Bionanomaterials for cancer therapy

Abstract

Cancer is the malignant and abnormal growth of cells, being the second reason leading to killing more than 9 million people annually across the world. This number stands for one in six deaths worldwide because of cancer approximately. The most common therapies for this disease are chemotherapy, radiotherapy surgery, and hormone therapy. Despite the side effects of radiation therapy, this strategy is essential for treating half of the patients with this disease. Although chemotherapy’s strong anticancer effects are due to cytotoxic drugs’ nonselective action and the targeting of cancerous and healthy cells, much toxicity is unfortunately distributed within the patient’s body treatment. Therefore, with this type of treatment and after, it is evident that getting rid of the long-term devastative effects of heart toxicity, neurological disorders, infertility, nephropathy, and chronic liver damage will be inevitable...

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CHAPTER 13
Bionanomaterials for cancer therapy
Monireh Ganjali
1
, Mansoureh Ganjali
2
, Mohammad Mahdi Adib Sereshki
3
,
Navid Ahmadinasab
4
, Arash Ghalandarzadeh
5
, Alaa A.A. Aljabali
6
,
Ahmed Barhoum
7,8
1
Bioengineering Research Group, Nanotechnology and Advanced Materials Department, Materials
and Energy Research Center (MERC), Tehran, Iran;
2
Nour Zoha Materials Engineering Research
Group (NMERG), Tehran, Iran;
3
Department of Hematology and Oncology, Iran University of
Medical Sciences, Tehran, Iran;
4
Department of Modern Technologies, Mangrove Research Center,
University of Hormozgan, Bandar Abbas, Iran;
5
School of Metallurgy and Materials Engineering,
Iran University of Science and Technology (IUST), Tehran, Iran;
6
Faculty of Pharmacy, Department
of Pharmaceutics and Pharmaceutical Technology, Yarmouk University, Irbid, Jordan;
7
NanoStruc
Research Group, Chemistry Department, Faculty of Science, Helwan University, Ain Helwan, Cairo,
Egypt;
8
School of Chemical Sciences, Fraunhofer Project Centre, Dublin City University, Dublin, Ireland
1. Introduction
Cancer is the malignant and abnormal growth of cells, being the second reason leading to
killing more than 9 million people annually across the world. This number stands for one
in six deaths worldwide because of cancer approximately. The most common therapies for
this disease are chemotherapy, radiotherapy surgery, and hormone therapy [1]. Despite the
side effects of radiation therapy, this strategy is essential for treating half of the patients
with this disease [2,3]. Although chemotherapy’s strong anticancer effects are due to
cytotoxic drugs’ nonselective action and the targeting of cancerous and healthy cells,
much toxicity is unfortunately distributed within the patient’s body treatment. Therefore,
with this type of treatment and after, it is evident that getting rid of the long-term
devastative effects of heart toxicity, neurological disorders, infertility, nephropathy, and
chronic liver damage will be inevitable [4e8].
A way to improve these devastative effects of cancer drugs is to include various advanced
drug delivery systems in encapsulation and nanoparticle loading application. It can be
performed by releasing and controlling the drug with minimal or even no toxicity to the
tumor site. Research has focused on killing cancer cells by targeting them and maintaining
healthy cells. New carriers for achieving this aim have been designed for anticancer drugs
that bring the drug to its intended location by more accurately identifying the target [9].
Bionanotechnology: Emerging Applications of Bionanomaterials. https://doi.org/10.1016/B978-0-12-823915-5.00015-0
Copyright ©2022 Elsevier Inc. All rights reserved. 443

