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Polypeptide-based artificial erythrocytes conjugated with near infrared photosensitizers for imaging-guided photodynamic therapy

Authors:
Le Liu at Pratt Institute
Le Liu
Tuanwei Li at University of Science and Technology of China
Tuanwei Li
Zheng Ruan at Dalhousie University
Zheng Ruan
Lifeng Yan at University of Science and Technology of China
Lifeng Yan
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Abstract and Figures

Photodynamic therapy (PDT) combining with near infrared (NIR) imaging is attractive. However, the intrinsic hypoxia in tumor and consumption of oxygen during treatment will decrease PDT. Here an artificial red cell was prepared using polypeptides conjugated hemoglobin as an oxygen carrier. A NIR photosensitizer-brominated 4,4-difluoro-4-bora-3a,a-diaza-s-indacene (BODIPY-Br2) possessing both high fluorescence emission and singlet oxygen generation efficiency was synthesized and also conjugated to polypeptides to achieve NIR imaging-guided PDT. In vitro studies performed on HepG2 cancer cells verified the oxygen carrier, cancer tracing and curing abilities of the as-prepared polymeric nanoparticles. Even under hypoxia condition, it also obviously increases the cell killing rate when exposed light at a low energy (25 mW/cm2, 10 min). Meanwhile, the fluorescence of BODIPY in NPs would light up cells for real-time imaging. These results show the potential of the biocompatible and biodegradable P-Hb-B NPs for enhancement of simultaneous tracing and treating of cancer.
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BIOMATERIALS
Polypeptide-based artificial erythrocytes conjugated
with near infrared photosensitizers for imaging-guided
photodynamic therapy
Le Liu
1
, Tuanwei Li
1
, Zheng Ruan
1
, and Lifeng Yan
1,
*
1
Hefei National Laboratory for Physical Sciences at the Microscale, CAS Key Laboratory of Soft Matter Chemistry, Department of
Chemical Physics, iCHEM, University of Science and Technology of China, Hefei 230026, People’s Republic of China
Received: 29 January 2018
Accepted: 27 March 2018
Published online:
4 April 2018
ÓSpringer Science+Business
Media, LLC, part of Springer
Nature 2018
ABSTRACT
Photodynamic therapy (PDT) combining with near infrared (NIR) imaging is
attractive. However, the intrinsic hypoxia in tumor and consumption of oxygen
during treatment will decrease PDT. Here an artificial red cell was prepared
using polypeptides conjugated hemoglobin as an oxygen carrier. A NIR pho-
tosensitizer-brominated 4,4-difluoro-4-bora-3a,a-diaza-s-indacene (BODIPY-Br
2
)
possessing both high fluorescence emission and singlet oxygen generation
efficiency was synthesized and also conjugated to polypeptides to achieve NIR
imaging-guided PDT. In vitro studies performed on HepG2 cancer cells verified
the oxygen carrier, cancer tracing and curing abilities of the as-prepared poly-
meric nanoparticles. Even under hypoxia condition, it also obviously increases
the cell killing rate when exposed light at a low energy (25 mW/cm
2
, 10 min).
Meanwhile, the fluorescence of BODIPY in NPs would light up cells for real-
time imaging. These results show the potential of the biocompatible and
biodegradable P-Hb-B NPs for enhancement of simultaneous tracing and
treating of cancer.
Introduction
Photodynamic therapy (PDT), as an emerging thera-
peutic modality, eradicates cancer tissues by reactive
oxygen species (ROS) with photosensitizers (PSs) and
light irradiation in the presence of oxygen [1]. Besides
efficient singlet oxygen (
1
O
2
, type II) generation,
excellent PSs should also have inherent high near-
infrared (NIR) emission for fluorescence imaging to
achieve imaging-guided PDT [2–4]. Among various
PSs, 4,4-difluoro-4-bora-3a,a-diaza-s-indacene (BOD-
IPY) PSs show their potential in ‘‘see and treat’’
application, especially after the heavy atom modifi-
cation [5]. In the family of BODIPYs, NIR dyes are
infrequent, and dyes with both high fluorescence and
singlet oxygen quantum yields are especially rare.
