Polyglycerol-Shelled Reduction-Sensitive Polymersome for DM1 Delivery to HER-2-Positive Breast Cancer.

Supramolecular delivery systems with the prolonged circulation, the potential for diverse functionalization, and few toxin-related limitations have been extensively studied. For the present study, we constructed a linear polyglycerol-shelled polymersome attached with the anti-HER-2-antibody trastuzumab. We then covalently loaded the anticancer drug DM1 in the polymersome via dynamic disulfide bonding. The resulted trastuzumab-polymersome-DM1 (Tra-PS-DM1) exhibits a mean size of 95.3 nm and remarkable drug loading efficiency % of 99.3%. In addition to its superior stability, we observed the rapid release of DM1 in a controlled manner under reductive conditions. Compared to the native polymersomes, Tra-PS-DM1 has shown greatly improved cellular uptake and significantly reduced IC50 up to 17-fold among HER-2-positive cancer cells. Moreover, Tra-PS-DM1 demonstrated superb growth inhibition of HER-2-positive tumoroids; specifically, BT474 tumoroids shrunk up to 62% after 12 h treatment. With exceptional stability and targetability, the PG-shelled Tra-PS-DM1 appears as an attractive approach for HER-2-positive tumor treatment.

Smart Polymersomes Dually Functionalized with cRGD and Fusogenic GALA Peptides Enable Specific and High-Efficiency Cytosolic Delivery of Apoptotic Proteins.

Low cell selectivity and uptake coupled with endosomal entrapment pose critical hurdles for intracellular delivery and clinical translation of therapeutic proteins. Herein, we report that smart polymersomes dually functionalized with cRGD and fusogenic GALA peptides (cRGD/GALA-Ps) enable ανß3-specific and high-efficiency cytosolic delivery of cytochrome C (CC), a model apoptotic protein, to A549 human lung cancer cells. cRGD/GALA-Ps was prepared with 20 mol % cRGD and varying GALA contents from 2 to 4 to 6 mol % via coassembly of PEG- b-poly(trimethylene carbonate- co-dithiolane trimethylene carbonate)-spermine (PEG- b-P(TMC- co-DTC)-spermine), cRGD-PEG- b-P(TMC- co-DTC), and maleimide-PEG- b-P(TMC- co-DTC) and postmodification using GALA-SH (sequence: CWEAALAEALAEALAEHLAEALAEALEALAA). cRGD/GALA-Ps loaded with ∼13 wt % CC displayed a small size of about 65 nm and fast glutathione-triggered protein release. Interestingly, cRGD/GALA-Ps maintained a similar targeting ability to cRGD-Ps in ανß3-positive A549 lung cancer cells, while markedly enhanced cytosolic release of FITC-labeled CC, as revealed by confocal microscopy. MTT assays exhibited that CC-loaded cRGD/GALA-Ps was significantly more potent than CC-loaded cRGD-Ps, in which cell viabilities of 76.2, 51.0, 29.6, and 35.5% were discerned for cRGD/GALA-Ps with 0, 2, 4, and 6 mol % GALA, respectively, at 15.4 µM CC. Apoptosis assays corroborated that cRGD/GALA-Ps-CC with 4 mol % GALA induced better apoptosis of A549 cells than cRGD-Ps-CC (cell apoptosis: 36.4 vs 14.4%). These results highlight that dual-functionalization of polymersomes with targeting and fusogenic peptides provides an appealing strategy for cytosolic protein delivery.

Construction of Small-Sized, Robust, and Reduction-Responsive Polypeptide Micelles for High Loading and Targeted Delivery of Chemotherapeutics.

