Fabrication of poly(ethylene glycol)‐based hydrogels entrapping enzyme‐immobilized silica nanoparticles

In this study, we immobilized enzymes by combining covalent surface immobilization and hydrogel entrapment. A model enzyme, glucose oxidase (GOX), was first covalently immobilized on the surface of silica nanoparticles (SNPs) via 3‐aminopropyltriethoxysilane (APTES), and the resultant SNP‐immobilized enzyme was physically entrapped within photopolymerized hydrogels prepared from two different molecular weights (MWs) (575 and 8000 Da) of poly(ethylene glycol)(PEG). The hydrogel entrapment resulted in a decrease in reaction rate and an increase in apparent K_m of SNP‐immobilized GOX, but these negative effects could be minimized by using hydrogel with a higher MW PEG, which provides higher water content and larger mesh size. The catalytic rate of the PEG 8000 hydrogel was about ten times faster than that of the PEG 575 hydrogel because of enhanced mass transfer. Long‐term stability test demonstrated that SNP‐immobilized GOX entrapped within hydrogel maintained more than 60% of its initial activity after a week, whereas non‐entrapped SNP‐immobilized GOX and entrapped GOX without SNP immobilization maintained less than 20% of their initial activity. Incorporation of SNPs into hydrogel enhanced the mechanical strength of the hydrogel six‐fold relative to bare hydrogels. Finally, a hydrogel microarray entrapping SNP‐immobilized GOX was fabricated using photolithography and successfully used for quantitative glucose detection. Copyright © 2009 John Wiley & Sons, Ltd.     

Target delivery of photo-triggered nanocarrier for externally activated chemo-photodynamic therapy of prostate cancer

Objective therapeutics such as photodynamic therapy (PDT) play an imperative role where targeted delivery of nanotherapeutics could achieve the highest level of therapeutic efficiency for the treatment of cancer. For an effective combination of chemotherapy and PDT, a multimodal-targeted system is vital to achieving effective therapeutic efficacy to counter cancer. In this study, an upconversion nanoparticle-based dual-mode nanocarrier was established where doxorubicin, a chemotherapeutic drug, and tetra carboxy zinc phthalocyanine, a reactive oxygen species (ROS) generator, were successfully embedded onto metal-organic framework (ZIF-8) for synergistic photodynamic therapy. For controlled drug release, amine-PEG was wrapped around UCNPs@MOF. In addition, targeting efficiency was enhanced by employing a prostate cancer-specific ligand (folic acid, FA), which is recognized by prostate-specific membrane antigen (PSMA). Indeed, the nanocomposite-coupled FA was uptaken more in LNCaP (PSMA positive) cells compared to DU145 (PSMA negative) cells. Interestingly, coating the nanocomposite with biocompatible polyethylene glycol significantly inhibited doxorubicin (DOX) release even under a lower pH condition. This effect is abrogated by near-infrared irradiation, whereupon NIR irradiation, the nanocomposite accelerates the production of ROS, as well as chemotherapeutic drug release. These results suggest that the release of DOX was more tightly controlled by a polymer coating. As observed by in vitro cytotoxicity experiment, LNCaP cells showed descending pattern in the cell viability than DU145 cells under the NIR irradiation condition. All these results, taken together, show a promising system for NIR-based targeted PDT where burst release of drug and ROS is achieved to improve the synergistic therapeutics.     

Grafted copolymer micelles with pH triggered charge reversibility for efficient doxorubicin delivery

