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     

Novel functional hyperbranched polyether polyols as prospective drug delivery systems

Multifunctional hyperbranched polyether polyols bearing protective poly(ethylene glycol) (PEG) chains with or without the folate targeting ligand at their end have been prepared. Solubilization in these polymers of a fluorescent probe, pyrene, and an anticancer drug, tamoxifen, was physicochemically investigated. It was found that PEG chains attached at the surface of these hyperbranched polymers, in addition to their well-established protective role, enhance the encapsulation efficiency of the polymers. The release of pyrene and tamoxifen observed upon addition of sodium chloride is, in most of the cases, significant only at concentrations exceeding the physiological extracellular concentration. Thus, a significant amount of the probe or drug remains solubilized inside the carriers, which is an encouraging result if the polymers are to be used for drug delivery.     

A novel micellar PEGylated hyperbranched polyester as a prospective drug delivery system for paclitaxel

A hyperbranched aliphatic polyester has been functionalized with PEG chains to afford a novel water-soluble BH40-PEG polymer which exhibits unimolecular micellar properties, and is therefore appropriate for application as a drug-delivery system. The solubility of the anticancer drug paclitaxel was enhanced by a factor of 35, 110, 230, and 355 in aqueous solutions of BH40-PEG of 10, 30, 60, and 90 mg x mL(-1), respectively. More than 50% of the drug is released at a steady rate and release is almost complete within 10 h. The toxicity of BH40-PEG was assessed in vitro with A549 human lung carcinoma cells and found to be nontoxic for 3 h incubation up to a 1.75 mg x mL(-1) concentration while LD50 was 3.5 mg x mL(-1). Finally, it was efficiently internalized in cells, primarily in the absence of foetal bovine serum, while confocal microscopy revealed the preferential localization of the compound in cell nuclei. [Figure: see text].     

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     

Amine containing cationic methacrylate copolymers as efficient gene delivery vehicles to retinal epithelial cells

Non‐viral gene delivery vectors have emerged as potential alternatives in the field of gene therapy by replacing the biological viral vectors. DNA–cationic polymer complexes are one of the most promising systems to target many inborn or acquired diseases without the utilization of conventional drugs. Despite the excellent binding efficiency of cationic polymers, the gene transfection seems limited to date. In this work, a series of ammonium‐based block‐copolymers with different alkyl side chains (ethyl, butyl, and hexyl) and functionality (alcohol, amine, and alkyl) have been prepared to evaluate their capacity to deliver genetic material. First, different ionic liquid monomers with different pendent functional groups were prepared and characterized. Then, polyplexes elaborated with different polymers at several polymer DNA ratios (w/w) were characterized in terms of size, zeta potential, and DNA binding, release, and protection capacity. Finally, the transfection efficiency and cell viability was evaluated in ARPE19 cells. We found that only the systems containing the amine pendent group were able to transfect ARPE19 cell and, that this amine containing polymer was less cytotoxic even at high polymer/DNA ratios (30:1). In conclusion, our studies suggested that the proper selection of the pendent group substantially impacts overall transfection efficiency of cationic polymers. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 280–287     

聚合物胶束型抗癌药物给药系统研究进展

综述了聚合物胶束的性质、制备、以及影响胶束性能的因素,对聚合物胶束在抗肿瘤药物药系统中的研究实例作了简要介绍。     

Amphiphilic Multi‐Arm Block Copolymer Based on Hyperbranched Polyester,Poly(L‐lactide) and Poly(ethylene glycol) as a Drug Delivery Carrier

A novel type of biodegradable/biocompatible amphiphilic hyperbranched copolymer (H40‐PLA‐b‐MPEG) was synthesized. Its micellar properties were studied by DLS, fluorescence spectroscopy and TEM. The drug release profile showed that the H40‐PLA‐b‐MPEG micelles provide an initial burst release, followed by a sustained release of the entrapped hydrophobic model drug over a period of 4 to 58 h. The copolymer degraded hydrolytically within 6 weeks under physiological conditions. The MTT assay showed no obvious cytotoxicity against a human endothelial cell line at a concentration range of 0–400 µg · mL⁻¹. These results indicate that the H40‐PLA‐b‐MPEG micelles have great potential as hydrophobic drug delivery carriers.