Recently, a NIR BODIPY dye based on thiophene and
bromine has been synthesized in our group with
fluorescence quantum yield of 0.45 with photo-sta-
bility, and singlet oxygen quantum yield of 0.36,
Address correspondence to E-mail: lfyan@ustc.edu.cn
https://doi.org/10.1007/s10853-018-2276-6
J Mater Sci (2018) 53:9368–9381
Biomaterials
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Two years later, Liu and colleagues [61] investigated the phototoxic effect and O 2-carrying ability of Hb-nanoconjugated biodegradable polypeptides, Hb-BODIPY-Br2 NPs, denoted as p-Hb-B-NPs, on HepG2 monolayers (620 nm, 25 mW/cm 2 , 10 min) under normal or N 2 atmosphere and compared to that of p-B-NPs. Both nanoconjugates exerted a cytotoxic effect under a normal atmosphere, with the best effect achieved at a concentration of 4 µM p-Hb-B-NPs; however, an insignificant effect was noted under an N 2 atmosphere [61]. ...
... Two years later, Liu and colleagues [61] investigated the phototoxic effect and O 2-carrying ability of Hb-nanoconjugated biodegradable polypeptides, Hb-BODIPY-Br2 NPs, denoted as p-Hb-B-NPs, on HepG2 monolayers (620 nm, 25 mW/cm 2 , 10 min) under normal or N 2 atmosphere and compared to that of p-B-NPs. Both nanoconjugates exerted a cytotoxic effect under a normal atmosphere, with the best effect achieved at a concentration of 4 µM p-Hb-B-NPs; however, an insignificant effect was noted under an N 2 atmosphere [61]. Additionally, it was noted that p-Hb-B-NPs could release oxygen even in hypoxic conditions. ...
Anti-Hypoxia Nanoplatforms for Enhanced Photosensitizer Uptake and Photodynamic Therapy Effects in Cancer Cells
Article
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  • Jan 2023
  • INT J MOL SCI
Photodynamic therapy (PDT) holds great promise in cancer eradication due to its target selectivity, non-invasiveness, and low systemic toxicity. However, due to the hypoxic nature of many native tumors, PDT is frequently limited in its therapeutic effect. Additionally, oxygen consumption during PDT may exacerbate the tumor’s hypoxic condition, which stimulates tumor proliferation, metastasis, and invasion, resulting in poor treatment outcomes. Therefore, various strategies have been developed to combat hypoxia in PDT, such as oxygen carriers, reactive oxygen supplements, and the modulation of tumor microenvironments. However, most PDT-related studies are still conducted on two-dimensional (2D) cell cultures, which fail to accurately reflect tissue complexity. Thus, three-dimensional (3D) cell cultures are ideal models for drug screening, disease simulation and targeted cancer therapy, since they accurately replicate the tumor tissue architecture and microenvironment. This review summarizes recent advances in the development of strategies to overcome tumor hypoxia for enhanced PDT efficiency, with a particular focus on nanoparticle-based photosensitizer (PS) delivery systems, as well as the advantages of 3D cell cultures.
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... Some examples of different promising transition polypeptide systems are listed in Table 2, categorized into the most commonly used categories. polylysine doxorubicin pH stability transition [34] polylysine gemcitabine GSH stability transition [35] polyglutamic acid camptothecin GSH stability transition [36] decapeptide consisting of leucine and lysine doxorubicin pH stability transition [40] polymethionine piperlongumine ROS stability transition [45] polyglutamate doxorubicin hypoxia stability transition [42] polylysine dendrigraft curcumin and doxorubicin pH and enzyme stability transition [41] polyaspartate and polyphenylalanine tirapazamine light and hypoxia stability transition [47] polyglutamic acid cisplatin pH and enzyme surface transition [49] polylysine and polycysteine nitric oxide donor and doxorubicin pH and light surface transition [56] polyaspartate siRNA pH surface transition [60] polylysine and polyleucine doxorubicin pH surface transition [52] polylysine doxorubicin pH surface transition [58] polyaspartate paclitaxel and curcumin pH surface and size transition [54] polylysine doxorubicin pH stability and surface transition [53] polylysine and polycysteine doxorubicin pH and GSH stability and surface transition [57] polylysine doxorubicin pH and GSH stability and surface transition [61] polylysine triptolide and doxorubicin pH and GSH stability and surface transition [59] polylysine and polyglutamic acid doxorubicin pH and GSH stability and surface transition [62] polyglutamic acid doxorubicin pH size transition [65] polylysine doxorubicin enzyme surface and size transition [66] hexadecapeptide consisting of lysine and glutamic acid SN-38 pH size transition [69] polylysine and polycysteine doxorubicin pH and GSH 3S transition [71] polylysine and polyglutamic acid cisplatin pH and GSH 3S transition [70] polyaspartate photosensitizers and hemoglobin no stimuli no transition [72] ...
