Polymeric Micelles in Cancer Immunotherapy

Cancer immunotherapies have generated some miracles in the clinic by orchestrating our immune system to combat cancer cells. However, the safety and efficacy concerns of the systemic delivery of these immunostimulatory agents has limited their application. Nanomedicine-based delivery strategies (e.g., liposomes, polymeric nanoparticles, silico, etc.) play an essential role in improving cancer immunotherapies, either by enhancing the anti-tumor immune response, or reducing their systemic adverse effects. The versatility of working with biocompatible polymers helps these polymeric nanoparticles stand out as a key carrier to improve bioavailability and achieve specific delivery at the site of action. This review provides a summary of the latest advancements in the use of polymeric micelles for cancer immunotherapy, including their application in delivering immunological checkpoint inhibitors, immunostimulatory molecules, engineered T cells, and cancer vaccines.     

温度响应性单分子聚合物胶束

单分子聚合物胶束和传统的胶束一样具有核-壳结构,因其结构固定并具有良好的热力学稳定性而越来越受到研究者的关注。当这类胶束的核层或者壳层含有温敏性高分子的时候就可以形成具有温度响应性的单分子聚合物胶束。近年来,人们在温敏性的单分子聚合物胶束的合成与性能研究方面做了大量的工作。本文概述了具有温度响应行为的单分子聚合物胶束的类型、制备方法以及应用等方面取得的新进展,同时结合本实验室的工作,总结了基于超支化大分子的温敏性单分子聚合物胶束的相转变行为研究,并对这类胶束体系的发展进行了展望。     

聚合物胶束结合靶向在肿瘤化疗中的研究进展

肿瘤研究的一个主要方向是开发高效无毒副作用的药物载体系统。聚合物胶束由内部可装载难溶性药物的疏水内核,外部能提高体内运输作用的亲水外壳组成,粒径一般为10～100nm左右。这种粒径范围的载药体系既能逃脱肾脏的排泄清除,又能躲避内皮网状系统的吞噬,延长药物在血液中的循环时间。聚合物胶束结合肿瘤靶向在化疗方面的应用,能够有效改善化疗药物的水溶性,提高化疗药物的利用率和抗肿瘤活性,降低对机体正常细胞组织的毒副作用,克服多药耐药性问题,进而极大地提高了肿瘤化疗效果和促进了肿瘤化疗的发展进步。本文着重综述聚合物胶束在化疗药物载药与靶向策略方面的研究现状与进展。     

RAFT聚合法制备聚合物胶束及其应用前景

聚合物胶束由于具有优良的组织渗透性、增容效果好、结构多样性和热稳定性等特点,成为国内外研究的热点之一。本文综述了近几年发展起来的一些具有特殊结构和特殊性能的双亲性嵌段聚合物胶束的研究进展,详细阐述了RAFT聚合法合成聚合物胶束的机理和优势,表明了RAFT聚合法可直接在水溶液中方便快捷地制备出温度和pH双响应性聚合物胶束。然而,当聚合物胶束的浓度低于其临界胶束浓度时,胶束的稀释效应大大影响了其实际应用,为提高聚合物胶束的稳定性,文章归纳总结了一系列有关壳交联聚合物胶束的制备方法及研究进展。最后,文章展望了聚合物胶束在药物可控释放、靶向、生物成像、催化剂负载及其他领域的应用前景。     

Polymeric Micelles Loading Proteins through Concurrent Ion Complexation and pH‐Cleavable Covalent Bonding for In Vivo Delivery

Protein drugs have great potential as targeted therapies, yet their application suffers from several drawbacks, such as instability, short half‐life, and adverse immune responses. Thus, protein delivery approaches based on stimuli‐responsive nanocarriers can provide effective strategies for selectively enhancing the availability and activation of proteins in targeted tissues. Herein, polymeric micelles with the ability of encapsulating proteins are developed via concurrent ion complexation and pH‐cleavable covalent bonding between proteins and block copolymers directed to pH‐triggered release of the protein payload. Carboxydimethylmaleic anhydride (CDM) is selected as the pH‐sensitive moiety, since the CDM? amide bond is stable at physiological pH (pH 7.4), while it cleaves at pH 6.5, that is, the pathophysiological pH of tumors and inflammatory tissues. By using poly(ethylene glycol)‐poly(l ‐lysine) block copolymers having 45% CDM addition, different proteins with various sizes and isoelectric points are loaded successfully. By using myoglobin‐loaded micelles (myo/m) as a model, the stability of the micelles in physiological conditions and the dissociation and release of functional myoglobin at pH 6.5 are successfully confirmed. Moreover, myo/m shows extended half‐life in blood compared to free myoglobin and micelles assembled solely by polyion complex, indicating the potential of this system for in vivo delivery of proteins.     