The instability and premature charge reversal at pH 7.4 have become the major limitations of charge‐reversal delivery systems. To address this problem, graft copolymer of poly(butylene succinate)‐g‐cysteamine‐bi‐poly(ethylene glycol) (PBS‐g‐CS‐bi‐PEG, bi = benzoic imine bond) was designed and synthesized through facile thiol‐ene click reaction and subsequent Schiff's base reaction. Then, PBS‐g‐CS‐bi‐PEG and carboxyl‐functionalized polyester of poly(butylene succinate)‐g‐3‐mercaptopropionic acid (PBS‐g‐MPA) co‐assemble in aqueous solution to give PEG shell‐sheddable charge‐reversal micelles with sizes of 85–103 nm and low polydispersity of 0.11–0.12. Interestingly, the PBS‐g‐MPA/CS‐bi‐PEG micelles could sensitively and arbitrarily switch their surface charges between negative and positive status in response to pH fluctuation via reversible protonation and deprotonation of carboxyl and amino groups, which endows the desired stability of co‐assembly micelles either during long‐term storage or under physiological conditions. Doxorubicin (DOX) was loaded into PBS‐g‐MPA/CS‐bi‐PEG micelles with a high drug‐loading content of 10.2% and entrapment efficiency of 68% as a result of electrostatic attraction. In vitro release studies revealed that less than 25% of DOX was released within 24 h in the environment mimicking the physiological condition, whereas up to 81% of DOX was released in 24 h under weak‐acid condition resembling microenvironment in endosome/lysosome. In vitro cytotoxicity study suggested that blank PBS‐g‐MPA/CS‐bi‐PEG micelles possessed excellent biocompatibility, while DOX‐loaded PBS‐g‐MPA/CS‐bi‐PEG micelles showed significant cytotoxicity with half‐maximal inhibitory concentration (IC₅₀) of 1.55–1.67 μg DOX equiv/mL. This study provides a facile and effective approach for the preparation of novel charge‐reversal micelles with switchable charges and excellent biocompatibility, which are highly promising to be used as safe nanocarriers for efficient intracellular drug delivery. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 2036–2046     

Self‐Assembled Micelles Based on PEG‐Polypeptide Hybrid Copolymers for Drug Delivery

A series of amphiphilic poly(L ‐leucine)‐block‐poly(ethylene glycol)‐block‐poly(L ‐leucine) (PLL‐PEG‐PLL) hybrid triblock copolymers have been synthesized. All the blocks in this system have good biocompatibility and low toxicity. The PLL‐PEG‐PLL copolymers could self‐assemble into micelles with PLL blocks as the hydrophobic core and PEG blocks as the hydrophilic shell, which were characterized by FT‐IR, ¹H NMR, and transmission electron microscopy analysis. The critical micellar concentration of the copolymer was 95.0 mg · L⁻¹. The circular dichroism spectrum shows that the PLL segments adopt a unique α‐helical conformation, which is found to play an important role in controlling the drug release rate. The drug release could be effectively sustained by encapsulation in the micelles. The copolymers may have potential applications in drug delivery.

     

Thermosensitive Micelles Based on Folate‐Conjugated Poly(N‐vinylcaprolactam)‐block‐Poly(ethylene glycol) for Tumor‐Targeted Drug Delivery

Thermosensitive PNVCL‐b‐PEG block copolymer coupled with folic acid was prepared as an anti‐cancer drug carrier. This polymer self‐assembled into stable micelles in aqueous solutions at above 33 °C. At 37 °C, the release profile of PNVCL‐b‐PEG‐FA micelles showed a slower and more controlled release of the entrapped 5‐FU than that at 25 °C. The blank and 5‐FU‐loaded PNVCL‐b‐PEG‐FA micelles did not induce remarkable cytotoxicity against the EA.hy 926 human endothelial cell line; however, 5‐FU‐loaded PNVCL‐b‐PEG‐FA micelles showed a cytotoxicity effect against 4T1 mouse mammary carcinoma cells due to the availability of loaded anti‐cancer drugs delivered to the inside of the cancer cells by the folate‐receptor‐mediated endocytosis process.

     

Drug Self‐Delivery Systems Based on Hyperbranched Polyprodrugs towards Tumor Therapy