     

Hyperbranched polymers as delivery vectors for oligonucleotides

We report on the synthesis and characterization of hyperbranched dimethylaminoethyl methacrylate (DMAEMA) polymers using reversible addition fragmentation chain transfer polymerization. These polymers are unimolecular and globular and hence interact differently with DNA than conventional DMAEMA or block copolymers. The polymers were shown to effectively bind and condense oligonucleotides (ODNs); visualization of the bound complexes was achieved using atomic force microscopy, whereas isothermal titration calorimetry described the thermodynamics of binding. The ODNs were effectively protected from enzymatic degradation (DNAses) when condensed by all the polycations studied. However, internalization of the complexes into HeLa cells was less effective when the polycation was chain extended with polyethyleneglycol monomethylether methacrylate. Conjugation of folic acid to the periphery of the polycation facilitated much enhanced uptake of the oligomeric DNA into the HeLa cells due to overexpression of folate receptors on the surface of HeLa cells. Although significant cytotoxicity was observed at high polymer concentrations, this could be alleviated by shielding of the polycation using poly(ethyleneglycol monomethylether methacrylate). These results suggest that hyperbranched polymers formed in this way exhibit interesting complexation behavior with ODNs and thus are promising models to study as gene delivery vectors. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Synthesis and characterization of a biodegradable ABC triblock terpolymer as co‐delivery carrier of doxorubicin and DNA

This study is aimed to develop a well‐defined ABC triblock terpolymer, poly(ethylethylene phosphate)‐block‐poly(ε‐caprolactone)‐block‐poly[2‐(dimethylamino)ethyl methacrylate] (PEEP‐b‐PCL‐b‐PDMAEMA), for co‐encapsulating anticancer drug doxorubicin (DOX) and DNA to form polyplexes. The terpolymer is first synthesized via a combination of ring‐opening polymerization and atom‐transfer radical polymerization techniques, and characterized by ¹H NMR and gel permeation chromatography. Subsequently, the self‐assembly behavior of the terpolymer and the micelles loaded with DOX or DNA are investigated by dynamic light scattering, ζ potential, transmission electron microscopy, and gel retardation assay, respectively. In vitro release study reveals that much more DOX is released at pH 5.0 than that at pH 7.4 in the same period. The simultaneous delivery of DOX and green fluorescent protein (GFP)‐labeled DNA is studied by a fluorescence microscope and the results demonstrate that both drug and GFP–DNA can be efficiently delivered into HeLa cells. This system presents a practical and promising carrier for the co‐delivery of drugs and genes. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 3005–3016     

Polyaspartamide-graft-polymethacrylate nanoparticles for doxorubicin delivery

A new PHEA‐IB‐PMANa⁺ copolymer has been synthesized and its pH‐induced self‐assembly has been investigated in an aqueous medium. PHEA‐IB‐PMANa⁺ formed nanoparticles with diameters from 25 to 50 nm upon protonation of the carboxylic acid moieties dislocated along the grafted polymethacrylate sodium salt side chains. The physico‐chemical characterization of the nanoparticles was performed using light scattering, zeta‐potential measurements, SEM, and AFM. Doxorubicin‐loaded nanoparticles were prepared and drug release profiles were evaluated under conditions mimicking physiological media. A biological characterization was carried out by testing the cytotoxicity on Caco‐2 cells, and cellular uptake on mouse monocyte macrophage (J774 A.1) and Caco‐2 cells.

     

PEGylated anti-MUC1 aptamer-doxorubicin complex for targeted drug delivery to MCF7 breast cancer cells

Targeted drug delivery is especially important in cancer treatment as many anti-cancer drugs are non-specific and highly toxic to both cancer and normal cells. The targeted drug delivery of DOX to the MUC1-expressing breast cancer cell line (MCF7) was obtained using APT as a carrier. Modification of the APT-DOX complex by PEG increases the survivability of the macrophage control (RAW 264.7) by about six-fold as compared to free DOX treatment without significantly affecting the cytotoxicity toward the target cell line. Thus, PEG-APT-DOX is potentially a new therapeutic agent for targeted drug delivery to MUC1-expressing cell lines.     