Tunable‐Sized Polymeric Micelles and Their Assembly for the Preparation of Large Mesoporous Platinum Nanoparticles

Platinum nanoparticles with continuously tunable mesoporous structures were prepared by a simple, one‐step polymeric approach. By virtue of their large pore size, these structures have a high surface area that is accessible to reagents. In the synthetic method, variation of the solvent composition plays an essential role in the systematic control of pore size and particle shape. The mesoporous Pt catalyst exhibited superior electrocatalytic activity for the methanol oxidation reaction compared to commercially available Pt catalysts. This polymeric‐micelle approach provides an additional design concept for the creation of next generation of metallic catalysts.     

Enhanced Oral Absorption of Icaritin by Using Mixed Polymeric Micelles Prepared with a Creative Acid-Base Shift Method

The purpose of this study was to develop mixed polymeric micelles with high drug loading capacity to improve the oral bioavailability of icaritin with Soluplus^® and Poloxamer 407 using a creative acid-base shift (ABS) method, which exhibits the advantages of exclusion of organic solvents, high drug loading and ease of scaling-up. The feasibility of the ABS method was successfully demonstrated by studies of icaritin-loaded polymeric micelles (IPMs). The prepared IPMs were characterized to have a spherical shape with a size of 72.74 ± 0.51 nm, and 13.18% drug loading content. In vitro release tests confirmed the faster release of icaritin from IPMs compared to an oil suspension. Furthermore, bioavailability of icaritin in IPMs in beagle dogs displayed a 14.9-fold increase when compared with the oil suspension. Transcellular transport studies of IPMs across Caco-2 cell monolayers confirmed that the IPMs were endocytosed in their intact forms through macropinocytosis, clathrin-, and caveolae-mediated pathways. In conclusion, the results suggested that the mixed micelles of Soluplus^® and Poloxamer 407 could be a feasible drug delivery system to enhance oral bioavailability of icaritin, and the ABS method might be a promising technology for the preparation of polymeric micelles to encapsulate poorly water-soluble weakly acidic and alkaline drugs.     

Co-assembly of Patchy Polymeric Micelles and Protein Molecules

The development in the synthesis and self-assembly of patchy nanoparticles has resulted in the creation of complex hierarchical structures. Co-assembly of polymeric nanoparticles and protein molecules combines the advantages of polymeric materials and biomolecules, and will produce new functional materials. Co-assembly of positively charged patchy micelles and negatively charged bovine serum albumin (BSA) molecules is investigated. The patchy micelles, which were synthesized using block copolymer brushes as templates, leads to co-assembly with protein molecules into vesicular structures. The average size of the assembled structures can be controlled by the molar ratio of BSA to patchy micelles. The assembled structures are dissociated in the presence of trypsin. The protein–polymer hybrid vesicles could find potential applications in medicine.     

Highly Ordered Hexagonal Arrays of Hybridized Micelles from Bimodal Self‐Assemblies of Diblock Copolymer Micelles

We demonstrate the formation of highly ordered hexagonal arrays of hybridized polystyrene–poly(4‐vinyl pyridine), PS–PVP, micelles with controllable size by solvent annealing techniques. Because the formation of hybridized micelles was prohibited in the mixture solutions of two different‐sized PS–PVP micelles, single‐layered films with bimodal self‐assemblies of small and large micelles were fabricated from the mixture solutions by adjusting their mixing ratios. When the single‐layered films were solvent annealed by saturated vapor of tetrahydrofuran (THF), on the other hand, small and large PS–PVP micelles in the bimodal self‐assemblies merged together to form hybridized micelles. In addition, the hybridized micelles arranged themselves in a highly ordered hexagonal array, the diameter and center‐to‐center distance of which were precisely adjusted by varying the mixing ratio of small to large micelles in the bimodal assemblies.