Amphiphilic hyperbranched polyprodrugs (DOX‐S‐S‐PEG) with drug repeat units in hydrophobic core linked by disulfide bonds were developed as drug self‐delivery systems for cancer therapy. The hydroxyl groups and the amine group in doxorubicin (DOX) were linked by 3,3′‐dithiodipropanoic acid as hydrophobic hyperbranched cores, then amino‐terminated polyethylene glycol monomethyl ether (mPEG‐NH₂) as hydrophilic shell was linked to hydrophobic cores to form amphiphilic and glutathione (GSH)‐responsive micelle of hyperbranched polyprodrugs. The amphiphilic micelles can be disrupted under GSH (1 mg mL^?1) circumstance. Cell viability of A549 cells and 293T cells was evaluated by CCK‐8 and Muse Annexin V & Dead Cell Kit. The disrupted polyprodrugs maintained drug activity for killing tumor cells. Meanwhile, the undisrupted polyprodrugs possessed low cytotoxicity to normal cells. The cell uptake experiments showed that the micelles of DOX‐S‐S‐PEG were taken up by A549 cells and distributed to cell nuclei. Thus, the drug self‐delivery systems with drug repeat units in hydrophobic cores linked by disulfide bonds showed significant special advantages: 1) facile one‐pot synthesis; 2) completely without toxic or non‐degradable polymers; 3) DOX itself functions as fluorescent labeled molecule and self‐delivery carrier; 4) drug with inactive form in hyperbranched cores and low cytotoxicity to normal cells. These advantages make them excellent drug self‐delivery systems for potential high efficient cancer therapy.     

Preparation and Biological Evaluation of [99mTc]Tc-CNGU as a PSMA-Targeted Radiotracer for the Imaging of Prostate Cancer

Prostate-specific membrane antigen (PSMA) is a well-established biological target that is overexpressed on the surface of prostate cancer lesions. Radionuclide-labeled small-molecule PSMA inhibitors have been shown to be promising PSMA-specific agents for the diagnosis and therapy of prostate cancer. In this study, a glutamate-urea-based PSMA-targeted ligand containing an isonitrile (CNGU) was synthesized and labeled with ^99mTc to prepare [^99mTc]Tc-CNGU with a high radiochemical purity (RCP). The CNGU ligand showed a high affinity toward PSMA (K_i value is 8.79 nM) in LNCaP cells. The [^99mTc]Tc-CNGU exhibited a good stability in vitro and hydrophilicity (log P = −1.97 ± 0.03). In biodistribution studies, BALB/c nude mice bearing LNCaP xenografts showed that the complex had a high tumor uptake with 4.86 ± 1.19% ID/g, which decreased to 1.74 ± 0.90% ID/g after a pre-injection of the selective PSMA inhibitor ZJ-43, suggesting that it was a PSMA-specific agent. Micro-SPECT imaging demonstrated that the [^99mTc]Tc-CNGU had a tumor uptake and that the uptake was reduced in the image after blocking with ZJ-43, further confirming its PSMA specificity. All of the results in this work indicated that [^99mTc]Tc-CNGU is a promising PSMA-specific tracer for the imaging of prostate cancer.     

A Self‐Delivery Chimeric Peptide for Photodynamic Therapy Amplified Immunotherapy

In this paper, a self‐delivery chimeric peptide PpIX‐PEG₈‐KVPRNQDWL is designed for photodynamic therapy (PDT) amplified immunotherapy against malignant melanoma. After self‐assembly into nanoparticles (designated as PPMA), this self‐delivery system shows high drug loading rate, good dispersion, and stability as well as an excellent capability in producing reactive oxygen species (ROS). After cellular uptake, the ROS generated under light irradiation could induce the apoptosis and/or necrosis of tumor cells, which would subsequently stimulate the anti‐tumor immune response. On the other hand, the melanoma specific antigen (KVPRNQDWL) peptide could also activate the specific cytotoxic T cells for anti‐tumor immunity. Compared to immunotherapy alone, the combined photodynamic immunotherapy exhibits significantly enhanced inhibition of melanoma growth. Both in vitro and in vivo investigations confirm that PDT of PPMA has a positive effect on anti‐tumor immune response. This self‐delivery system demonstrates a great potential of this PDT amplified immunotherapy strategy for advanced or metastatic tumor treatment.     

Fluorinated PEG‐Polypeptide Polyplex Micelles Have Good Serum‐Resistance and Low Cytotoxicity for Gene Delivery

A novel PEGylation polypeptide, poly(ethylene glycol)‐b‐poly(l ‐lysine)‐b‐poly(l ‐cysteine) (PEG‐PLL‐PCys) triblock copolymer is synthesized via the sequential ring‐opening polymerization of amino acid N‐carboxyanhydrides initiated by methoxypolyethylene glycol amine (mPEG‐NH₂, M _w is 2 kDa). Subsequently, the obtained polypeptide is partially conjugated with fluorocarbon chains via disulfide exchange reaction. PLL segment can condense plasmid DNA through an electrostatic force to form a complex core, PEG segment surrounding the complex like a corona can prevent the complex from precipitation and reduce the adsorption of serum, while PCys segment with fluorocarbon can enhance the cellular uptake and the stability of the formed polyplex micelles in physiological conditions. Experiment results exhibit that the fluorinated polypeptides have low cytotoxicity and good gene transfection efficiency even in the presence of 50% fetal bovine serum.