Polypeptide micelles, though having been proved to be an appealing nanoplatform for cancer chemotherapy, are met with issues like inefficient drug encapsulation, gradual drug release, and low tumor cell selectivity and uptake. Here, we report on cRGD-decorated, small-sized, robust, and reduction-responsive polytyrosine micelles (cRGD-rPTM) based on poly(ethylene glycol)- b-poly(l-tyrosine)-lipoic acid (PEG- b-PTyr-LA) conjugate for high loading and targeted delivery of doxorubicin (Dox). Notably, cRGD-rPTM exhibited efficient loading of Dox, giving cRGD-rPTM-Dox with a drug loading content (DLC) of 18.5 wt % and a small size of 45 nm at a theoretical DLC of 20 wt %. cRGD-rPTM-Dox displayed reduction-triggered drug release, high selectivity and superior antiproliferative activity toward αvß3 integrin positive MDA-MB-231 breast cancer cells (IC50 = 1.5 µg/mL) to both nontargeted rPTM-Dox and clinical liposomal formulation (LP-Dox). cRGD-rPTM-Dox demonstrated a prolonged circulation time compared with the noncrosslinked cRGD-PTM-Dox control and significantly better accumulation in MDA-MB-231 breast tumor xenografts than nontargeted rPTM-Dox. Moreover, cRGD-rPTM-Dox at 6 mg Dox equiv/kg could remarkably suppress growth of MDA-MB-231 human breast tumor without inducing obvious side effects, outperforming both rPTM-Dox and LP-Dox. These reduction-responsive multifunctional polytyrosine micelles appear to be a viable and versatile nanoplatform for targeted chemotherapy.

Tuning the Properties of Polymer Capsules for Cellular Interactions.

Particle-cell interactions are governed by, among other factors, the composition and surface properties of the particles. Herein, we report the preparation of various polymer capsules with different compositions and properties via atom transfer radical polymerization mediated continuous assembly of polymers (CAPATRP), where the cellular interactions of these capsules, particularly fouling and specific targeting, are examined by flow cytometry and deconvolution microscopy. Acrylated eight-arm poly(ethylene glycol) (8-PEG) and poly(N-(2-hydroxypropyl)-methacrylamide) (PHPMA) as well as methacrylated hyaluronic acid (HA), poly(glutamic acid) (PGA), and poly(methacrylic acid) (PMA) are used as macro-cross-linkers to obtain a range of polymer capsules with different compositions (PEG, PHPMA, HA, PGA, and PMA). Capsules composed of low-fouling polymers, PEG and PHPMA, show negligible association with macrophage Raw 264.7, monocyte THP-1, and HeLa cells. HA capsules, although moderately low-fouling (<22%) to HeLa, BT474, Raw 264.7, and THP-1 cells, exhibit high targeting specificity to CD44-over-expressing MDA-MB-231 cells. In contrast, PGA and PMA capsules show high cellular association toward phagocytic Raw 264.7 and THP-1 cells. These findings demonstrate the capability of the CAPATRP technique in preparing polymer capsules with specific cellular interactions.

Engineered Metal-Phenolic Capsules Show Tunable Targeted Delivery to Cancer Cells.

We engineered metal-phenolic capsules with both high targeting and low nonspecific cell binding properties. The capsules were prepared by coating phenolic-functionalized hyaluronic acid (HA) and poly(ethylene glycol) (PEG) on calcium carbonate templates, followed by cross-linking the phenolic groups with metal ions and removing the templates. The incorporation of HA significantly enhanced binding and association with a CD44 overexpressing (CD44+) cancer cell line, while the incorporation of PEG reduced nonspecific interactions with a CD44 minimal-expressing (CD44-) cell line. Moreover, high specific targeting to CD44+ cells can be balanced with low nonspecific binding to CD44- cells simply by using an optimized feed-ratio of HA and PEG to vary the content of HA and PEG incorporated into the capsules. Loading an anticancer drug (i.e., doxorubicin) into the obtained capsules resulted in significantly higher cytotoxicity to CD44+ cells but lower cytotoxicity to CD44- cells.

pH-Responsive Capsules Engineered from Metal-Phenolic Networks for Anticancer Drug Delivery.