     

表面活性剂胶束实现疏水分子在聚合物微凝胶层层组装膜中的高效负载

基于层层组装技术制备了聚烯丙基胺-葡聚糖微凝胶(记作PAH-D)/透明质酸钠(HA)膜, 将包覆有芘分子的十二烷基硫酸钠(SDS)表面活性剂胶束基于静电作用力负载到PAH-D/HA微凝胶膜中, 实现了疏水分子芘在微凝胶膜中的高效负载. 紫外-可见吸收光谱和荧光光谱证实了SDS胶束包覆的芘分子被稳定地负载在PAH-D微凝胶膜中. 透过光谱表明负载有芘分子的(PAH-D/HA)*10微凝胶膜在可见光区仍保持良好光学透过性. 芘在膜中的负载量可以通过改变PAH-D/HA微凝胶膜的沉积周期数和SDS胶束中包覆芘分子的浓度而实现调控. 具有光致变色性质的螺吡喃分子同样可以借助SDS胶束负载到PAH-D/HA微凝胶膜中, 制备具有光致变色性质的层层组装膜. 本工作为疏水有机分子在层层组装聚合物膜中的高效负载提供了一种简便、易行的方法.     

核中含有羧基官能团的聚合物胶束的高效制备

通过化学交联反应诱导胶束化以较高的效率制备了PMCC(聚合物的质量浓度高达50 g/L). 首先制备嵌段共聚物聚苯乙烯-b-聚丙烯酸(PS-b-PAA), 然后对PAA嵌段中的羧基实行酰氯化, 在酰氯化产物聚苯乙烯-b-聚丙烯酰氯(PS-b-PACl)的共同溶剂二氯甲烷中加入交联剂乙二醇交联PACl嵌段. 交联反应使得PACl嵌段聚集, 同时, PS嵌段的保护作用使得PACl嵌段的聚集在有限个分子链间发生, 从而生成以PS为壳, 以含有羧基官能团的聚丙烯酸酯交联网络为核的PMCC.     

高分子微泡体系中光解水的研究：（Ⅱ）聚卵磷脂微泡在光解水中的应用

本文研究以卵磷脂为单体形成的微泡体系,以Co~(60)辐照为聚合方式,通过超声波作用将联吡啶钌和EDTA,甲基紫精和铂溶胶等光解水的试剂置于微泡的不同区域,从而获得不同的光解水效果。     

Exploring the Biocompatibility of Zwitterionic Copolymers for Controlling Macrophage Phagocytosis of Bacteria

This paper provides a biomaterial derived from zwitterionic polymer for controlling macrophage phagocytosis of bacteria. A series of zwitterionic copolymers, named DMAPS‐co‐AA, are synthesized with 3‐dimethyl (methacryloyloxyethyl) ammonium propane sulfonate (DMAPS) and acrylic acid (AA). The biocompatibility of DMAPS‐co‐AA copolymers can be adjusted by adjusting the DMAPS‐content or pH value. As the DMAPS‐content increases, the biocompatibility of zwitterionic copolymer increases. The zwitterionic copolymers with DMAPS content above 30 wt% have higher biocompatibility. Moreover, the biocompatibility also increases significantly as the pH increases from 3.4 to 7.2. By adjusting the pH above 5.8, the zwitterionic copolymer with lower DMAPS‐content also shows higher biocompatibility. Importantly, after incubation with the DMAPS‐co‐AA copolymer solutions at different pH values, phagocytosis behavior of macrophage RAW264.7 cells can also be adjusted. The phagocytosis of bacteria is enhanced at pH = 7.2. Thus, it is proposed that zwitterionic copolymers can be used for controlling phagocytosis of bacteria.

     

Antitumor Drug Delivery Modulated by A Polymeric Micelle with an Upper Critical Solution Temperature

Thermally sensitive polymeric nanocarriers were developed to optimize the release profile of encapsulated compounds to improve treatment efficiency. However, when referring to thermally sensitive polymeric nanocarriers, this usually means systems fabricated from lower critical solution temperature (LCST) polymers, which have been intensively studied. To extend the field of thermally sensitive polymeric nanocarriers, we for the first time fabricated a polymeric drug delivery system having an upper critical solution temperature (UCST) of 43 °C based on an amphiphilic polymer poly(AAm‐co‐AN)‐g‐PEG. The resulting polymeric micelles could effectively encapsulate doxorubicin and exhibited thermally sensitive drug release both in vitro and in vivo. A drastically improved anticancer efficiency (IC₅₀ decreased from 4.6 to 1.6 μg mL^?1, tumor inhibition rate increased from 55.6 % to 92.8 %) was observed. These results suggest that UCST‐based drug delivery can be an alternative to thermally sensitive LCST‐based drug delivery systems for an enhanced antitumor efficiency.     