     

Design of Block Copolymer Micellar Aggregates for Co‐Delivery of Enzyme and Anticancer Prodrug

Traditional enzyme–prodrug therapy (EPT) is a two‐step strategy, which has many serious deficiencies, so having a one‐step EPT treatment becomes a problem of immediate interest. This study aims to achieve an effective co‐delivery of horseradish peroxidase (HRP) as a kind of enzyme for prodrug activation and ethyl 3‐indoleacetate (EIA) as anticancer prodrug. A ternary block copolymer PEG‐PAsp(AED)‐CA consisting of poly(ethylene glycol) (PEG), reduction‐sensitive poly (N ‐(2,2′‐dithiobis(ethylamine)) aspartamide) PAsp(AED), and cholic acid (CA) was synthesized and assembled into spherical micelles which encapsulated EIA in its hydrophobic core and HRP in a reduction‐sensitive interlayer. TEM photographs show that the polymer micelle is around 40 nm, and the cell survival rate test shows that the EIA/HRP polymer micelle is highly lethal to human lung adenocarcinoma cells. Thus, co‐delivery of EIA and HRP demonstrates great potential in cancer therapy, offering a structurally simple and highly tunable platform for the synchronous delivery of enzymes and prodrugs in EPT.     

Pt(II) complexes immobilized on polymer‐modified magnetic carbon nanotubes as a new platinum drug delivery system

We combine nanotechnology and chemical synthesis to create a novel multifunctional platinum drug delivery vehicle based on magnetic carbon nanotubes (multiwall carbon nanotubes/Fe₃O₄@poly(citric acid)/cis‐[(Pt(1,7‐phenanthroline)(DMSO)Cl₂)]‐b‐poly(ethylene glycol) (MCNTs/FO@PC/Pt(II)‐b‐PEG)) for targeted cancer therapy. MCNTs/FO@PC/Pt(II)‐b‐PEG was conveniently prepared by conjugating cis‐[Pt(1,7‐phenanthroline)(DMSO)Cl₂] complex to MCNTs/FO@PC‐b‐PEG via strong hydrogen‐bonding interactions. In comparison with free cisplatin and Pt(II) complex, MCNTs/FO@PC/Pt(II)‐b‐PEG shows higher solubility in aqueous solution and higher cytotoxicity towards human cervical cancer HeLa cells and human breast cancer MDA‐MB‐231 cells. In vitro release experiments revealed that the platinum drug‐loaded delivery system is relatively stable under physiological conditions (pH = 7.4 and 37 °C) but susceptible to acidic environments (pH = 5.6 and 37 °C) which would trigger the release of loaded drugs. Fluorescence microscopy studies revealed that this magnetic nanohybrid system possesses marked cell‐specific targeting in vitro in the presence of an external magnetic field. The results indicated that the prepared superparamagnetic MCNTs/FO@PC/Pt(II)‐b‐PEG nanohybrid system is a promising candidate for inhibiting the proliferation of cancer cells.     

Gold Nanorods with Phase‐Changing Polymer Corona for Remotely Near‐Infrared‐Triggered Drug Release