Among these, nanoparticles have received more attention because they have a more
straightforward production method and can be prepared through biocompatible polymers.
Because of the more incredible permeability of the vessels around the growth tissue than
the ordinary tissue vessels and because of the quick development of the requirement for
more oxygen and supplements, malignancy cells will want to ingest better medications
because of the improved penetrability and maintenance (EPR) wonder [10,11].
Nanoparticles discussed in this chapter can be well used in drug delivery. In previous
years, drug-carrying nanostructures’ ability, control, and access to authorized drug
molecules have also been made possible. Over the last half-century, advances in related
sciences, such as polymer and chemistry, biology, as well as mechanics, and physics, have
all been able to influence the diversity of nanocarriers and the various categories of
carriers, and they could introduce to medical science with unique characteristics and other
performance [12]. Among the applications of nanostructured materials in drug delivery
systems (DDSs) include drug carriers in diseases, such as cancer, cardiovascular disease,
and Alzheimer’s disease [13].
The primary purpose of designing a helpful DDS using technology is to target the drug to
specific cells or tissues, increasing its therapeutic effects, reducing its therapeutic dose,
and modifying biocompatible nanomaterials for drug delivery [13].
2. Cancer disease: types and statistics
Development of healthy cells into cancer cells is a condition that usually proceeds from a
precancerous lesion into some malignant tumor cells. Cancer is the world’s second-highest
source of death, reported at 9.6 million fatalities in 2018. Approximately one in six cancer
deaths worldwide are due to cancer. In low- and middle-economy countries, approximately
70% of deaths from cancer arise. The International Cancers Research Organization (IARC)
reports that 1 out of 5 men and 1 out of 6 women in the world grow cancer over their lives
and that 1 out of 8 men and 1 out of 11 women are killed by their illness, as shown in
Fig. 13.1.
Cancerous cells vary in several respects from normal cells because they become
unregulated and aggressive. An essential distinction is the reduced specialization of
cancerous cells than usual. Although regular cells grow into many different types of cells
with distinct roles, cancerous cells should not. As mentioned earlier, it is another reason
why cancer cells start to split without stopping, unlike healthy cells. Cancer cells are often
capable of missed signaling that cells typically avoid separating or initiating a mechanism
programmed cell death or apoptosis, which the body uses to clear unwanted cells. More
than 100 tumor forms occur. Cancer forms are typically named by the tissues or organs in
which cancer occurs. For instance, lung cancer occurs in lung tissue, and brain cancer
444 Chapter 13

begins in brain cells, as depicted in Fig. 13.2. Cancer can be categorized into four main
categories: (1) the most prevalent form of cancer is carcinomas. They consist of epithelial
cells, which cover the body’s [14] inner and outer layers. Several different types of
epithelial cells also come underneath a microscope as columns (2) sarcomas are bones and
soft tissue tumors, comprising muscle, fat, arteries of the blood, lymph vessels, and fibrous
tissue (such as ligaments and tendons [15]). (3) Leukemias are classified as tumors starting
in bone marrow blood-forming tissue. Muscular tumors are not produced in these cancers.
Afterward, the blood and bone marrow got to be overflowed by an endless sum of unusual
white blood cells (leukemia and leukemia impact), padding solid blood cells. The low rate
of healthy blood cells will make it increasingly challenging for the body to obtain oxygen,
regulate inflammation, or combat pathogens [16] (4). Lymphoma would be a lymphocytic
cancerous tumor that begins with (T cells or B cells). These are white blood cells that
combat disease and contribute to the immune response. In lymphoma, the lymph node,
lymphatic vessels, and other bodies are damaged by irregular lymphocytes [17].
3. Anticancer nanocarriers
In general, drug carriers can be classified into two main groups: (1) organic carriers,
including ceramic NPs, metal NPs, and carbon NPs, and (2) inorganic carriers include
Figure 13.1
Estimated percentages of the reported number of cancer cases distributed worldwide as the
International Agency for Research on Cancer (IARC) reports in 2018. source @IARC GLOBOCAN
2018.
Bionanomaterials for cancer therapy 445

liposomes, solid lipid nanoparticles (SLNs), polymeric micelles (polymeric micelles),
dendrimers, polymersomes, hydrogel NPs, and biodegradable polymers [19e22]. The most
common materials in drug delivery in the form of nanoparticles are polymers. Polymer
nanoparticles (PNPs) are defined as colloidal particles with sizes between 10 and 1000 nm
[23]. Moreover, they are composed of natural (chitosan, gelatin, sodium alginate, and
albumin) [24e27] or artificial biodegradable polymers, such as polylactic acid (PLA),
polyglycolides (PGAs), poly(lactide co-glycolides) (PLGAs), polyanhydrides,
Figure 13.2
Common cancer types, such as lung, breast, colorectal, esophagus, and kidney cancers due to
distinct factors [18].
446 Chapter 13

polyorthoesters, polycyanoacrylates, polycaprolactone, polyglutamic acid, polymalic acid,
poly(N-vinyl pyrrolidone), poly(methyl methacrylate), poly(vinyl alcohol), poly(acrylic
acid), polyacrylamide, poly(ethylene glycol) (PEG), and poly(methacrylic acid) [28e39],
which is biocompatible and nontoxic; more examples are depicted in Fig. 13.3.
Biocompatible and nontoxic are common characteristics of natural polymer nanoparticles;
however, their low solubility has limited application, when offered in various biological
membranes [40]. Such delivery exposes the nanoparticles to various pHs. This change in
pH and some other issues sometimes restrict their use. Features such as biocompatibility
are required for potential applications in tissue engineering, drug and gene delivery, and
new vaccination strategies.
Figure 13.3
Nanoparticle drug delivery system to selectively target the desired cells. Therapeutic agents are
loaded into appropriately selected polymer nanoparticles that may enter the target cells through
the process of endocytosis and release therapeutic agents inside the endolysosomal effect of the
cell cytoplasm. Alternatively, the cationic nanocarriers can fuse with the negatively charged
cellular plasma member and release the therapeutics into the desired cells. One of the
disadvantages of using nontargeted therapeutics as free drugs is the membrane-active drug efflux
pumps that expel the therapeutic from the cytoplasm to the outside of the cell.
Bionanomaterials for cancer therapy 447