Highly efficient intracellular drug delivery with a negatively charged hyperbranched polysulfonamine

Efficient intracellular translocation is achieved using an easily prepared hyperbranched polysulfonamine that remains negatively charged at physiological pH. Investigations on the cellular uptake mechanism and the subcellular distribution of PSA are reported. The in vitro cytotoxicity of PSA is found to be low. Using doxorubicin as a model drug, a PSA/drug complex is prepared by electrostatic interaction with a high drug payload that exhibits a controlled release in response to pH. Efficient intracellular drug delivery, strong growth inhibition of tumor cells, and low cytotoxicity to normal cells are observed. The results suggest a possible way to utilize anionic polymers for intracellular delivery of therapeutic moieties or drugs.     

Hyperbranched poly (amine‐ester)‐poly (lactide‐co‐glycolide) copolymer and their nanoparticles as paclitaxel delivery system

A new hyperbranched poly (amine‐ester)‐poly (lactide‐co‐glycolide) copolymer (HPAE‐co‐PLGA) was synthesized by ring‐opening polymerization of D , L ‐lactide (DLLA) glycolid and branched poly (amine‐ester) (HPAE‐OHs) with Sn(Oct)₂ as catalyst. The chemical structures of copolymers were determined by FT‐IR, ¹H‐NMR(¹³C NMR), TGA and their molecular weights were determined by gel permeation chromatography (GPC). Paclitaxel‐loaded copolymer nanoparticles were prepared by the nanoprecipitation method. Their physicochemical characteristics, e.g. morphology and nanoparticles size distribution were then evaluated by means of fluorescence spectroscopy, environmental scanning electron microscopy (ESEM), and dynamic light scattering (DLS). Paclitaxel‐loaded nanoparticles assumed a spherical shape and have unimodal size distribution. It was found that the chemical composition of the nanoparticles was a key factor in controlling nanoparticles size, drug‐loading content, and drug release behavior. As the molar ratio of DL ‐lactide/glycolide to HPAE increased, the nanoparticles size and drug‐loading content increased, and the drug release rate decreased. The antitumor activity of the paclitaxel‐loaded HPAE‐co‐PLGA nanoparticles against human liver cancer H7402 cells was evaluated by 3‐(4, 5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide (MTT) method. The paclitaxel‐loaded HPAE‐co‐PLGA nanoparticles showed comparable anticancer efficacy with the free drug. Copyright © 2010 John Wiley & Sons, Ltd.     

Folate-decorated succinylchitosan nanoparticles conjugated with doxorubicin for targeted drug delivery

Amphiphilic biodegradable succinylchitosan nanoparticles modified with folic acid are described that act as an emulsifier to form nanoparticles. Their molecular structures and physicochemical as well as self‐assembly properties are characterized by means of FT‐IR, ¹H NMR, FESEM, DLS, and TEM. The nanoparticles are 60–80 nm in size and are not toxic in vitro. They are immobilized with the cytostatic drug doxorubicin. Specific transport of doxorubicin by the nanoparticles into the folate‐receptor‐overexpressing cancer cells and its biological activity as well as in vitro release are demonstrated. It is shown that under acidic condition more drug is released. The nanoparticles can thus not only specifically deliver doxorubicin to its target, but also release the drug depending on the pH.

     

Hyperbranched Polyamidoamines Containing β‐Cyclodextrin for Controlled Release of Chlorambucil

This work is focused on the controlled drug release behavior of hyperbranched HPMA in the presence of β‐CD. Hence, three HPMA‐β‐CDs and a pure HPMA were synthesized by Michael addition polymerization. As a model drug, CLB (an anti‐cancer drug) was loaded into them via a solution method for in vitro release studies. The DSC results indicate that the CLB/polymer interactions are at the molecular level. Loading CLB into these polymers results in an evident increase in their glass transition temperatures, and ΔT_g depends on the β‐CD content. The controlled‐release experiments show that the presence of β‐CD can appropriately slow the release of CLB from HPMA‐β‐CDs and adjust the ratio of CLB released in total drug loading.

     

Fluorescent micelles based on star amphiphilic copolymer with a porphyrin core for bioimaging and drug delivery

Star-shaped poly(ε-caprolactone)-b-poly(ethylene oxide) amphiphilic copolymer with a tetrakis-(4-aminophenyl)-terminated porphyrin core was synthesized. Paclitaxel (PTX)-loaded polymeric micelles were prepared by the self-assembly of the star copolymer and in situ encapsulation of PTX. The fluorescent characteristic of the porphyrin moiety allowed the cellular uptake and biodistribution of the PTX-loaded micelles to be monitored by fluorescent imaging. The PTX-loaded micelles can be readily internalized by cancer cells and have a slightly higher cytotoxicity than clinic PTX injection Taxol. In vivo real-time fluorescent imaging revealed that the micelles could accumulate at tumor site via the blood circulation in tumor-bearing mice. In vivo antitumor efficacy examinations indicated that the PTX-loaded micelles had significantly superior efficacy in impeding tumor growth than Taxol and low toxicity to the living mice.     

