ACS Appl Bio Mater. 2024 Sep 16;7(9):5810-5822. doi: 10.1021/acsabm.4c00878. Epub 2024 Aug 26.
Amphiphilic self-indicating and responsive polymer-based prodrugs have generated much interest as potential stimuli-responsive intelligent drug delivery systems (DDS) due to their ability to selectively deliver drugs to the cancer cells and to monitor real-time cellular uptake of the drug by imaging technique(s). In this direction, we have synthesized a new pH-responsive -vinyl-2-pyrrolidone and coumarin-based fluorescent self-indicating polymeric prodrug (SIPD), poly(NVP)--poly(FPA.DOX--FPA--CA). This block copolymer prodrug self-assembled into stable micellar nanoparticles under physiological conditions that reduced undesirable drug leakage to normal cells but resulted in the release of the anticancer drug doxorubicin (DOX) in cancer cells because of acidic pH-induced cleavage of imine bonds between DOX and the copolymer. While the polymer was found to be highly biocompatible with both normal (HEK-293) cells and cancer (MCF-7) cells even at high concentrations by MTT assay, the polymer prodrug nanoparticles showed toxicity even higher than that of free DOX in cancer cells. Phase contrast microscopy also depicted the cytotoxic effects of the nanoparticles on cancer cells. The coumarin units present in the polymer served as a fluorescence resonance energy transfer (FRET) pair with the covalently attached DOX molecules, which was established by steady-state and time-resolved fluorescence spectroscopy. Furthermore, confocal microscopy results confirmed the FRET phenomenon, as the fluorescence intensity of coumarin in the micellar nanoparticles remained quenched initially in MCF-7 cells but recovered with time as the DOX molecules were released and gradually shifted toward the targeted nucleus. All of these studies implied that the synthesized prodrug nanoparticles may provide another viable option for delivering chemotherapeutic drugs into cancer cells with a capability of real-time monitoring of drug release.
两亲性自指示和响应型聚合物前药由于能够选择性地将药物递送到癌细胞中，并通过成像技术实时监测药物的细胞摄取，因此作为潜在的刺激响应智能药物传递系统 (DDS) 引起了广泛关注。在这一方向上，我们合成了一种新的 pH 响应型 -乙烯基-2-吡咯烷酮和香豆素基荧光自指示聚合物前药（SIPD），聚（NVP）-聚（FPA.DOX-FPA-CA）。该嵌段共聚物前药在生理条件下自组装成稳定的胶束纳米粒子，可减少药物向正常细胞的不必要泄漏，但由于酸性 pH 诱导 DOX 与共聚物之间亚胺键的断裂，导致在癌细胞中释放抗癌药物阿霉素（DOX）。虽然通过 MTT 测定法发现该聚合物即使在高浓度下对正常（HEK-293）细胞和癌细胞（MCF-7）均具有高度的生物相容性，但聚合物前药纳米粒子在癌细胞中的毒性甚至高于游离 DOX。相差显微镜还描绘了纳米粒子对癌细胞的细胞毒性作用。聚合物中存在的香豆素单元与共价连接的 DOX 分子形成荧光共振能量转移（FRET）对，这通过稳态和时间分辨荧光光谱得到证实。此外，共聚焦显微镜结果证实了 FRET 现象，因为胶束纳米粒子中香豆素的荧光强度最初在 MCF-7 细胞中被猝灭，但随着 DOX 分子的释放，时间的推移逐渐恢复，并逐渐向靶向核转移。所有这些研究都表明，合成的前药纳米粒子可能为将化疗药物递送到癌细胞中提供另一种可行的选择，并且具有实时监测药物释放的能力。