3.1 Polymeric nanocomposite drug delivery
PNCs are a combination of different polymers with nanoparticles established themselves
as a suitable type of nanocomposite (NC) biomaterials for regenerative medicine as well
as drug delivery applications and are widely investigated as multifunctional nanomaterials.
These PNCs can be classified into four types with different nanofiller, which are discussed
in this section.
3.1.1 Polymerepolymer nanocomposites
Most researchers are currently focusing on polymer-based bioNCs. Their NCs in various
forms, such as micelles, hydrogels, polymers, and liposomes, play an essential role in
treating cancer with unparalleled design capacity, environmentally friendly nature, and
comfortable and cost-effective production. PNCs are composed of polymers and
nanomaterials in various types, shapes, and sizes. The interaction of the polymer matrix
and nanoparticles is significant in determining the hybrid structure’s compositional
properties. They can provide higher payloads, extended circulation time of drugs, drug
targeting, and solubility [18].
PNPs comprise a large group of compounds, including vesicular systems (nanocapsules)
and matrix systems (nanospheres) (see Fig. 13.4). The drug is trapped inside a polymer
cavity in nanocapsules; however, the drug is dispersed in a polymer matrix [41].
Figure 13.4
Various examples of nanomaterial constructed from various metallic and nonmetallic
nanomaterials, mesoporous silica nanoparticles (MSNs), iron oxide nanomaterials, carbon
nanotubes, dendrimer, micelle, quantum dots as coreeshell nanomaterials and their applications
as nanocarriers with surface functionalities for the selective targeting to the target cell, which will
lead to the therapeutic release after specific stimulants within the target cell [42].
448 Chapter 13

Abraxane was the first polymer nanoparticle introduced to the world pharmaceutical
market in 2005 by American Pharmaceutical Partners and American Bioscience company,
which comprised of nanoparticles of the drug paclitaxel, bound to albumin [43,44]
(Fig. 13.5). This formulation is fabricated to release a compound called chromophore-EL,
present in previous paclitaxel formulations by increasing solubility. Chromophore causes
severe allergies in certain patients that can threaten their life. With this great success of
Abraxane, it has been proven that nanotechnology can introduce products to overcome the
challenges of formulation science.
The hydrophilic layer of polymeric micelles (PMs) with coreeshell structure has
coreeshell PMs due to a hydrophilic shell making them a good candidate as a nanocarrier
for loading hydrophobic drugs into the core. Blanco et al. [45] reported the effect of
encapsulation of b-lapachone in PEGePLA NPs on A549 cell lysates and orthotopic
Figure 13.5
The usual surface modifications of polymeric nanoparticles, PEGylation, carboxylate, amine,
antibodies, aptamer, peptides, glycans, and surface charge. Generated nanomaterials could be
classified as natural nanomaterials, such as proteins, liposomes, dendrimers, and liposomes, and
synthetic nanomaterials, including coreeshell nanomaterials, hydrogels, carbon nanotypes, and
metallic nanoparticles. The obtained nanomaterials vary in their shape from spherical, cuboidal,
start, plate, triangular, and rod-shaped with various desired sizes [51].
Bionanomaterials for cancer therapy 449