... However, the therapeutic effect of PDT is frequently limited due to the hypoxic nature that is characteristic of many solid tumors [77]. Thus, numerous efforts have been made to increase the oxygen content in tumors to enhance PDT efficacy [72]. Our group is now focusing on the synthesis of perfluorodecalin-filled oxygen carriers, using polypeptides as encapsulating shell materials, which allow for fast gas exchange [78]. ...
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  • May 2022
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Polypeptides have attracted considerable attention in recent decades due to their inherent biodegradability and biocompatibility. This mini-review focuses on various ways to synthesize polypeptides, as well as on their biomedical applications as anti-tumor drug carriers over the past five years. Various approaches to preparing polypeptides are summarized, including solid phase peptide synthesis, recombinant DNA techniques, and the polymerization of activated amino acid monomers. More details on the polymerization of specifically activated amino acid monomers, such as amino acid N-carboxyanhydrides (NCAs), amino acid N-thiocarboxyanhydrides (NTAs), and N-phenoxycarbonyl amino acids (NPCs), are introduced. Some stimuli-responsive polypeptide-based drug delivery systems that can undergo different transitions, including stability, surface, and size transition, to realize a better anti-tumor effect, are elaborated upon. Finally, the challenges and opportunities in this field are briefly discussed.
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... Furthermore, Liu et al. synthesized a NIR photosensitizer, BODIPY-Br 2 , with a high fluorescence quantum yield and ROS yield. This compound was combined with peptides and Hb, forming artificial RBCs serving as oxygen carriers for NIR imaging-guided PDT [16]. Notably, in vitro experiments revealed a significant increase in the rate of cancer cell killing under conditions of low oxygen and low power (25 mW cm -2 , 10 min) irradiation. ...
Active-oxygenating hollow Prussian blue nanosystems loaded with biomacromolecules for photodynamic/photothermal therapy of cancer and alleviating hypoxic tumors
Article
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  • Dec 2023
  • Mater Des
Such is the hypoxia in solid tumor that II-type photodynamic therapy (PDT) has not yet achieved significantly satisfactory consequences. Despite the rapid advancement in nanotechnology-based PDT for alleviating the hypoxic tumor microenvironment, several challenges persist. These include inefficient passive oxygen-supply mechanisms, low stability of oxygen-delivery nanosystems, and the complexity of their modification processes. To address these issues, we developed integrative nanoformulations (HHI NPs) by sequentially inserting biomacromolecule hemoglobin (Hb) and IR783 (photosensitizer) into hollow mesoporous Prussian blue (HPB NPs) through a straightforward and gentle diffusion method. Intriguingly, the resulting hybrid nanocomposites based on hollow mesoporous structure provided stability of biomacromolecule Hb, ensuring active and efficient oxygen delivery. In these nanosystems, HHI NPs equipped with high oxygen-carrying Hb efficiently generated reactive oxygen species over HepG2 cells cultured in hypoxic condition under NIR irradiation. Additionally, HPB NPs served not only as nanocarriers but also as photothermal agents exhibiting excellent photothermal conversion effects. which were beneficial for photothermal therapy (PTT) of cancer. HHI NPs co-loaded with Hb and IR783 not only actively relieved the hypoxic TME through the stable protection of the hollow structure from HPB NPs, but also achieve the significant synergistic therapy by combining PDT and PTT for tumor treatment.
