Parhizkar M, Reardon P J T, Harker A H, Browning R J, Stride E, Pedley R B, Knowles J C, Edirisinghe M
School of Pharmacy, University College London London UK
Mechanical Engineering, University College London London UK.
Nanoscale Adv. 2020 Jan 27;2(3):1177-1186. doi: 10.1039/c9na00684b. eCollection 2020 Mar 17.
There are several limitations with monodrug cancer therapy, including poor bioavailability, rapid clearance and drug resistance. Combination therapy addresses these by exploiting synergism between different drugs against cancer cells. In particular, the combination of epigenetic therapies with conventional chemotherapeutic agents can improve the initial tumour response and overcome acquired drug resistance. Co-encapsulation of multiple therapeutic agents into a single polymeric nanoparticle is one of the many approaches taken to enhance therapeutic effect and improve the pharmacokinetic profile. In this study, different types of poly(lactic--glycolic acid) (PLGA) nanoparticles (NPs), matrix and core-shell (CS), were investigated for simultaneous encapsulation of a demethylating drug, decitabine, and a potent anticancer agent, cisplatin. It was shown that by altering the configuration of the CS structure, the release profile could be tuned. In order to investigate whether this could enhance the anticancer effect compared to cisplatin, human ovarian carcinoma cell line (A2780) and its cisplatin resistant variant (A2780cis) were exposed to free cisplatin and the CS-NPs. A better response was obtained in both cell lines (11% and 51% viability of A2780 and A2780cis, respectively) using CS-NPs than cisplatin alone (27%, 82% viability of A2780 and A2780cis, respectively) or in combination with decitabine (22%, 96% viability of A2780 and A2780cis, respectively) at equivalent doses (10 μM).
单药癌症治疗存在若干局限性，包括生物利用度低、清除迅速和耐药性。联合疗法通过利用不同药物对癌细胞的协同作用来解决这些问题。特别是，表观遗传疗法与传统化疗药物的联合可以改善初始肿瘤反应并克服获得性耐药。将多种治疗剂共包封到单个聚合物纳米颗粒中是提高治疗效果和改善药代动力学特征的众多方法之一。在本研究中，研究了不同类型的聚乳酸-乙醇酸共聚物（PLGA）纳米颗粒（NPs），即基质型和核壳型（CS），用于同时包封一种去甲基化药物地西他滨和一种强效抗癌剂顺铂。结果表明，通过改变CS结构的构型，可以调节释放曲线。为了研究与顺铂相比，这是否能增强抗癌效果，将人卵巢癌细胞系（A2780）及其顺铂耐药变体（A2780cis）暴露于游离顺铂和CS-NPs中。在等效剂量（10μM）下，使用CS-NPs在两种细胞系中均获得了比单独使用顺铂（A2780和A2780cis的存活率分别为27%、82%）或与地西他滨联合使用（A2780和A2780cis的存活率分别为22%、96%）更好的反应（A2780和A2780cis的存活率分别为11%和51%）。
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