A new class of pH-responsive capsules based on metal-phenolic networks (MPNs) for anticancer drug loading, delivery and release is reported. The fabrication of drug-loaded MPN capsules, which is based on the formation of coordination complexes between natural polyphenols and metal ions over a drug-coated template, represents a rapid strategy to engineer robust and versatile drug delivery carriers.

Enzymatically and reductively degradable α-amino acid-based poly(ester amide)s: synthesis, cell compatibility, and intracellular anticancer drug delivery.

A novel and versatile family of enzymatically and reductively degradable α-amino acid-based poly(ester amide)s (SS-PEAs) were developed from solution polycondensation of disulfide-containing di-p-toluenesulfonic acid salts of bis-l-phenylalanine diesters (SS-Phe-2TsOH) with di-p-nitrophenyl adipate (NA) in N,N-dimethylformamide (DMF). SS-PEAs with Mn ranging from 16.6 to 23.6 kg/mol were obtained, depending on NA/SS-Phe-2TsOH molar ratios. The chemical structures of SS-PEAs were confirmed by (1)H NMR and FTIR spectra. Thermal analyses showed that the obtained SS-PEAs were amorphous with a glass transition temperature (Tg) in the range of 35.2-39.5 °C. The in vitro degradation studies of SS-PEA films revealed that SS-PEAs underwent surface erosion in the presence of 0.1 mg/mL α-chymotrypsin and bulk degradation under a reductive environment containing 10 mM dithiothreitol (DTT). The preliminary cell culture studies displayed that SS-PEA films could well support adhesion and proliferation of L929 fibroblast cells, indicating that SS-PEAs have excellent cell compatibility. The nanoparticles prepared from SS-PEA with PVA as a surfactant had an average size of 167 nm in phosphate buffer (PB, 10 mM, pH 7.4). SS-PEA nanoparticles while stable under physiological environment undergo rapid disintegration under an enzymatic or reductive condition. The in vitro drug release studies showed that DOX release was accelerated in the presence of 0.1 mg/mL α-chymotrypsin or 10 mM DTT. Confocal microscopy observation displayed that SS-PEA nanoparticles effectively transported DOX into both drug-sensitive and -resistant MCF-7 cells. MTT assays revealed that DOX-loaded SS-PEA nanoparticles had a high antitumor activity approaching that of free DOX in drug-sensitive MCF-7 cells, while more than 10 times higher than free DOX in drug-resistant MCF-7/ADR cells. These enzymatically and reductively degradable α-amino acid-based poly(ester amide)s have provided an appealing platform for biomedical technology in particular controlled drug delivery applications.

Galactose-decorated reduction-sensitive degradable chimaeric polymersomes as a multifunctional nanocarrier to efficiently chaperone apoptotic proteins into hepatoma cells.

Hepatoma-targeting reduction-sensitive chimaeric biodegradable polymersomes were designed and developed based on galactose-poly(ethylene glycol)-poly(ε-caprolactone) (Gal-PEG-PCL), PEG-PCL-poly(2-(diethylamino)ethyl methacrylate) (PEG-PCL-PDEA, asymmetric), and PEG-SS-PCL for facile loading and triggered intracellular delivery of proteins. The chimaeric polymersomes formed from PEG-PCL-PDEA and PEG-SS-PCL had a monodisperse distribution with average sizes ranging from 95.5 to 199.2 nm depending on PEG-SS-PCL contents. Notably, these polymersomes displayed decent loading of bovine serum albumin (BSA), ovalbumin (OVA), and cytochrome C (CC) proteins likely due to presence of electrostatic and hydrogen bonding interactions between proteins and PDEA block located in the interior of polymersomes. The in vitro release studies showed that protein release was largely accelerated under a reductive condition containing 10 mM dithiothreitol (DTT). For example, ca. 77.2 and 22.1% of FITC-BSA were released from CP(SS50) (chimaeric polymersomes containing 50 wt % PEG-SS-PCL) at 37 °C in 12 h in the presence and absence of 10 mM DTT, respectively. Confocal microscopy showed that FITC-CC-loaded Gal-decorated CP(SS40) could efficiently deliver and release FITC-CC into HepG2 cells following 24 h treatment, in contrast to little or negligible fluorescence detected in HepG2 cells treated with FITC-CC-loaded nontargeting polymersomes or free CC. MTT assays revealed that CC-loaded Gal-decorated CP(SS40) exhibited apparent targetability and pronounced antitumor activity to HepG2 cells, in which cell viabilities decreased from 81.9, 60.6, 49.5, 42.2 to 31.5% with increasing Gal-PEG-PCL contents from 0, 10, 20, 30 to 40 wt %. Most remarkably, granzyme B-loaded Gal-decorated chimaeric polymersomes effectively caused apoptosis of HepG2 cells with a markedly low half-maximal inhibitory concentration (IC(50)) of 2.7 nM. These reduction-responsive chimaeric biodegradable polymersomes offer a multifunctional platform for efficient intracellular protein delivery.