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... This result confirmed that the grafting between the magnetic nanoparticle and the polymer was successful. Also, the shift in C ¼ O peak from 1,620 cm À1 in pure magnetic nanoparticle to 1,626 cm À1 in Fe 3 O 4 -Alg suggests that Alg has bonded successfully to the surface of Fe 3 O 4 [45] . FTIR spectra of the Fe 3 O 4 nanoparticle, Fe 3 O 4 -ßCD, Fe 3 O 4 -ßCD/DOX nanoparticles has been shown in Figure 3. ...
In vitro and in silico characteristics of doxorubicin-loaded four polymeric-based polysaccharides-modified super paramagnetic iron oxide nanoparticles for cancer chemotherapy and magnetic resonance imaging
Article
  • Oct 2022
Super Paramagnetic Iron Oxide Nanoparticles have attracted much attention in drug delivery systems because of their considerable surface-to-volume ratio and content as well. In this regard, in this study, four different formulations of magnetic nanoparticles were synthesized via various polymeric coating layer (beta-cyclodextrin, Chitosan, Gum Arabic, and Alginate) in order to find an appropriate polymer in terms of higher drug loading efficiency and capacity. Molecular dynamics simulation and Quantum mechanics were manipulated to examine the interaction mechanism between the polysaccharide polymers and Doxorubicin. Based on the calculated results, As the best candidate, βCD was chosen for DOX loading. DOX, a hydrophilic drug, was loaded into each of the four formulations. The optimum formulation, Fe3O4-ßCD, possessed loading efficiency and capacity, with 97% and 13%, respectively. The selected nanocarrier was fully characterized by Fourier Transform Infrared, VSM, TGA, XRD, SEM, UV-Vis, DLS, and TEM. TEM result exhibited the prepared Fe3O4-ßCD-DOX nanoparticles had a spherical shape (core and shell) and the size of around 15 nm. In vitro release investigation was conducted using HPLC analysis in the phosphate-buffered saline in acidic (pH = 5.4) and neutral (pH = 7.4) medium. The obtained results demonstrated that a sustain release performance for more than 72 h with the amount of 50% DOX release in pH = 5.4. Cytotoxicity assay showed the toxicity of bare Fe3O4 and Fe3O4-ßCDNPsagainst MDA-MB468 cancerous cell and MCF10A normal cell was negligible and DOX-loaded NPs (Fe3O4-ßCD-DOX) illustrated a higher toxicity in MDA-MB468 cancerous cells than MCF 10 A normal cells. The results showed that Fe3O4-ßCD-DOXNPs could improve the therapeutic efficacy and also reduce the adversarial effects; accordingly, the prepared system could be served as a promising drug delivery system in cancer treatment.
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... This result confirmed that the grafting between the magnetic nanoparticle and the polymer was successful. Also, the shift in C ¼ O peak from 1,620 cm À1 in pure magnetic nanoparticle to 1,626 cm À1 in Fe 3 O 4 -Alg suggests that Alg has bonded successfully to the surface of Fe 3 O 4 [45] . FTIR spectra of the Fe 3 O 4 nanoparticle, Fe 3 O 4 -ßCD, Fe 3 O 4 -ßCD/DOX nanoparticles has been shown in Figure 3. ...
View
... Short chain polypeptide is often small in size, easily to be synthesized and usually not immunogenic [18][19][20][21], and the peptides with specific sequences could target corresponding organelles [22,23]. Therefore, peptide-mediated cell membrane targeting NIRF probe is likely to be an efficient and accurate biological imaging technology to be applied in the diagnosis and treatment of tumors [24]. Liu et al. used a cell membrane-targeted photodynamic therapy (PDT) technique using a charge reversible self-delivery chimeric peptide C 16 -PRP-DMA. ...
A dual-usage near-infrared (NIR) cell membrane targeting chimeric peptide for cancer cell membrane imaging and photothermal ablation
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Due to the low background and deep tissue penetration of near-infrared light, near-infrared fluorescence (NIRF) probes have received much attention in recent years. Cell membrane targeting probes can be used in in vitro and in vivo for living cell imaging, disease diagnosis and tumor targeted therapy. However, most of the currently available cell membrane probes are blue or green emissive fluorophores, NIRF probes are relatively rare. Herein, we designed and prepared a NIRF chimeric peptide probe named C16-CARK, which could target the tumor cell membrane with longtime retention (more than 4 h). Moreover, the C16-CARK can heat and disrupt the cell membrane upon high irradiation dose, revealing its dual roles as a cell membrane imaging probe and a photothermal agent. This kind of near-infrared fluorescence probe with cell membrane targeting and retention property provides a well design paradigm for the field of cancer imaging and treatment.