Nanocrystal-Loaded Micelles for the Enhanced In Vivo Circulation of Docetaxel

Prolonging in vivo circulation has proved to be an efficient route for enhancing the therapeutic effect of rapidly metabolized drugs. In this study, we aimed to construct a nanocrystal-loaded micelles delivery system to enhance the blood circulation of docetaxel (DOC). We employed high-pressure homogenization to prepare docetaxel nanocrystals (DOC(Nc)), and then produced docetaxel nanocrystal-loaded micelles (DOC(Nc)@mPEG-PLA) by a thin-film hydration method. The particle sizes of optimized DOC(Nc), docetaxel micelles (DOC@mPEG-PLA), and DOC(Nc)@mPEG-PLA were 168.4, 36.3, and 72.5 nm, respectively. The crystallinity of docetaxel was decreased after transforming it into nanocrystals, and the crystalline state of docetaxel in micelles was amorphous. The constructed DOC(Nc)@mPEG-PLA showed good stability as its particle size showed no significant change in 7 days. Despite their rapid dissolution, docetaxel nanocrystals exhibited higher bioavailability. The micelles prolonged the retention time of docetaxel in the circulation system of rats, and DOC(Nc)@mPEG-PLA exhibited the highest retention time and bioavailability. These results reveal that constructing nanocrystal-loaded micelles may be a promising way to enhance the in vivo circulation and bioavailability of rapidly metabolized drugs such as docetaxel.     

Thermo/pH Dual Responsive Mixed‐Shell Polymeric Micelles Based on the Complementary Multiple Hydrogen Bonds for Drug Delivery

Thermo/pH dual responsive mixed‐shell polymeric micelles based on multiple hydrogen bonding were prepared by self‐assembly of diaminotriazine‐terminated poly(?‐caprolactone) (DAT‐PCL), uracil‐terminated methoxy poly(ethylene glycol) (MPEG‐U), and uracil‐terminated poly(N‐vinylcaprolactam) (PNVCL‐U) at room temperature. PCL acted as the core and MPEG/PNVCL as the mixed shell. Increasing the temperature, PNVCL collapsed and enclosed the PCL core, while MPEG penetrated through the PNVCL shell, thereby leading to the formation of MPEG channels on the micelles surface. The low cytotoxicity of the mixed micelles was confirmed by an MTT assay against BGC‐823 cells. Studies on the in vitro drug release showed that a much faster release rate was observed at pH 5.0 compared to physiological pH, owing to the dissociation of hydrogen bonds. Therefore, the mixed‐shell polymeric micelles would be very promising candidates in drug delivery systems.     

Computer Study of Stimuli-Responsive Polyelectrolyte Micelles in Aqueous Media. Comparison of Monte Carlo and Self-Consistent Field Approaches

The behavior of polyelectrolyte micelles with kinetically frozen hydrophobic cores in aqueous solutions was studied by Monte Carlo (MC) simulations and self-consistent field (SCF) calculations. Some results have already been published. The structure of water-soluble shells formed by weak polyelectrolytes, both pure and containing a low fraction of strongly hydrophobic units arranged either in a short sequence or distributed uniformly in the shell-forming chains was studied in detail. In the case of sequenced system, the analysis of concentration profiles of individual species reveals strong segregation and important self-organization of hydrophobic units in the shell. A comparison and critical analysis of results of MC and SCF methods is presented.     

Maintenance of Amyloid β Peptide Homeostasis by Artificial Chaperones Based on Mixed‐Shell Polymeric Micelles

The disruption of Aβ homeostasis, which results in the accumulation of neurotoxic amyloids, is the fundamental cause of Alzheimer’s disease (AD). Molecular chaperones play a critical role in controlling undesired protein misfolding and maintaining intricate proteostasis in vivo. Inspired by a natural molecular chaperone, an artificial chaperone consisting of mixed‐shell polymeric micelles (MSPMs) has been devised with tunable surface properties, serving as a suppressor of AD. Taking advantage of biocompatibility, selectivity toward aberrant proteins, and long blood circulation, these MSPM‐based chaperones can maintain Aβ homeostasis by a combination of inhibiting Aβ fibrillation and facilitating Aβ aggregate clearance and simultaneously reducing Aβ‐mediated neurotoxicity. The balance of hydrophilic/hydrophobic moieties on the surface of MSPMs is important for their enhanced therapeutic effect.