Ligand-directed reduction-sensitive shell-sheddable biodegradable micelles actively deliver doxorubicin into the nuclei of target cancer cells.

The therapeutic performance of biodegradable micellar drugs is far from optimal due to existing challenges like poor tumor cell uptake and intracellular drug release. Here, we report on ligand-directed reduction-sensitive shell-sheddable biodegradable micelles based on poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) copolymer actively delivering doxorubicin (DOX) into the nuclei of target cancer cells, inducing superb in vitro antitumor effects. The micelles were constructed from PEG-SS-PCL and galactose-PEG-PCL (Gal-PEG-PCL) block copolymers, in which Gal-PEG-PCL was designed with a longer PEG than that in PEG-SS-PCL (6.0 vs 5.0 kDa) to fully expose Gal ligands onto the surface of micelles for effective targeting to hepatocellular carcinoma cells. PEG-SS-PCL combining with 10 or 20 wt % of Gal-PEG-PCL formed uniform micelles with average sizes of 56.1 and 58.2 nm (denoted as PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20, respectively). The in vitro release studies showed that about 81.1 and 75.0% DOX was released in 12 h from PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20 micelles under a reducing condition containing 10 mM dithiothreitol (DTT). In contrast, minimal DOX release (<12%) was observed for PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20 micelles under nonreducing conditions as well as for reduction-insensitive Gal-PEG-PCL and PEG-PCL/Gal20 micelles in the presence of 10 mM DTT. MTT assays in HeLa and HepG2 cells showed that DOX-loaded PEG-SS-PCL/Gal20 micelles exhibited apparent targetability and significantly enhanced antitumor efficacy toward asialoglycoprotein receptor (ASGP-R)-overexpressing HepG2 cells with a particularly low half maximal inhibitory concentration (IC50) of 1.58 µg DOX equiv/mL, which was comparable to free DOX and approximately six times lower than that for nontargeting PEG-SS-PCL counterparts under otherwise the same conditions. Interestingly, confocal microscopy observations using FITC-labeled PEG-SS-PCL/Gal20 micelles showed that DOX was efficiently delivered and released into the nuclei of HepG2 cells in 8 h. Flow cytometry revealed that cellular DOX level in HepG2 cells treated with DOX-loaded PEG-SS-PCL/Gal20 micelles was much greater than that with reduction-insensitive PEG-PCL/Gal20 and nontargeting PEG-SS-PCL controls, signifying the importance of combining shell-shedding and active targeting. Ligand-directed, reduction-sensitive, shell-sheddable, and biodegradable micelles have emerged as a versatile and potent platform for targeted cancer chemotherapy.

α-Amino acid containing degradable polymers as functional biomaterials: rational design, synthetic pathway, and biomedical applications.