Thermosensitive t‐PLA‐b‐PNIPAAm tri‐armed star block copolymer nanoscale micelles for camptothecin drug release

Thermosensitive polylactide‐block‐poly(N‐isopropylacrylamide) (t‐PLA‐b‐PNIPAAm) tri‐armed star block copolymers were synthesized by atom transfer radical polymerization (ATRP) of monomer NIPAAm using t‐PLA‐Cl as macroinitiator. The synthesis of t‐PLA‐Cl was accomplished by esterification of star polylactides (t‐PLA) with 2‐chloropropionyl chloride using trimethylolpropane as a center molecule. FT‐IR, ¹H NMR, and GPC analyses confirmed that the t‐PLA‐b‐PNIPAAm star block copolymers had well‐defined structure and controlled molecular weights. The block copolymers could form core‐shell micelle nanoparticles due to their hydrophilic‐hydrophobic trait in aqueous media, and the critical micelle concentrations (CMC) were from 6.7 to 32.9 mg L^?1, depending on the system composition. The as‐prepared micelle nanoparticles showed reversible phase changes in transmittance with temperature: transparent below low critical solution temperature (LCST) and opaque above the LCST. Transmission electron microscopy (TEM) observations revealed that the micelle nanoparticles were spherical in shape with core‐shell structure. The hydrodynamic diameters of the micelle nanoparticles depended on copolymer compositions, micelle concentrations and media. MTT assays were conducted to evaluate cytotoxicity of the camptothecin‐loaded copolymer micelles. Camptothecin drug release studies showed that the copolymer micelles exhibited thermo‐triggered targeting drug release behavior, and thus had potential application values in drug controlled delivery. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 4429–4439     

功能化修饰的超支化聚缩水甘油醚在药物载体领域的应用

随着纳米医学的发展,具有控制释放药物和生物活性分子、靶向刺激响应生理环境的聚合物纳米载体成为该领域活跃而具潜力的研究方向。超支化聚缩水甘油醚因其特定的三维结构、良好的亲水性、生物相容性和可修饰性而引起生物材料界的广泛关注。而经功能化修饰的超支化聚缩水甘油醚还可自组装成胶束、囊泡等药物载体或共价偶联成大分子前药。本文从超支化聚缩水甘油醚的疏水两亲修饰、环境敏感性功能化和超分子组装体改性三方面综述了功能化修饰的超支化聚缩水甘油醚在药物载体领域的研究进展。并系统归纳了超支化聚缩水甘油醚两亲功能化、环境敏感功能化的分子设计策略。另外,对基于环糊精主客体作用的超支化超分子聚缩水甘油醚共聚物的组装行为进行了简述。     

Dendritic polyurethane-based prodrug as unimolecular micelles for precise ultrasound-activated localized drug delivery

Ultrasound has been recognized as an exciting tool to enhance the therapeutic efficacy in tumor chemotherapy owing to the triggered drug release, facilitated intracellular drug delivery, and improved spatial precision. Aiming for a precise localized drug delivery, novel dendritic polyurethane-based prodrug (DOX-DPU-PEG) was fabricated with a drug content of 18.9% here by conjugating DOX onto the end groups of the functionalized dendritic polyurethane via acid-labile imine bonds. It could easily form unimolecular micelles around 38 nm. Compared with the non-covalently drug-loaded unimolecular micelles (DOX@Ph-DPU-PEG), they showed excellent pH/ultrasound dual-triggered drug release performance, with drug leakage of only 4% at pH 7.4, but cumulative release of 14% and 88% at pH 5.0 without and with ultrasound, respectively. The ultrasound responsiveness was attributed to the unique strawberry-shaped topological structure of the DOX-DPU-PEG, in which DOX was embedded in the skin layer of the hydrophobic DPU cores. With ultrasound, the DOX-DPU-PEG unimolecular micelles possessed enhanced tumor growth inhibition than free DOX but showed no obvious cytotoxicity on the tumor cells without ultrasound. Such feature makes them promising potential for precise localized drug delivery.