Lewis lung carcinoma (LLC). The results indicated a drastically reduced tumor growth and
metastatic tumor burden when compared with free b-lapachone [45]. In another study,
MPEGePLA and Pluronic were employed to deliver docetaxel [46]. The investigation
showed that the volume of tumor size significantly reduced more when treated with mixed
micelles. Jun et al. demonstrated that CP570 micelles could be used as a carrier to deliver
docetaxel [47]. Their study showed that CP570 micelles did not significantly affect the
improvement of the pharmacokinetics of docetaxel. Furthermore, Park et al. compared
conjugated and encapsulated PLGAePEG MPs containing doxorubicin (DOX) [48]. The
drug release of the conjugated DOXePLGAePEG MPs was more significant than
encapsulating PLGePEG MPs due to gradually hydrolyzing conjugated DOXePLGA and
controlled release water solution DOXePLGA in the incubation medium. The stable
release of DOX from DOXePLGAePEG micelles was similarly observed in compounds
containing microspheres and prepared PLGA nanoparticles with various hydrophilic drugs
to PLGA [49,50]. PNPs surface has been modified with different methods, such as charge
modification, bioactive peptides graft, amphipathic compound graft, and siRNA to obtain
the appropriate functions to fit the tumor environment or properties of drugs as shown in
Fig. 13.5.
3.1.2 Polymericemagnetic nanocomposites
Magnetic NPs are widely used in magnetic resonance imaging (MRI), biosensors,
theranostics, delivery, magnetic hyperthermia, photodynamic therapy, and photothermal
ablation therapy [52e58]. However, magnetic NPs, due to aggregation and low stability in
biological environments, are often coated with or embedded in a polymer [59,60]. This
surface coating has a sufficient role in improving some MNPs’ properties such as
pharmacokinetics, systemic toxicity and clearance rate, nonspecific protein adsorption or
cell interactions, and sustained drug release. Magnetic NPecoated polymers are proposed
as new materials for releasing the chemotherapeutic cancer drugs in the desired tissue or
organ. Many researchers have extensively studied polymericemagnetic NCs for innovative
triggered release in controlled drug delivery. An overview of polymericemagnetic NCs for
drug delivery applications is listed in Table 13.1 [61].
In addition to chemotherapy drugs, implantable magnetic (Fe
3
O
4
)-reinforced
polydimethylsiloxane NCs for the localized breast cancer treatment via hyperthermia were
explored by Kan-Dapaah et al. [76]. It has been identified in the study that the thermal
dose coverage influences NC shape and size. Recently, an alternating current (AC)
magnetic field has developed a novel fabrication technique for synthesizing spherical
microactuators of PLGA/Mg-gFe
2
O
3
NCs [77]. The release rate results showed an
increased diffusion rate in the excited PLGA/Mg-gFe
2
O
3
NCs by the AC magnetic field.
450 Chapter 13

The schematic structures of eight biological source-based MNPs as drugs has been
approved by the US Food and Drug Administration (FDA), European Medicines Agency
(EMEA), Japanese Ministry of Health, and Australia’s Therapeutic Goods Administration
for different clinical applications and derivatives as shown in Fig. 13.6 [78e81].
Moreover, some other magnetic NPebased drugs including Feraheme, Endorem,
Gastromark, Lumiren, Ferumoxytol, Combidex, Radiogardase, Feridex, and NanoTherm
have been recently approved by the FDA and European Medicines Agency (EMA) for
various applications in iron deficiency, iron replacement therapy, the lymph node
metastases imaging, MRI, pharmaceutical contrast agents or oral antidotes for heavy metal
contamination in humans, and the treatment of intermittent glioblastoma multiforme
[82e84].
3.1.3 Polymeremetallic nanocomposites
Metallic NPs are nanosized metals with dimensions (length, width, or thickness) within the
size range of 1e100 nm and can be synthesized in different forms through various
Table 13.1: Distinct polymericemagnetic nanaocomposites for specific drug delivery
applications.
Magnetic nanoparticles Polymer Drug loaded/application References
Carbonyl iron Poly(butylcyanoacrylate) 5-Fluorouracil
Ftorafur
[62]
Fe
3
O
4
Starch-g-
poly(methylmethacrylate-co-
PEG-acrylamide)
Doxorubicin [63]
Fe
3
O
4
Poly(lactic acid)/PEG Doxorubicin
hydrochloride
[64]
Fe
3
O
4
APSePEGeTFEE Doxorubicin [65]
Fe
3
O
4
PEG-b-poly(4-
vinylbenzylphosphonate)
Doxorubicin [66]
Fe
3
O
4
@LaF3:Ce3
þ
, Tb3
þ
nanoparticles
Chitosan Paclitaxel [67]
Fe
3
O
4
Poly[(N-isopropylacrylamide-r-
acrylamide)-b-L-lactic acid]
Paclitaxel [68]
Fe
3
O
4
Cisplatin Heparin [69]
Fe
3
O
4
Chitosan Gemcitabine [70]
Fe
3
O
4
PEGylated PLGA Sorafenib [71]
Fe
3
O
4
Chitosan Bortezomib [72]
Fe
3
O
4
Chitosan Gemcitabine [73]
Mesoporous silica PEG-co-poly(vinyl pyridine) Doxorubicin [74]
Fe
3
O
4
Chitosanepolymethacrylic
acid
Doxorubicin [75]
Bionanomaterials for cancer therapy 451