Currently, biomedical engineering is rapidly expanding, especially in the areas of drug delivery, gene transfer, tissue engineering, and regenerative medicine. A prerequisite for further development is the design and synthesis of novel multifunctional biomaterials that are biocompatible and biologically active, are biodegradable with a controlled degradation rate, and have tunable mechanical properties. In the past decades, different types of α-amino acid-containing degradable polymers have been actively developed with the aim to obtain biomimicking functional biomaterials. The use of α-amino acids as building units for degradable polymers may offer several advantages: (i) imparting chemical functionality, such as hydroxyl, amine, carboxyl, and thiol groups, which not only results in improved hydrophilicity and possible interactions with proteins and genes, but also facilitates further modification with bioactive molecules (e.g., drugs or biological cues); (ii) possibly improving materials biological properties, including cell-materials interactions (e.g., cell adhesion, migration) and degradability; (iii) enhancing thermal and mechanical properties; and (iv) providing metabolizable building units/blocks. In this paper, recent developments in the field of α-amino acid-containing degradable polymers are reviewed. First, synthetic approaches to prepare α-amino acid-containing degradable polymers will be discussed. Subsequently, the biomedical applications of these polymers in areas such as drug delivery, gene delivery and tissue engineering will be reviewed. Finally, the future perspectives of α-amino acid-containing degradable polymers will be evaluated.

Shell-sheddable micelles based on dextran-SS-poly(epsilon-caprolactone) diblock copolymer for efficient intracellular release of doxorubicin.

Reduction-responsive biodegradable micelles were developed from disulfide-linked dextran-b-poly(epsilon-caprolactone) diblock copolymer (Dex-SS-PCL) and applied for triggered release of doxorubicin (DOX) in vitro and inside cells. Dex-SS-PCL was readily synthesized by thiol-disulfide exchange reaction between dextran orthopyridyl disulfide (Dex-SS-py, 6000 Da) and mercapto PCL (PCL-SH, 3100 Da). Dynamic light scattering (DLS) measurements showed that Dex-SS-PCL yielded micelles with an average size of about 60 nm and a low polydispersity index (PDI 0.1-0.2) in PB (50 mM, pH 7.4). Interestingly, these micelles formed large aggregates rapidly in response to 10 mM dithiothreitol (DTT), most likely due to shedding of the dextran shells through reductive cleavage of the intermediate disulfide bonds. DOX could be efficiently loaded into the micelles with a drug loading efficiency of about 70%. Notably, the in vitro release studies revealed that Dex-SS-PCL micelles released DOX quantitatively in 10 h under a reductive environment, mimicking that of the intracellular compartments such as cytosol and the cell nucleus, whereas only about 27% DOX was released from reduction insensitive Dex-PCL micelles in 11.5 h under otherwise the same conditions and about 20% DOX released from Dex-SS-PCL micelles in 20 h under the nonreductive conditions. The cell experiments using fluorescence microscopy and confocal laser scanning microscopy (CLSM) showed clearly that DOX was rapidly released to the cytoplasm as well as to the cell nucleus. MTT studies revealed a markedly enhanced drug efficacy of DOX-loaded Dex-SS-PCL micelles as compared to DOX-loaded reduction-insensitive Dex-PCL micelles. These reduction-responsive biodegradable micelles have appeared highly promising for the targeted intracellular delivery of hydrophobic chemotherapeutics in cancer therapy.

Self-assembly of paramagnetic amphiphilic copolymers for synergistic therapy.