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... Liu and his team [42] synthesized Hb-conjugated biodegradable polypeptides as O2 carrier via click reaction between polypeptides and Hb-BODIPY-Br2 NPs denoted (p-Hb-B-NPs). The O2carrying ability of the prepared NPs was confirmed by comparing the dissolved O2 concentration of p-Hb-B-NPs to that of O2 saturated ultrapure water. ...
Fighting hypoxia to improve PDT
Article
Full-text available
  • Oct 2019
Photodynamic therapy (PDT) has drawn great interest in recent years mainly due to its low side effects and few drug resistances. Nevertheless, one of the issues of PDT is the need for oxygen to induce a photodynamic effect. Tumours often have low oxygen concentrations, related to the abnormal structure of the microvessels leading to an ineffective blood distribution. Moreover, PDT consumes O2. In order to improve the oxygenation of tumour or decrease hypoxia, different strategies are developed and are described in this review: 1) The use of O2 vehicle; 2) the modification of the tumour microenvironment (TME); 3) combining other therapies with PDT; 4) hypoxia-independent PDT; 5) hypoxia-dependent PDT and 6) fractional PDT.
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Utilizing graphene oxide/gold/methylene blue ternary nanocomposite as a visible light photocatalyst for a plasmon-enhanced singlet oxygen generation
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In this study, graphene oxide/gold/methylene blue (GO/Au/MB) ternary composites were synthesized and characterized through UV–vis, FTIR, XRD, XPS, SEM, and TEM analyses towards plasmon-enhanced singlet oxygen (1O2) generation. Through using gold nanoparticles and MB photosensitizers, the visible light adsorption capability of GO was enhanced by 115%. Moreover, applying this ternary composite as a photocatalyst under visible light interestingly revealed a drastic step-increase of 14% (i.e., from 9 to 23%) in the conversion of photooxygenation of Anthracene. This behavior was rationalized using finite-difference time-domain (FDTD) simulations which confirms the plasmonic field of gold nanoparticles with a diameter of 16 nm obtained from TEM. Time-dependent density functional theory (TD-DFT) calculations suggest that the presence of an electric field can favor the intersystem crossing of methylene blue to enhance 1O2 generation.
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Recent advances in in-situ oxygen-generating and oxygen-replenishing strategies for hypoxic-enhanced photodynamic therapy
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Cancer is a leading cause of death worldwide, accounting for an estimated 10 million deaths by 2020. Over the decades, various strategies for tumor therapy have been developed and evaluated. Photodynamic therapy (PDT) has attracted increasing attention due to its unique characteristics, including low systemic toxicity and minimally invasive nature. Despite the excellent clinical promise of PDT, hypoxia is still the Achilles' heel associated with its oxygen-dependent nature related to increased tumor proliferation, angiogenesis, and distant metastases. Moreover, PDT-mediated oxygen consumption further exacerbates the hypoxia condition, which will eventually lead to the poor effect of drug treatment and resistance and irreversible tumor metastasis, even limiting its effective application in the treatment of hypoxic tumors. Hypoxia, with increased oxygen consumption, may occur in acute and chronic hypoxia conditions in developing tumors. Tumor cells farther away from the capillaries have much lower oxygen levels than cells in adjacent areas. However, it is difficult to change the tumor's deep hypoxia state through different ways to reduce the tumor tissue's oxygen consumption. Therefore, it will become more difficult to cure malignant tumors completely. In recent years, numerous investigations have focused on improving PDT therapy's efficacy by providing molecular oxygen directly or indirectly to tumor tissues. In this review, different molecular oxygen supplementation methods are summarized to alleviate tumor hypoxia from the innovative perspective of using supplemental oxygen. Besides, the existing problems, future prospects and potential challenges of this strategy are also discussed.