methods [85e88]. Metallic NPs, such as silver (Ag), gold (Au), titanium (Ti), platinum
(Pt), palladium (Pd), and copper (Cu), are generally used as drug carriers and contrast
agents in cancer treatment [89e91]. The applications of these substances due to their
antiproliferative and apoptotic induction properties for use in cancer therapy have been
studied by many researchers [92e95].
Tumor blood vessels are often large and have an insufficient lymphatic system [96,97];
therefore, metallic-based NPs can easily penetrate the cancerous cells and kill them. The
cytotoxic effects of silver nanoparticles (AgNPs) on the MCF-7 breast cancer cell line
were studied in a previous work. The MTT assay results demonstrated a significant
reduction of cancer cell proliferation after 24 h [98]. In another work, the effect of silver
Figure 13.6
Schematic diagram depicting various inorganic nanodrug delivery platforms (NDDPs) loaded with
anticancer chemotherapeutic agents employed for cancer treatment. iNPs, inorganic
nanoparticles; MWCNTs, multiwalled carbon nanotubes; SWCNTs, single-walled carbon
nanotubes [42].
452 Chapter 13

(AgNPs) and gold nanoparticles (AuNPs) as an antitumor treatment in vitro against human
breast cancer cells (MCF-7) was investigated [99]. The mechanism of cytotoxic effects of
silver and gold nanoparticles (AgNPs, AuNPs) on cancer cells is proposed to be due to the
increasing disruption of reactive oxygen species (ROS) released by the nanoparticle
toward mitochondria. This disruption leads to reduced cellular energy production (ATP),
which eventually causes DNA damage and cell death [100,101]. However, it has been used
to combine AgNPs with an anticancer drug to get over chemoresistance and undesired side
effects of chemotherapeutic drugs. Gopinath et al. investigated the combination of AgNPs
and 5-fluorouracil (5-FU) effects on the baby hamster kidney (BHK21) and human colon
adenocarcinoma (HT29) cell lines [102]. The study revealed that AgNPs can act as a
therapeutic drug and represent a new chemosensitization strategy for future gene therapy
applications. Furthermore, the results indicated that AgNPs apoptotic cells’ mechanism
associated with mitochondrial membranes’ damage is same as the mechanism induced by
other drugs or gene therapy treatments.
DOX is an anthracycline type of chemotherapy with broad-spectrum activity and is used to
treat various cancer types. Hekmat et al. demonstrated that the combination of AgNPs and
DOX could alter DNA structure [103]. Moreover, the study identified that the AgNPs and
DOX improved the cytotoxic effect of DOX on MCF7 cells and T47D cells compared
with stand-alone DOX or AgNPs.
Platinum complexes are another typical metallic NPs that are introduced as cancer
treatment agents in 1968, due to various oxidation states, chelating properties, redox
potentials, uneven ground, and excited electronic states [104]. Thus, several approved
platinum-based drugs by the FDA, Japan, China, and Korea, are used in different cancer
treatments as listed in Table 13.2.
Nevertheless, the metallic NPs are unstable in the blood and have low cellular uptake in
cancer, limiting their clinical application. Besides, severe chronic kidney disease,
neurological disorder, and ototoxicity are the main effects of these materials.
Consequently, to overcome these problems, the surface of metallic NPs has been modified
with biocompatible polymers and encapsulated of drugs in nanosized drug carries to avoid
aggregation of nanosized metal and preserve their properties and increase the duration of
drug action without the loss of their volume and activity. On the other hand, inhibition of
tumor cells without harmful effects on healthy tissue should be considered [115,116].
The cytotoxicity effect of the conjugated DOX onto coreeshell Ag/PNCs was investigated
[117]. The coreeshell Ag/PNCs consist of AgNPs as a core, and three FDA-approved
polymers (PVA, PEG, and PVP) were as a shell. The MTT results showed that DOX/Ag
NCs are more cytotoxic to MCF-7 cells than normal 1BR hTERT cells. The results also
showed that DOXeAg/polymeric (PVA, PEG, and PVP) NCs showed IC50 at 10-fold
reduced doses than free DOX and DOXeAgNCs. Based on the experimental results, it can
Bionanomaterials for cancer therapy 453