Engineering nanoparticles (NPs) with multifunctionality has become a promising strategy for cancer theranostics. Herein, theranostic polymer NPs are fabricated via the assembly of amphiphilic paramagnetic block copolymers (PCL-b-PIEtMn), in which IR-780 and doxorubicin (DOX) were co-encapsulated, for magnetic resonance (MR) and near infrared fluorescence (NIRF) imaging as well as for photo thermal therapy (PTT)-enhanced chemotherapy. The synthesized amphiphilic paramagnetic block copolymers demonstrated high relaxivity (r1 = 7.05 mM-1 s-1). The encapsulated DOX could be released with the trigger of near infrared (NIR) light. In vivo imaging confirmed that the paramagnetic NPs could be accumulated effectively at the tumor sites. Upon the NIR laser irradiation, tumor growth was inhibited by PTT-enhanced chemotherapy. The advantages of the reported system lie in the one-step convergence of multiple functions (i.e., imaging and therapy agents) into a one delivery vehicle and the dual mode imaging-guided synergistic PTT and chemotherapy. This study represents a new drug delivery vehicle of paramagnetic NPs for visualized theranostics.

cRGD-decorated biodegradable polytyrosine nanoparticles for robust encapsulation and targeted delivery of doxorubicin to colorectal cancer in vivo.

The clinical success of nanomedicines demands on the development of simple biodegradable nanocarriers that can efficiently and stably encapsulate chemotherapeutics while quickly release the payloads into target cancer cells. Herein, we report that cRGD-decorated biodegradable polytyrosine nanoparticles (cRGD-PTN) boost encapsulation and targeted delivery of doxorubicin (DOX) to colorectal cancer in vivo. The co-assembly of poly(ethylene glycol)-poly(L-tyrosine) (PEG-PTyr) and cRGD-functionalized PEG-PTyr (mol/mol, 80/20) yielded small-sized cRGD-PTN of 70 nm. Interestingly, cRGD-PTN exhibited an ultra-high DOX encapsulation with drug loading contents ranging from 18.5 to 54.1 wt%. DOX-loaded cRGD-PTN (cRGD-PTN-DOX) was highly stable against dilution, serum, and Triton X-100 surfactant, while quickly released DOX in HCT-116 cancer cells, likely resulting from enzymatic degradation of PTyr. Flow cytometry, confocal microscopy and MTT assays displayed that cRGD-PTN-DOX was efficiently internalized into αvß5 overexpressing HCT-116 colorectal cancer cells, rapidly released DOX into the nuclei, and induced several folds better antitumor activity than non-targeted PTN-DOX and clinically used liposomal DOX (Lipo-DOX). SPECT/CT imaging revealed strong tumor accumulation of 125I-labeled cRGD-PTN, which was 2.8-fold higher than 125I-labeled PTN. Notably, cRGD-PTN-DOX exhibited over 5 times better toleration than Lipo-DOX and significantly more effective inhibition of HCT-116 colorectal tumor than non-targeted PTN-DOX control, affording markedly improved survival rate in HCT-116 tumor-bearing mice with depleting side effects at 6 or 12 mg DOX equiv./kg. cRGD-PTN-DOX with great simplicity, robust drug encapsulation and efficient nucleic drug release appears promising for targeted chemotherapy of colorectal tumor.

Cellular Targeting of Bispecific Antibody-Functionalized Poly(ethylene glycol) Capsules: Do Shape and Size Matter?

In the present study, a capsule system that consists of a stealth carrier based on poly(ethylene glycol) (PEG) and functionalized with bispecific antibodies (BsAbs) is introduced to examine the influence of the capsule shape and size on cellular targeting. Hollow spherical and rod-shaped PEG capsules with tunable aspect ratios (ARs) of 1, 7, and 18 were synthesized and subsequently functionalized with BsAbs that exhibit dual specificities to PEG and epidermal growth factor receptor (EGFR). Dosimetry (variation between the concentrations of capsules present and capsules that reach the cell surface) was controlled through "dynamic" incubation (i.e., continuously mixing the incubation medium). The results obtained were compared with those obtained from the "static" incubation experiments. Regardless of the incubation method and the capsule shape and size studied, BsAb-functionalized PEG capsules showed >90% specific cellular association to EGFR-positive human breast cancer cells MDA-MB-468 and negligible association with both control cell lines (EGFR negative Chinese hamster ovary cells CHO-K1 and murine macrophages RAW 264.7) after incubation for 5 h. When dosimetry was controlled and the dose concentration was normalized to the capsule surface area, the size or shape had a minimal influence on the cell association behavior of the capsules. However, different cellular internalization behaviors were observed, and the capsules with ARs 7 and 18 were, respectively, the least and most optimal shape for achieving high cell internalization under both dynamic and static conditions. Dynamic incubation showed a greater impact on the internalization of rod-shaped capsules (∼58-67% change) than on the spherical capsules (∼24-29% change). The BsAb-functionalized PEG capsules reported provide a versatile particle platform for the evaluation and comparison of cellular targeting performance of capsules with different sizes and shapes in vitro.

