Academy of Scientific and Innovative Research, (AcSIR) , New Delhi 110025 , India.
Department of Chemical Sciences , Indian Institute of Science Education and Research , Mohanpur, Kolkata 741246 , India.
Bioconjug Chem. 2019 Mar 20;30(3):633-646. doi: 10.1021/acs.bioconjchem.8b00831. Epub 2019 Jan 9.
Glycopolypeptide-based nanocarriers are an attractive class of drug delivery vehicles because of the involvement of carbohydrates in the receptor-mediated endocytosis process. To enhance their efficacy toward controlled and programmable drug delivery, we have prepared stable glycopolypeptide-based bioactive dual-stimuli-responsive (redox and enzyme) micelles for delivery of anticancer drugs specifically to the cancer cells. The amphiphilic biocompatible miktoarm star copolymer, which comprises two hydrophobic poly(ε-caprolactone) blocks, a short poly(propargyl glycine) middle block, and a hydrophilic galactose glycopolypeptide block, was designed and synthesized. The star copolymer is initially self-assembled into un-cross-linked (UCL) micelles, and free alkyne groups at the core-shell interface of the UCL micelles, which were cross-linked by bis(azidoethyl) disulfide (BADS) via click chemistry to form interface cross-linked (ICL) micelles. ICL micelles were found to be stable against dilution. BADS imparted redox-responsive properties to the micelles, while PCL rendered them enzyme-degradable. Dual-stimuli-responsive release behavior with Dox as model drug was studied individually as well as synergistically by applying two stimuli in different sequences. The galactose-containing UCL and ICL micelles were shown to be nontoxic. Intracellular Dox release from UCL and ICL micelles was demonstrated in liver cancer cells (HepG2) by time-dependent cellular uptake studies, and controlled release from ICL micelles compared to UCL micelles was observed. The present report opens a new approach toward targeted and programmable drug delivery in tumor tissues via a specifically targeted (receptor-mediated), dual-responsive, and stable cross-linked nanocarrier system.
基于糖肽的纳米载体由于其涉及碳水化合物在受体介导的内吞作用过程中，是一类有吸引力的药物传递载体。为了提高它们对控制和可编程药物传递的功效，我们已经制备了稳定的基于糖肽的生物活性双刺激响应（氧化还原和酶）胶束，用于将抗癌药物特异性递送到癌细胞。两亲性生物相容的杂臂星型共聚物由两个疏水性聚（ε-己内酯）块、一个短的聚（丙炔基甘氨酸）中间块和一个亲水性半乳糖糖肽块组成，被设计和合成。该星型共聚物最初自组装成未交联（UCL）胶束，并且 UCL 胶束的核壳界面上的游离炔基通过点击化学用双（叠氮乙基）二硫化物（BADS）交联，形成界面交联（ICL）胶束。发现 ICL 胶束在稀释时稳定。BADS 赋予胶束氧化还原响应特性，而 PCL 则使它们可被酶降解。通过以不同顺序施加两种刺激，分别以及协同地研究了作为模型药物的阿霉素的双重刺激响应释放行为。含有半乳糖的 UCL 和 ICL 胶束被证明是无毒的。通过时间依赖性细胞摄取研究，在肝癌细胞（HepG2）中证明了 UCL 和 ICL 胶束中细胞内阿霉素的释放，并且与 UCL 胶束相比，ICL 胶束观察到了控制释放。本报告为通过专门靶向（受体介导）、双响应和稳定交联纳米载体系统在肿瘤组织中进行靶向和可编程药物传递开辟了新途径。