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Theoretical Design of High Performance Boron Dipyrromethenes Dyes by Introducing Heterocyclic to Tune Photoelectric Properties
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As a “sister” of porphyrins, boron dipyrromethenes (BODIPY) has attracted widespread attention due to its strong absorption in the visible region. Although many modifications have been made to its structure, the photoelectric conversion efficiency (PCE) below 10% limits its practical application in dyesensitized solar cells (DSSCs). In this work, heterocycles were introduced into BODIPY bridge to improve the photoelectric properties of dyes. Theoretical calculations show that the introduction of heterocycles, such as cyclopentadiene, pyrrole, furan and thiophene, not only increases the molecular planarity, narrows the band gap, but also enhances the light harvesting ability. Based on these exciting results, the dye/(TiO2)38 adsorption models and parameters related to DSSC performance including shortcircuit current, open circuit voltage, and PCE were considered to evaluate the overall properties of the investigated dyes. These dyes achieve a PCE value of at least 15.25%, wherein the PCE value of dye inserted thiophene into BODIPY can be as high as 23.12%, which are expected to have potential application in DSSC devices.
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Zeolitic imidazolate metal organic framework-8 as an efficient pH-controlled delivery vehicle for zinc phthalocyanine in photodynamic therapy
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To improve the aqueous solubility and cancer targeting of the photosensitizers in photodynamic therapy (PDT), we encapsulated the photosensitizer in a biocompatibility and pH-sensitive drug delivery system, zeolitic imidazolate frameworks-8 (ZIF-8) nanospheres. Powder X-ray diffraction and electron microscopy show that our nanospheres are uniform and single-crystalline particles. Owing to the cleavage of zinc–ligand coordination bonds, more ZnPc–COOH were released much faster in the mild acidic conditions (pH 5.0 and 6.0) in comparison with physiological environment (pH 7.4). By incorporating ZnPc–COOH in ZIF-8, our nanospheres exhibited high singlet oxygen quantum yield and intracellular ROS generation. Cell viability experiments toward HepG2 cells demonstrated the low toxicity of ZIF-8 and the good anticancer efficacy of the nanospheres with low IC50 values (4.2–4.9 μg/mL) under light illumination (670 nm, 1.5 J/cm²). Collectively, these results suggested that our nanospheres are the promising pH-responsive drug delivery systems for PDT.
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Design of Tumor Acidity-Responsive Sheddable Nanoparticles for Fluorescence/Magnetic Resonance Imaging-Guided Photodynamic Therapy
Article
Full-text available
  • Mar 2017
  • thno
Imaging-guided cancer therapy, which integrates diagnostic and therapeutic functionalities into a single system, holds great promise to enhance the accuracy of diagnosis and improve the efficacy of therapy. Specifically, for photodynamic therapy (PDT), it is highly desirable to precisely focus laser light onto the tumor areas to generate reactive oxygen species (ROS) that are cytotoxic tumor cells and avoid light-associated side effects. Herein, a distinct three-layer nanostructured particle with tumor acidity-responsiveness (S-NP) that encapsulates the photosensitizer chlorin e6 (Ce6) and chelates Gd³⁺ is successfully developed for fluorescence/magnetic resonance (MR) dual-model imaging-guided precision PDT. We show clear evidence that the outer PEG layer significantly prolongs circulation time, and the inner poly(ε-caprolactone) (PCL) core can physically encapsulate Ce6. More interestingly, the middle layer of the S-NP, acting as a molecular fence to keep Ce6 in the circulation system, was dismantled by the slightly acidic tumor microenvironment. Afterwards, the PEG shell is deshielded from the S-NP at the tumor tissue, resulting in improved cell uptake, enlarged MR signal intensity, rapid release of Ce6 within tumor cells, and elevated PDT efficacy. Our results suggest that tumor-acidity-responsive nanoparticles with fine design could serve as a theranostic platform with great potential in imaging-guided PDT treatment of cancer.