Reduction-sensitive polymeric nanomedicines: An emerging multifunctional platform for targeted cancer therapy.

The development of smart delivery systems that are robust in circulation and quickly release drugs following selective internalization into target cancer cells is a key to precision cancer therapy. Interestingly, reduction-sensitive polymeric nanomedicines showing high plasma stability and triggered cytoplasmic drug release behavior have recently emerged as one of the most exciting platforms for targeted delivery of various anticancer drugs including small chemical drugs, proteins, and nucleic acids. In vivo studies in varying tumor models reveal that these reduction-sensitive multifunctional nanomedicines outperform the currently used clinical formulations and reduction-insensitive counterparts, bringing about not only significantly enhanced tumor selectivity, accumulation and inhibition efficacy but also markedly reduced systemic toxicity and improved therapeutic index. In this review, we will highlight the cutting-edge advancement with a focus on in vivo performances as well as future perspectives on reduction-sensitive polymeric nanomedicines for targeted cancer therapy.

Peptide-decorated polymeric nanomedicines for precision cancer therapy.

The advancement of tissue and cell-specific drug delivery systems is a key to precision cancer therapy. Peptides, with easy synthesis, low immunogenicity and biological functions closely mimicking or surpassing natural proteins, have been actively engineered and explored to provide nanomedicines with the ability to overcome various extracellular and intracellular delivery barriers ranging from phagocytic clearance in the circulation, low tumor penetration, poor cancer cell selectivity, inferior cell penetration, to endosomal entrapment as well as poor blood brain barrier permeation for brain cancer therapy. Anti-tumor studies with peptide-decorated polymeric nanomedicines are currently in the experimental stage. Most of the reported peptide-directed polymeric nanomedicines do have a rather complex design requiring a multi-step reproducible fabrication process. Moreover, many of the proposed peptide-decorated polymeric nanomedicines are still not able to effectively overcome the drug delivery cascade barriers. Consequently, in order to facilitate clinical translation the complexity of the systems has to be reduced, while maintaining the added functions after the introduction of the different peptides and further progress has to be made in passing the various drug delivery barriers. In this review, we give an overview of the rational design, development and preclinical performance of peptide-decorated polymeric nanomedicines, and further discuss their challenges and future perspectives as a next generation cancer treatment modality.

Lipopepsomes: A novel and robust family of nano-vesicles capable of highly efficient encapsulation and tumor-targeted delivery of doxorubicin hydrochloride in vivo.

