Near-Infrared Fluorescent Micelles from Poly(norbornene) Brush Triblock Copolymers for Nanotheranostics
Near-Infrared Fluorescent Micelles from Poly(norbornene) Brush Triblock Copolymers for Nanotheranostics
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DOI：
10.1021/acs.biomac.1c01196
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发表时间：
2021-12-13
影响因子：
6.2
通讯作者：
Weck, Marcus
中科院分区：
文献类型：
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作者：
Braga, Carolyne B.;Pilli, Ronaldo A.;Weck, Marcus
这篇文章描述了基于两亲性刷状嵌段共聚物（BBCPs）的多功能胶束的设计和合成，用于天然抗癌化合物的成像和选择性药物递送。通过一锅法多步开环易位聚合（ROMP）合成了结构明确的双嵌段共聚物（BBCP）。所采用的三烯含有聚（乙二醇）甲基醚链、烷基溴链和/或近红外（NIR）荧光花青染料。嵌段共聚后，使用溴-叠氮取代进行聚合后转化，然后进行应变促进的叠氮-炔环加成（SPAAC），使BBCP与piplartine（PPT）部分官能化，这是一种具有充分证明的细胞毒性的天然产物。通过药物和聚合物侧链之间的酯连接基对抗癌细胞系。动态光散射分析和透射电子显微镜证实，两亲性BBCPs在水介质中自组装成具有中性表面电荷的纳米球形胶束。在自组装过程中，紫杉醇（PTX）可以有效地封装到疏水核中，形成稳定的载紫杉醇胶束具有高负载量和包封率。的NIR荧光染料含有胶束表现出显着的生物物理性质，在生理条件下，和pH值诱导的拆卸在弱酸性条件下，允许以受控的方式释放的药物的良好的胶体稳定性。体外研究表明，不含药物的胶束（空白胶束）在高达1 mg/mL（-1）的浓度下具有生物相容性，并对MCF-7癌细胞具有高细胞内化能力。药物官能化的胶束显示出与游离PPT和PTX相当的体外细胞毒性，对抗MCF-7和PC 3癌细胞，证实了在细胞内化后有效的药物释放到肿瘤环境中。此外，与正常乳腺细胞系（MCF 10A）相比，药物功能化胶束表现出比原始药物更高的选择性，并且在人癌细胞系（MCF-7和PC 3）中优先被细胞吸收。这项研究为开发用于药物递送和图像引导诊断的多功能聚合物纳米系统提供了一种有效的策略。值得注意的是，BBCP侧链通过SPAAC的容易官能化开辟了制备含有其他药物或功能（例如用于识别的靶基团）的多功能系统库的可能性。
This contribution describes the design and synthesis of multifunctional micelles based on amphiphilic brush block copolymers (BBCPs) for imaging and selective drug delivery of natural anticancer compounds. Well-defined BBCPs were synthesized via one-pot multi-step sequential grafting-through ring-opening metathesis polymerization (ROMP) of norbornene-based macroinitiators. The norbornenes employed contain a poly(ethylene glycol) methyl ether chain, an alkyl bromide chain, and/or a near-infrared (NIR) fluorescent cyanine dye. After block copolymerization, post-polymerization transformations using bromide-azide substitution, followed by the strain-promoted azide-alkyne cycloaddition (SPAAC) allowed for the functionalization of the BBCPs with the piplartine (PPT) moiety, a natural product with well-documented cytotoxicity against cancer cell lines, via an ester linker between the drug and the polymer side chain. The amphiphilic BBCPs self-assembled in aqueous media into nano-sized spherical micelles with neutral surface charges, as confirmed by dynamic light scattering analysis and transmission electron microscopy. During self-assembly, paclitaxel (PTX) could be effectively encapsulated into the hydrophobic core to form stable PTX-loaded micelles with high loading capacities and encapsulation efficiencies. The NIR fluorescent dye-containing micelles exhibited remarkable photophysical properties, excellent colloidal stability under physiological conditions, and a pH-induced disassembly under slightly acidic conditions, allowing for the release of the drug in a controlled manner. The in vitro studies demonstrated that the micelles without the drug (blank micelles) are biocompatible at concentrations of up to 1 mg mL(-1) and present a high cellular internalization capacity toward MCF-7 cancer cells. The drug-functionalized micelles showed in vitro cytotoxicity comparable to free PPT and PTX against MCF-7 and PC3 cancer cells, confirming efficient drug release into the tumor environment upon cellular internalization. Furthermore, the drug-functionalized micelles exhibited higher selectivity than the pristine drugs and preferential cellular uptake in human cancer cell lines (MCF-7 and PC3) when compared to the normal breast cell line (MCF10A). This study provides an efficient strategy for the development of versatile polymeric nanosystems for drug delivery and image-guided diagnostics. Notably, the easy functionalization of BBCP side chains via SPAAC opens up the possibility for the preparation of a library of multifunctional systems containing other drugs or functionalities, such as target groups for recognition.