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Functional peptide-based nanoparticles for photodynamic therapy
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Photodynamic therapy as a non-invasive approach has obtained great research attention during the last decade. However, photodynamic therapy still suffers from low tumor selectivity and therapeutic efficacy due to the unspecific distribution of photosensitizer in normal tissues/cells. To overcome these hurldes, functional peptides have been introduced in photodynamic therapy systems due to their advantages of functional diversity, bioactivty, high biocompability and biodegradability. Herein, we review various peptide-based self-assemblies or hybrid nanoparticles which have already been reported to achieve tumor tissue, cell or subcellular organelles targeted photodynamic therapy. The role of tumor microenvironments, cellular/sucellular location, physical/chemical properties of peptide-based nanoparticles in facilitating the photodynamic therapy efficiency are discussed in-depth. The novel development of peptide-based nanoparticles described here should offer great potential to achieve better photodynamic therapy in tumor.
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Enhanced Fluorescence Emission and Singlet Oxygen Generation of Photosensitizers Embedded in Injectable Hydrogels for Imaging-Guided Photodynamic Cancer Therapy
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Benefiting from their inherent localized and controlled release properties, hydrogels are ideal delivery systems for therapeutic drugs or nanoparticles. In particular, the applications of hydrogels for the delivery and release of photo-responsive drugs or nanoparticles are receiving increasing attention. However, the effect of the hydrogel matrix on the fluorescence emission and singlet oxygen generation efficiency of the embedded photosensitizers (PSs) has not been clarified. Herein, meso-tetrakis (1-methylpyridinium-4-yl) porphyrin (TMPyP) as a water-soluble PS is encapsulated into an injectable hydrogel formed by glycol chitosan and dibenzaldehyde-terminated telechelic poly(ethylene glycol). Compared to free TMPyP, the TMPyP encapsulated in the hydrogel exhibits three distinct advantages: (1) More singlet oxygen was generated under the same laser irradiation condition; (2) Much longer tumor retention was observed due to the low fluidity of the hydrogel; (3) The fluorescence intensity of TMPyP was significantly enhanced in the hydrogel due to its decreased self-quenching effect. These excellent characteristics lead to remarkable anticancer efficacy and superior fluorescence emission property of the TMPyP-hydrogel system, promoting the development of imaging-guided photodynamic therapy.
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Renal‐Clearable PEGylated Porphyrin Nanoparticles for Image‐Guided Photodynamic Cancer Therapy
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Nanomaterials with renal clearance from the body within a reasonable timescale have shown great promises in the area of nanomedicine recently. However, the integration of theranostic and renal clearance properties into a single ultrasmall nanostructure remains a great challenge. Herein, meso-tetra(4-carboxyphenyl)porphyrin (TCPP) structure is utilized as a model, for the first time using noninvasive dynamic positron emission tomography (PET) imaging to investigate the balance of the renal clearance and tumor uptake behaviors of polyethylene glycol (PEG)-modified porphyrin nanoparticles (TCPP-PEG) with various molecular weights. This study finds that TCPP-PEG nanoparticles with larger molecular weight show higher tumor uptake due to the enhanced permeability and retention effect, while the lower ones tend to be better for renal clearance. Based on dynamic PET and fluorescence dual-modal imaging modalities, the TCPP-PEG10K nanoparticles seem to be an excellent choice for the balance of renal clearance and tumor retention. In vitro and in vivo photodynamic therapy confirms an excellent therapeutic efficacy. Therefore, this work presents a simplified approach to fabricate and select biocompatible multifunctional TCPP-PEG-based theranostic agents with renal clearance behavior, which highlights the clinical application potential of TCPP-PEG nanoparticles as theranostic probes for imaging-guided cancer therapy.
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Manipulating Tumor Hypoxia toward Enhanced Photodynamic Therapy (PDT)
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Photodynamic therapy (PDT) has been considered as a promising approach for the treatment of cancer, which is achieved via the photosensitizer (PS)-mediated incomplete reduction of oxygen upon light irradiation that generates high levels of reactive oxygen species (ROS) to induce potent vascular damage and direct tumor cell killing. However, there is an undesirable impediment that tumor tissues generally suffer from serious hypoxia, which significantly hurdles the efficiency of PDT. Additionally, PDT that consumes oxygen will further aggravate tumor hypoxia, thus leading to multiple undesirable consequences such as angiogenesis, tumor invasiveness, and tumor metastasis. This mini-review provides a comprehensive overview of the recent research progresses on overcoming or utilizing tumor hypoxia to enhance the therapeutic efficacy of PDT.
