Das Manita, Joshi Apeksha, Devkar Ranjitsinh, Seshadri Sriram, Thakore Sonal
Department of Chemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390 002, India.
Department of Zoology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390 002, India.
Bioconjug Chem. 2022 Feb 16;33(2):369-385. doi: 10.1021/acs.bioconjchem.1c00614. Epub 2022 Jan 11.
An effective nanocarrier-mediated drug delivery to cancer cells primarily faces limitations like the presence of successive drug delivery barriers, insufficient circulation time, drug leakage, and decreased tumor penetration capacity. With the aim of addressing this paradox, a self-therapeutic, curcumin-derived copolymer was synthesized by conjugation with PEGylated biotin via enzyme- and acid-labile ester and acetal linkages. This copolymer is a prodrug of curcumin and self-assembles into ∼150-200 nm-sized nanomicelles; it is capable of encapsulating doxorubicin (DOX) and hence can be designated as self-therapeutic. pH- and enzyme-responsive linkages in the polymer skeleton assist in its hierarchical disassembly only in the tumor microenvironment. Further, the conjugation of biotin and poly(ethylene glycol) (PEG) imparts features of tumor specificity and improved circulation times to the nanocarrier. The dynamic light scattering (DLS) analysis supports this claim and demonstrates rapid swelling and disruption of micelles under acidic pH. UV-vis spectroscopy provided evidence of an accelerated acetal degradation at pH 4.0 and 5.0. The release studies revealed a controlled release of DOX under acidic conditions and curcumin release in response to the enzyme. The value of the combination index calculated on HepG2 cells was found to be <1, and hence, the drug pair curcumin and DOX acts synergistically for tumor regression. To prove the efficiency of acid-labile linkages and the prodrug strategy for effective cancer therapy, curcumin-derived polymers devoid of sensitive linkages were also prepared. The prodrug stimuli-responsive nanomicelles showed enhanced cell cytotoxicity and tumor penetration capability on HepG2 cells as well as drug-resistant MCF-7 cell lines and no effect on normal NIH/3T3 fibroblasts as compared to the nonresponsive micelles. The results were also supported by evidence on a hepatocellular carcinoma (HCC)-induced nude mice model. An evident decrease in MMP-2, MMP-9, and α-fetoprotein (AFP), the biomarkers specific to tumor progression, was observed along with metastasis upon treatment with the drug-loaded dual-responsive nanomicelles. These observations corroborated with the SGOT and SGPT data as well as the histoarchitecture of the liver tissue in mice.
有效的纳米载体介导的药物递送至癌细胞主要面临一系列限制，如存在连续的药物递送屏障、循环时间不足、药物泄漏以及肿瘤渗透能力下降。为了解决这一矛盾，通过酶和酸不稳定的酯及缩醛键与聚乙二醇化生物素偶联，合成了一种自治疗性的、源自姜黄素的共聚物。这种共聚物是姜黄素的前药，可自组装成约150 - 200纳米大小的纳米胶束；它能够包裹阿霉素（DOX），因此可被指定为自治疗性药物。聚合物骨架中的pH和酶响应性键仅在肿瘤微环境中协助其分级拆解。此外，生物素和聚乙二醇（PEG）的偶联赋予了纳米载体肿瘤特异性和延长循环时间的特性。动态光散射（DLS）分析支持了这一说法，并证明了胶束在酸性pH下会快速膨胀和破坏。紫外可见光谱提供了在pH 4.0和5.0时缩醛加速降解的证据。释放研究表明，在酸性条件下阿霉素可控释放，且姜黄素响应酶而释放。在HepG2细胞上计算得到的联合指数值小于1，因此，姜黄素和阿霉素药物组合对肿瘤消退具有协同作用。为了证明酸不稳定键和前药策略对有效癌症治疗的有效性，还制备了不含敏感键的源自姜黄素的聚合物。与无响应的胶束相比，前药刺激响应性纳米胶束对HepG2细胞以及耐药MCF - 7细胞系显示出增强的细胞毒性和肿瘤渗透能力，而对正常NIH/3T3成纤维细胞无影响。肝细胞癌（HCC）诱导的裸鼠模型的证据也支持了这些结果。在用载药双响应纳米胶束治疗后，观察到肿瘤进展特异性生物标志物MMP - 2、MMP - 9和甲胎蛋白（AFP）明显下降，同时伴有转移。这些观察结果与小鼠的谷草转氨酶和谷丙转氨酶数据以及肝组织的组织结构相佐证。