Doxil® is the first FDA-approved anti-cancer nano-drug. Notably, no targeted liposomal formulation has advanced to clinical stage despite tremendous work undertaken, partly due to a low stability of liposomes. Here, we report on novel lipopepsomes self-assembled from poly(ethylene glycol)-b-poly(α-aminopalmitic acid) as a stable and versatile alternative to liposomes for highly efficient encapsulation and tumor-targeted delivery of doxorubicin hydrochloride (Dox·HCl). Interestingly, lipopepsomes could be easily decorated with 20mol% cRGD peptide and loaded with 17.4wt% Dox·HCl, giving cRGD-LPP-Dox with a small size of ~80nm. cRGD-LPP-Dox exhibited a high stability against 10% FBS and restrained drug release under physiological conditions. Flow cytometry, confocal microscopy and MTT assays using αvß3-overexpressing A549 tumor cells showed obviously more efficient uptake and higher anticancer activity for cRGD-LPP-Dox than for non-targeted LPP-Dox and clinically used liposomal Dox (Lipo-Dox) controls. Notably, cRGD-LPP-Dox exhibited markedly enhanced toleration and tumor accumulation than Lipo-Dox. The therapeutic studies demonstrated that cRGD-LPP-Dox achieved effective suppression of orthotopic A549 human lung tumor in nude mice, resulting in significantly improved survival rate as compared to LPP-Dox and Lipo-Dox groups. Lipopepsomes with small size, efficient loading of Dox·HCl, high stability and versatile ligand decoration have appeared as a highly attractive nanoplatform for targeted tumor chemotherapy.

Hyaluronic acid coated PLGA nanoparticulate docetaxel effectively targets and suppresses orthotopic human lung cancer.

PLGA nanotherapeutics though representing a most promising platform for targeted cancer therapy are confronted with low stability and insufficient tumor cell uptake. Here, we report that hyaluronic acid (HA) coated PLGA nanoparticulate docetaxel (DTX-HPLGA) is particularly robust and can effectively target and suppress orthotopic human lung cancer. DTX-HPLGA was easily prepared with a small size of 154nm and negative surface charge of -22.7mV by nanoprecipitation and covalent coating with HA. DTX-HPLGA displayed a low IC50 of 0.91µg/mL in CD44+ A549 cells and a prolonged elimination half-life of 4.13h in nude mice. Interestingly, DTX-HPLGA demonstrated 4.4-fold higher accumulation in the cancerous lung than free DTX, reaching a remarkable level of 13.7%ID/g at 8h post-injection, in orthotopic human A549 lung cancer-bearing mice. Accordingly, DTX-HPLGA exhibited significantly better inhibition of tumor growth than free DTX, leading to healthy mice growth and markedly improved survival time. DTX-HPLGA with easy fabrication, excellent stability and tumor accumulation, effective tumor suppression, and low side effects is of particular interest for targeted chemotherapy of lung cancers.

αvß3 Integrin-targeted reduction-sensitive micellar mertansine prodrug: Superb drug loading, enhanced stability, and effective inhibition of melanoma growth in vivo.

Antibody-maytansinoid conjugates (AMCs) have emerged as one of the most promising active targeting cancer therapeutics. Their clinical use is, however, challenged by their low drug content, poor stability, high cost and potential immune response. Here, we designed and developed robust, cRGD-functionalized, reduction-sensitive polymeric micellar mertansine (DM1) prodrug (cRGD-MMP) that showed targeted treatment of B16F10 melanoma-bearing C57BL/6 mice. cRGD-MMP was obtained with a superb drug content of ~40wt.% and a small size of ~45nm from poly(ethylene glycol)-b-(poly(trimethylene carbonate)-graft-SSDM1) (PEG-P(TMC-g-SSDM1)) and cRGD-functionalized PEG-P(TMC-g-SSDM1) copolymers. cRGD-MMP exhibited excellent stability in 10% fetal bovine serum and cell culture medium while fast swelling and markedly accelerated drug release under a reductive environment. Confocal microscopy, flow cytometry and MTT assays indicated receptor-mediated uptake and high antitumor effect of cRGD-MMP in αvß3 integrin over-expressing B16F10 melanoma cells. Notably, cRGD-MMP displayed a long elimination half-life of 5.25h and 4-fold better maximum-tolerated dose than free DM1. The in vivo studies demonstrated that cRGD-MMP effectively inhibited B16F10 melanoma growth and greatly improved mice survival rate as compared to free DM1 and non-targeted MMP control. cRGD-MMP with superior stability, drug loading, and αvß3 targetability offers an attractive alternative to AMCs for malignant tumor therapy.