Herein, we report a new drug‐delivery system (DDS) that is comprised of a near‐infrared (NIR)‐light‐sensitive gold‐nanorod (GNR) core and a phase‐changing poly(ε‐caprolactone)‐b‐poly(ethylene glycol) polymer corona (GNR@PCL‐b‐PEG). The underlying mechanism of the drug‐loading and triggered‐release behaviors involves the entrapment of drug payloads among the PCL crystallites and a heat‐induced phase change, respectively. A low premature release of the pre‐loaded doxorubicin was observed in PBS buffer (pH 7.4) at 37 °C (<10 % of the entire payload after 48 h). However, release could be activated within 30 min by conventional heating at 50 °C, above the T_m of the crystalline PCL domain (43.5 °C), with about 60 % release over the subsequent 42 h at 37 °C. The NIR‐induced heating of an aqueous suspension of GNR@PCL‐b‐PEG under NIR irradiation (802 nm) was investigated in terms of the irradiation period, power, and concentration‐dependent heating behavior, as well as the NIR‐induced shape‐transformation of the GNR cores. Remotely NIR‐triggered release was also explored upon NIR irradiation for 30 min and about 70 % release was achieved in the following 42 h at 37 °C, with a mild warming (<4 °C) of the surroundings. The cytotoxicity of GNR@PCL‐b‐PEG against the mouse fibroblastic‐like L929 cell‐line was assessed by MTS assay and good compatibility was confirmed with a cell viability of over 90 % after incubation for 72 h. The cellular uptake of GNR@PCL‐b‐PEG by melanoma MEL‐5 cells was also confirmed, with an averaged uptake of 1250(±110) particles cell^?1 after incubation for 12 h (50 μg mL^?1). This GNR@PCL‐b‐PEG DDS is aimed at addressing the different requirements for therapeutic treatments and is envisaged to provide new insights into DDS targeting for remotely triggered release by NIR activation.     

Block copolymer micelles conjugated with anti‐EGFR antibody for targeted delivery of anticancer drug

Antiepidermal growth factor receptor antibody (anti‐EGFR antibody) was conjugated with the block copolymer micelle based on poly(ethylene glycol) (PEG) and poly(ε‐caprolactone) (PCL) for active targeting to EGFR overexpressing cancer cells. Doxorubicin (DOX) was encapsulated in the core of the block copolymer (MePEG‐b‐PCL) micelle (DOX‐micelle). The mean diameters of the DOX‐micelle and the anti‐EGFR‐PEG‐b‐PCL copolymer micelles loaded with DOX (DOX‐anti‐EGFR‐micelle) were about 25 and 31 nm, respectively. The RKO human colorectal cancer cells expressing moderate degree of EGFR were incubated with free DOX, DOX‐micelle, or DOX‐anti‐EGFR‐micelle to study the distribution of DOX in the cells. When cells were incubated with free DOX, moderate degree of DOX fluorescence was observed in the nuclei. In the cells treated with DOX‐micelle, the DOX fluorescence intensity in the cytoplasm was much greater than that in the nuclei. On the other hand, the nuclei of the cells treated with DOX‐anti‐EGFR‐micelle exhibited DOX fluorescence intensity similar to that in the cytoplasm. The cytotoxicity of DOX‐anti‐EGFR‐micelle to induce apoptosis in RKO cells was significantly greater than that of free DOX or DOX‐micelle. These results demonstrated that the presence of anti‐EGFR antibody on the DOX‐micelle surface (DOX‐anti‐EGFR‐micelle) increased the internalization of the DOX‐micelle and nuclear accumulation of DOX, and enhanced the DOX‐induced cell death. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 7321–7331, 2008     

Pluronic/Polyethylenimine Shell Crosslinked Nanocapsules with Embedded Magnetite Nanocrystals for Magnetically Triggered Delivery of siRNA

Pluronic/polyethylenimine shell crosslinked nanocapsules with embedded magnetite nanocrystals (PPMCs) were developed for magnetically triggered delivery of siRNA. The positively charged PPMCs formed stable nanosized polyelectrolyte complexes via electrostatic interactions with negatively charged siRNA‐polyethylene glycol conjugate (siRNA‐s‐s‐PEG) that was linked via a cleavable disulfide linkage. PPMC/siRNA‐s‐s‐PEG polyelectrolyte complexes were efficiently taken up by cancer cells upon exposure to a magnet, thereby enhancing intracellular uptake and silencing effect of siRNA. The present study suggests that these novel nanomaterials could be potentially utilized for magnetically triggered delivery of various nucleic acid‐based therapeutic agents.