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pH-Sensitive Amphiphilic Block-Copolymers for Transport and Controlled Release of Oxygen
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Saturated fluorocarbons, their derivatives and emulsions are capable of dissolving anomalously high amounts of oxygen and other gases. The mechanistic aspects of this remarkable effect remain to be explored experimentally. Here, the synthesis of a library of amphiphilic fluorous block-copolymers incorporating different fluorinated monomers is described, and the capacity of these copolymers for oxygen transport in water is systematically investigated. The structure of the fluorous monomer employed was found to have a profound effect on both the oxygen-carrying capacity and the gas release kinetics of the polymer emulsions. Furthermore, the release of O2 from the polymer dispersions could be triggered by changing the pH of the solution. This is the first example of a polymer-based system for controlled release of a non-polar, non-covalently entrapped respiratory gas.
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Tumor-Triggered Geometrical Shape Switch of Chimeric Peptide for Enhanced in Vivo Tumor Internalization and Photodynamic Therapy
Article
  • Mar 2017
  • ACS NANO
Geometrical shape of nanoparticles plays an important role in cellular internalization. However, the applicability in tumor selective therapeutics is still scarcely reported. In this paper, we designed a tumor extracellular acidity-responsive chimeric peptide with geometrical shape switch for enhanced tumor internalization and photodynamic therapy. This chimeric peptide could self-assemble into spherical nanoparticles at physiological condition. While at tumor extracellular acidic microenvironment, chimeric peptide underwent detachment of acidity-sensitive 2,3-dimethylmaleic anhydride groups. The subsequent recovery of ionic complementarity between chimeric peptides resulted in formation of rod-like nanoparticles. Both in vitro and in vivo studies demonstrated that this acidity-triggered geometrical shape switch endowed chimeric peptide with accelerated internalization in tumor cells, prolonged accumulation in tumor tissue, enhanced photodynamic therapy and minimal side effects. Our results suggested that fusing tumor microenvironment with geometrical shape switch should be a promising strategy for targeted drug delivery.
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NIR imaging-guided combined photodynamic therapy and chemotherapy by a pH-responsive amphiphilic polypeptide prodrug
Article
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pH-Sensitive doxorubicin conjugated polymeric micelles entrapped with near infrared (NIR) photosensitizer BODIPY (which works as an imaging agent at the same time) were designed and synthesized by ring opening polymerization of N-carboxyanhydride with mPEG-NH2 as the initiator, following reaction with doxorubicin to form the hydrazone-bond linker for pH responsiveness. Then the NIR dye (BODIPY) was loaded in the micelles for both bioimaging and photodynamic therapy (PDT). A significant cytotoxicity of NIR imaging-guided combined PDT and chemotherapy could be found by MTT assays, which was also confirmed with a fluorescence microscope, indicating a new kind of polymeric nanoparticle for potential theranostic treatment of cancers. In addition, the energy density of the laser for the PDT is extremely low.
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Development of ionic strength/pH/enzyme triple-responsive zwitterionic hydrogel of the mixed L-glutamic acid and L-lysine polypeptide for site-specific drug delivery
Article
  • Jan 2016
Environmentally responsive hydrogels show enormous potential in various applications, such as tissue engineering and drug delivery. The site-specific controlled drug delivery of hydrogels can improve the therapeutic outcome and minimize the negative side effects. In this work, enzymatically digestible hydrogels, which are composed of equally mixed l-glutamic acid (E) and l-lysine (K) polypeptides after being crosslinked by the coupling reaction between carboxyl groups and primary amines catalyzed by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide·HCl (EDC·HCl), were prepared to improve the biocompatibility through reducing the nonspecific protein adsorption and cell attachment. Hydrogels loaded with two model drugs, doxorubicin hydrochloride (DOX·HCl) (positively charged anti-cancer drug) and diclofenac sodium (negatively charged anti-inflammatory drug), showed accelerated complete drug release and full enzymatic degradation in the presence of trypsin, which was reported to be expressed in various carcinomas and inflammations. The drug release also responds to the pH change through tuning charge-charge interaction. These indicated that the prepared hydrogels were promising candidates for drug delivery systems.
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