be concluded that the efficiency of DOXeAg/polymeric (PVA, PEG, and PVP) NCs is the
same as DOX alone, but with less dose of DOX about 95%. In another study,
Venkatpurwar et al. synthesized novel carriers for anticancer drug delivery with capped
gold nanoparticles [118]. The result showed a significant enhancement in cytotoxicity of
DOXeAuNCs on human glioma cell lines (LN-229) compared with free DOX that can be
attributed to the increase of cellular internalization via AuNP-mediated endocytosis. The
role of AuNP-mediated endocytosis in the growth inhibition of cancer cells through the
release of the conjunction of methotrexateegold nanoparticles (MTXeAuNPs) inside
cancer cells was also reported by Chen et al. [119].
3.1.4 Polymer ceramic nanocomposites
Besides, hyperthermia (HT) is a novel strategy through the local application of heat to
inhibit cancer cells. HT is categorized into three groups, such as whole body, regional, and
localized. The body temperature in whole-body hyperthermia (WBH) is raised to 39.5 and
40.5"C (103.1 and 104.9"F) [120,121]. Indeed, this temperature is defined between 41.8
and 42"C (107.2e107.6"F) in Europe and the United States, where it is approximately
Table 13.2: Applications of platinum-based drugs.
Drugs Applications References
Cisplatin Testicular cancer, ovarian
cancer, cervical cancer, breast
cancer, bladder cancer, head
and neck cancer, esophageal
cancer, lung cancer,
mesothelioma, brain tumors,
and neuroblastoma
[105,108e111]
Carboplatin Ovarian cancer, lung, head and
neck, endometrial, esophageal,
bladder, breast, and cervical;
central nervous system or germ
cell tumors; osteogenic
sarcoma; and as preparation
for a stem cell or bone marrow
transplant
[105,108e110]
Oxaliplatin Advanced cancer of the colon
and rectum
[105,106,109]
Nedaplatin Advanced or recurrent
esophageal cancer
[107,108]
Lobaplatin Breast cancer, esophageal
squamous cell carcinoma,
gastric carcinoma, lung cancer,
melanoma, and ovarian cancer
[107,113,114]
Heptaplatin Advanced gastric cancer [108,112]
454 Chapter 13

43e44"C (109e111"F) in Japan and Russia. This method raises the patient’s body
temperature by immersing in a hot water bath, heating blankets, or ultraviolet radiation.
Nevertheless, the body temperature in the case of local/regional hyperthermia remains
unchanged. All of these methods have certain side effects, such as pain at the site,
infection, bleeding, blood clots, swelling, burns, blistering, and damage to the skin,
muscles, and nerves near the treated area, nausea, vomiting, diarrhea, and problems with
heart, blood vessels, and other major organs [122].
Hyperthermia based on the combination of polymeric matrix embedding magnetic
bioceramic fillers is proposed to solve the challenges in conventional HT. By the
hyperthermia method, ferromagnetic glasseceramics (FGCs) have shown promising
outcomes for the treatment of deep tumors, such as osteosarcoma cells [123]. Kokubo
et al. synthesized the FGCs granule and showed that when it was located around the
tumors, strongly bonding it and bone, a bone-like apatite complex around the tumors is
formed [124]. Hence, tumor cells were inhibited due to efficient heat after exposure
toward an alternating magnetic field.
As a typical carrier material, ceramic nanoparticles have been extensively exploited for
imaging-guided therapy, including silica [125], NIR spectra of 5% Er
3þ
-doped
glasseceramics [126], and lanthanide-doped upconversion nanoparticles (UCNPs) [8e12].
Previous reports indicated that biomacromolecules were closely related to the bioinspired
mineralization process. For instance, the mineralization of CaCO
3
[127] can be induced
and regulated by regenerated silk fibroin (SF)-based nanostructures through an oriented
crystallization process [26,27]. A series of magnetic glasseceramics containing different
additions of P
2
O
5
or MnO
2
in the system Fe
2
O
3
eCaOeZnOeSiO
2
eB
2
O
3
for localized
treatment of cancer was studied by Abdel-Hameed et al. [128,129]. Increasing P
2
O
5
or
MnO
2
in the composite influences on thermal effect and decreases it. Tumor hypoxia is
caused by the rapidly proliferating cancer cells enclosed in the distorted tumor
vasculatures, which severely hinders the treatment efficacy of photodynamic therapy
(PDT) owing to the insufficient oxygen supply in the tumor microenvironment [28e30].
Significantly, MnO
2
nanoparticles can induce enzymatic decomposition of H
2
O
2
into water
and oxygen and thus may work as a crucial mediator to diminish tumor hypoxia [34,35].
Furthermore, MnO
2
can decompose in response to other tumor-specific environmental
cues, such as glutathione (GSH) or local acidity, and the produced Mn
2þ
is an excellent
contrast agent for T1-magnetic resonance (MR) imaging of tumoral tissues [130].
In a recent study, Yang and coworkers clinically confirmed that photosensitizer
indocyanine green (ICG) and chemotherapeutic drug DOX were coimmobilized into silk
fibroin (SF) nanoparticles, where MnO
2
mineralized the particle surface through a
bioinspired crystallization process (Fig. 13.7)[130].
Bionanomaterials for cancer therapy 455