     

Novel Biodegradable Block Copolymers of Poly(ethylene glycol) (PEG) and Cationic Polycarbonate: Effects of PEG Configuration on Gene Delivery

A novel amine‐functionalized polycarbonate was synthesized and its excellent gene transfection ability in vitro is demonstrated. In the framework of adapting the cationic polycarbonate for in vivo gene delivery applications, here the design and synthesis of biodegradable block copolymers of poly(ethylene glycol) (PEG) and amine‐functionalized polycarbonate with a well‐defined molecular architecture and molecular weight is achieved by metal‐free organocatalytic ring‐opening polymerization. Copolymers in triblock cationic polycarbonate‐block‐PEG‐block‐cationic polycarbonate and diblock PEG‐block‐cationic polycarbonate configurations, in comparison with a non‐PEGylated cationic polycarbonate control, are investigated for their influence on key aspects of gene delivery. Among the polymers with similar molecular weights and N content, the triblock copolymer exhibit more favorable physicochemical (i.e., DNA binding, size, zeta‐potential, and in vitro stability) and biological (i.e., cellular uptake and luciferase reporter gene expression) properties. Importantly, the various cationic polycarbonate/DNA complexes are biocompatible, inducing minimal cytotoxicities and hemolysis. These results suggest that the triblock copolymer is a more useful architecture in future cationic polymer designs for successful systemic therapeutic applications.     

New molecular markers for prostate tumor imaging: a study on 2-methylene substituted fatty acids as new AMACR inhibitors

The development of prostate carcinoma is associated with alterations in fatty acid metabolism. α‐Methylacyl‐CoA racemase (AMACR) is a peroxisomal and mitochondrial enzyme that catalyses interconversion between the (S)/(R)‐isomers of a range of α‐methylacyl‐CoA thioesters. AMACR is involved in the β‐oxidation of the dietary branched‐chain fatty acids and bile acid intermediates. It is highly expressed in prostate (more than 95 %), colon (92 %), and breast cancers (44 %) but not in the respective normal or hyperplastic tissues. Thus, targeting of AMACR could be a new strategy for molecular imaging and therapy of prostate and some other cancers. Unlabeled 2‐methylenacyl‐CoA thioesters ( 12 a – c ) were designed as AMACR binding ligands. The thioesters were tested for their ability to inhibit the AMACR‐mediated epimerization of (25R)‐THC‐CoA and were found to be strong AMACR inhibitors. Radioiodinated (E)‐¹³¹I‐13‐iodo‐2‐methylentridec‐12‐enoic acid (¹³¹I‐ 7 c ) demonstrated preferential retention in AMACR‐positive prostate tumor cells (LNCaP, LNCaP C4‐2wt and DU145) compared with both AMACR‐knockout LNCaP C4‐2 AMACR‐siRNA and benign BPH1 prostate cell lines. A significant protein‐bound radioactive fraction with main bands at 47 (sum of molecular weights of AMACR plus 12 c ), 70, and 75 kDa was detected in LNCaP C4‐2 wt cells. In contrast, only negligible amounts of protein‐bound radioactivity were found in LNCaP C4‐2 AMACR‐siRNA cells.     

Synthesis and characterization of novel brush copolymers with biodegradable polyphosphoester side chains for gene delivery

A novel kind of pH‐sensitive brush copolymer [poly(2‐hydroxyethyl methacrylate)‐graft‐poly(ethylethylene phosphate)]‐block‐poly[2‐(dimethylamino)ethyl methacrylate] [(PHEMA‐g‐PEEP)‐b‐PDMAEMA] with biodegradable polyphosphoester as the side chains, and its self‐assembled aggregates were developed for nonviral gene delivery. The brush copolymers were synthesized via a combination of single‐electron transfer living radical polymerization and ring‐opening polymerization. The chemical structures of these brush copolymers were characterized by FTIR, ¹H NMR, and ³¹P NMR measurements. The critical aggregation concentration values of (PHEMA‐g‐PEEP)‐b‐PDMAEMA in pH 7.4 buffer solution were determined by the fluorescence probe technique. The interaction of (PHEMA‐g‐PEEP)‐b‐PDMAEMA and DNA was studied by agarose gel retardation assay, and the formed complexes were further investigated by means of zeta potential, dynamic light scattering, and transmission electron microscopy measurements. In addition, the in vitro cytotoxicity and transfection tests indicated that these brush copolymers showed low toxicity and favorable transfection efficiency to HeLa cells. All these results demonstrated that these biocompatible brush copolymers may be a promising candidate as nonviral polymeric gene vector. © 2013 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

