid concentration also increased the drug entrapment efficiency. The in vitro drug release was in range 70.34-91.95% and the release mechanism follow the Higuchi model (R2=0.9888) and Fickian diffusion (n<0.5). The in vitro cytotoxicity assay and confocal microscopy of the optimized formulation demonstrate the good safety and better internalization of the LPHNPs. The cell antiproliferation showed the spatial and controlled action of the nanoformulation as compared to the plain drug solution. The results suggest that LPHNPs can be a promising delivery system envisioned to safe, stable and potentially controlled delivery of methotrexate to the cancer cells to achieve better therapeutic outcomes.

Folic acid functionalized nanoparticles as pharmaceutical carriers in drug delivery systems

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