Among the different ceramic nanoparticles developed so far, mesoporous SiO
2
has
attracted the scientific community’s attention for being applied as a drug delivery system
capable of controlling the drug release in space and time. Modifications of SiO
2
NPs with
different types of polymers were performed so far to imprint them a stimulus-responsive
behavior (namely, pH, redox potential, adenosine triphosphate, enzyme, or temperature) to
allow their application in cancer therapy, which is schematically represented in Fig. 13.8.
Several efforts have been executed via MSNs to target specific tissues through passive or
active targeting procedures [131].
Figure 13.7
Schematic of the synthetic procedure of SF@MnO
2
/ICG/DOX (SMID) nanoparticles as a
multifunctional drug delivery platform for in vivo MR/fluorescence imaging-assisted trimodal
therapy of cancer [130].
456 Chapter 13

In the beginning, MSNs were developed as an anticancer drug delivery system, mainly
based on their efficacy to store a high amount of chemotherapeutics into pores and exploit
the enhanced permeability and retention (EPR) effect for passive targeting to tumor
tissues. This part of the chapter will discuss the EPR effect and passive targeted cancer
therapy using MSNs. Later, MSN surface modifications by conjugating targeting ligands
were introduced to enhance MSN uptake in targeted cells. Different targeting moieties
have been employed to the surface of MSNs, e.g., small molecules, aptamers, short
peptides, antibodies, and antibody fragments [131].
Nasab et al. fabricated chitosan nanoparticles that are coated with curcumin [132]. The
results showed that mesoporous silica nanocarriers, refined by chitosan as a pH-responsive
polymer, improved curcumin’s solubility in the aqueous media and could be acted as a
nanocarrier against the U87MG glioblastoma cancer cell line. In another study, a
coreeshell system containing chitosanepoly(methacrylic acid) (CSePMAA) shells and
MSN cores was studied [133]. According to this study, the drug-releasing and release
behavior of loaded DOX hydrochlorideeMSN/CSPMAA composite showed high drug-
loading capacity encapsulation efficiency 22.3 #0.3% and 95.7 #2.0%, respectively.
Osteosarcoma (OS) or osteogenic sarcoma (OGS) (or only bone cancer) is a type of
cancerous tumor in a bone that is usually found in the long bones around the knee.
This type of cancer is found in children, adolescents, and young adult men than women [135].
Figure 13.8
Schematic representation shows different stimuli-responsive behaviors of mesoporous silica nano-
particles for cancer therapy [134].
Bionanomaterials for cancer therapy 457

This type of cancer is found in children, adolescents, and young adult men than women
[135]. Among the most common treatments for osteosarcoma are surgery, chemotherapy,
and radiation therapy.
Moreover, patients with higher-grade tumors are treated with a new method known as
neoadjuvant therapy (chemotherapy given before surgery) in recent times [136]. Apart
from the potential clinical benefits of chemotherapy drugs, due to localization of OS in a
wide area and cutting off from the blood vascular system resulting from crushing healthy
vessels [137], the defective drug reaches the tumor.
Additionally, since OS is spread to other tissues, a sensitive platform to recognize healthy
and tumor cells is required. Therefore, polymericeceramic NCs have received much
attention as a potential basis for one such advanced platform. The novel
hydroxyapatiteepolyvinyl alcoholedoxorubicin anticancer drug (HApePVAeDOX) NC
was developed for obstructive sleep apnea (OSA) treatment [138]. It was shown that the
DOXeHApePVA NC is highly toxic toward osteosarcoma cells (MG 63) with better
biological properties. Son et al. developed drug-loaded calcium phosphate (CaP) NC
system containing an anticancer drug, such as caffeic acid (CA-NP), chlorogenic acid
(CG-NP), or cisplatin (CP-NP) in the presence of alginate as a polymer template to control
the release rate of drugs for overall survival (OS) treatment [139]. The anticancer activity
of cisplatin-loaded CP-NP NC was higher than another NC on OS and dependent on drugs
and time concentration overall survival.
Furthermore, drug-loaded NCs were released at lower pH. Mondal et al. [140] utilized an
easy synthetic method with a two-step hydrothermal and wet chemical deposition
technique for the synthesis of iron oxide nanoparticles (Fe
3
O
4
), hydroxyapatite (HAp), and
coated hydroxyapatite (Fe
3
O
4
eHAp) for the treatment of cancer via magnetic
hyperthermia approach. First, a controlled hydrothermal synthesis procedure was
employed to synthesize Fe
3
O
4
nanoparticles followed by coating with HAp. The
cytotoxicity study of synthesized iron oxide, HAp, and Fe
3
O
4
eHAp nanoparticles was
performed with MG-63 osteosarcoma cell lines. The Fe
3
O
4
eHAp nanoparticles were
further studied for in vitro hyperthermia assessment. The promising results encourage the
future application of Fe
3
O
4
eHAp nanomaterials as a nanoheater for magnetic
hyperthermiaemediated cancer therapy (Fig. 13.9). Along this line, DOX-loaded
degradable MSNs with hyaluronic acid (HA) decoration (DOX-loaded HA-PMSNs) for
cancer treatment were synthesized by Palanikumar et al. [141]. The release profile of
DOX@MSN/CS-PMAA depicted that the DOX release rate was more dependent on pH in
DOX@MSN/CS-PMAA than DOX@MSN, whereas a faster release behavior was
observed with decreasing pH from 7.4 to 6.8 and 5.5 in DOX@MSN/CS-PMAA system
(Fig. 13.9). This issue is attributed to the effect of electrostatic interaction between DOX
and polymer nanoshells.
458 Chapter 13