Mannose‐Modified Serum Exosomes for the Elevated Uptake to Murine Dendritic Cells and Lymphatic Accumulation

The surface of bovine serum‐derived exosomes (EXOs) are modified with α‐d ‐mannose for facile interaction with mannose receptors on dendritic cells (DCs) and for efficient delivery of immune stimulators to the DCs. The surface of the EXOs is modified with polyethylene glycol (PEG) without particle aggregation (≈50 nm) via the incorporation of 1,2‐distearoyl‐sn‐glycero‐3‐phosphoethanolamine (DSPE) into the lipid layer of the EXO, compared to chemical conjugation by N‐hydroxysuccinimide activated PEG (NHS‐PEG). PEG modification onto the exosomal surface significantly decreases the non‐specific cellular uptake of the EXOs into the DCs. However, the EXOs with mannose‐conjugated PEG‐DSPE (EXO‐PEG‐man) exhibit excellent intracellular uptake into the DCs and boost the immune response by the incorporation of adjuvant, monophosphoryl lipid A (MPLA) within the EXO. After an intradermal injection, a higher retention of EXO‐PEG‐man is observed in the lymph nodes, which could be used for the efficient delivery of immune stimulators and antigens to the lymph nodes in vivo.     

Facile Generation of Tumor‐pH‐Labile Linkage‐Bridged Block Copolymers for Chemotherapeutic Delivery

Successful bench‐to‐bedside translation of nanomedicine relies heavily on the development of nanocarriers with superior therapeutic efficacy and high biocompatibility. However, the optimal strategy for improving one aspect often conflicts with the other. Herein, we report a tactic of designing tumor‐pH‐labile linkage‐bridged copolymers of clinically validated poly(d,l ‐lactide) and poly(ethylene glycol) (PEG‐Dlink_m‐PDLLA) for safe and effective drug delivery. Upon arriving at the tumor site, PEG‐Dlink_m‐PDLLA nanoparticles will lose the PEG layer and increase zeta potential by responding to tumor acidity, which significantly enhances cellular uptake and improves the in vivo tumor inhibition rate to 78.1 % in comparison to 47.8 % of the non‐responsive control. Furthermore, PEG‐Dlink_m‐PDLLA nanoparticles show comparable biocompatibility with the clinically used PEG‐b‐PDLLA micelle. The improved therapeutic efficacy and safety demonstrate great promise for our strategy in future translational studies.     

Magnetically polymeric nanocarriers for targeting delivery of curcumin and hyperthermia treatments toward cancer cells

Magnetically polymeric nanocarriers, Cur‐FA‐SAMN, were designed and synthesized for targeting, therapeutic treatments to cancer cells. Amine‐group immobilized iron oxides, Fe₃O₄‐NH₂, were attached on the surface of self‐assembled tri‐block copolymer, poly[(acrylic acid)‐block‐(N‐isopropylacrylamide)‐block‐(acrylic acid)] synthesized via reversible addition‐fragmentation chain‐transfer polymerization. For the purpose of targeting effect, folic acid was grafted on the surface of Fe₃O₄‐NH₂ attached nanoparticles. The nanocarriers were characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, vibrating sample magnetometer, and UV‐Vis spectral analysis. Therefore, a hydrophobic anti‐cancer drug, curcumin, gained water dispersity, and stable storage via encapsulating into and on the magnetically polymeric nanocarriers, and the release behaviors were studied in vitro, with and without high frequency magnetic field. Biocompatibility and cytotoxicity of inherent and curcumin‐loaded nanocarriers were investigated by MTT assay. Results displayed that our nanocarriers have no cytotoxicity while curcumin‐loaded nanocarriers offered significant death to MCF‐7, human breast camcer cells. Intracellular‐uptake experiments demonstrated tremendous uptake and the destroying effect to MCF‐7 cells, most of the cancer cells were killed and the surviving ones were surrounded by the curcumin‐loaded nanocarriers. According to the aforementioned characteristics, these magnetically polymeric nanocarriers will be able to apply as a potential device for practical therapy. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 2706–2713