Nanoselenium-poly-L-lactic acid (nSe-PLLA) NCs have been prepared to reduce bone
cancer cell functions by Stolzoff and Webster [142]. The SeNPePLLA samples had a
greater alkaline phosphatase (ALP) activity than healthy osteoblast tissue. Antioxidant-
loaded phosphorylated chitosan nanohydroxyapatite (HAp/PCS) and phosphorylated
chitosanenanohydroxyapatiteegingerol (HAP/PCS/G) composite scaffold for bone tissue
engineering was developed by Sumathra et al. to accelerate cell proliferation [143]. The
investigation showed that HAP/PCS/G composite scaffold had good properties as large
pore size, biocompatibility, and cytotoxicity and could be used as an osteoconductive
scaffold. In another study, Wu et al. prepared JQ1 (a bromodomain inhibitor)-loaded
n-HAp with and without Medronate (BP) as an amino acid protein [144]. According to
this study, the OS cell was selected by loaded n-HA with BP. The positive effects of this
synergy are evidenced by the consistently favorable effect achieved by HAp/BP/JQ1, not
Figure 13.9
Magnetic hydroxyapatite (IO-HAp)emediated hyperthermia study to treat cancer [140].
Bionanomaterials for cancer therapy 459

only reduced OS cell migration and viability of differentiated OS cells more than any
other HAp composition, but also selectively necrotized OS cells, similar to HAp/JQ1 and
HAp/BP.
Silica nanostructures (n-SiO
2
) as nanocarriers, due to advantages, such as biocompatible,
highly porous, easy-to-control fabrication, cost-effective, and easy to modify for
functionalization nature, have been widely used in drug delivery [145e148]. MSNs were
first synthesized by Kresge et al. [149]. The study reported that the fabrication of
interaction of silanol group of mesoporous n-SiO
2
(MSNs) with cellular membranes could
cause toxicity [149]. Therefore, surface modification of the MSNs with a polymer shell is
highly required to utilize them for potential anticancer as well as other biomedical
applications [150].
4. Conclusion
This chapter explains NCs with different nanofillers and their great potential as a single
platform with multifunctional capabilities for slow and controlled drug delivery emerging
as an attractive approach as compared with the traditional treatment containing
chemotherapy drugs, radiation, and surgical excision; NCs functionalized with a targeting
agent present a novel therapeutic approach. The entrapment procedure of chemotherapy
drugs into the NCs has resulted in more significant drug loading and slower drug release
properties. However, despite many remarkable studies, some critical questions need to be
answered toward clinical applications. Therefore, more data are required about the
appropriate shape and size nanofiller currently doped into the polymers. Subsequently,
more attempts should be made to improve nanofillers’ synthesis and properties for
successfully transporting chemo drugs to purposed targets. Besides, extra in vitro and
in vivo experiment for enhancing drug delivery from these nanocarriers is demanded.
Furthermore, several types of PNCs cannot be scaled up due to the high-cost process. In
this regard, nanocarriers based on PNCs should be fabricated at low cost and fast. The
next major challenge encountered in PNC for drug delivery is their biocompatibility and
acceptability since synthetic materials with body cells in vivo experiments are different
from in vitro tests and in biological media. Besides, fundamental challenges in PNC
systems are stability, solubility, permeability, and sustained release.
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