Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI, 53705, United States.
Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, 777 Highland Avenue, Madison, WI, 53705, United States.
J Control Release. 2021 Feb 10;330:1004-1015. doi: 10.1016/j.jconrel.2020.11.008. Epub 2020 Nov 7.
Poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-b-PLA) and poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) form nano-assemblies, including micelles and nanoparticles, that increase the water solubility of anticancer drugs for injection. PEG-b-PLA and PEG-b-PCL are less toxic than commonly used organic solvents or solubilizers for injection, such as Cremophor EL® in Taxol®. Formulating paclitaxel in PEG-b-PLA micelles, as Genexol-PM®, permits dose escalation over Taxol®, enhancing antitumor efficacy in breast, lung and ovarian cancers. To expand the repertoire of anticancer drugs for injection, acyl and oligo(lactic acid) ester prodrugs have been synthesized for PEG-b-PLA and PEG-b-PCL nano-assemblies, compatibility, and novel nanomedicines for injection. Notably, acyl and oligo(lactic acid) taxane prodrugs delivered by PEG-b-PLA and PEG-b-PCL nano-assemblies display heightened plasma exposure, reduction in biodistribution into major organs and enhanced tumor exposure in murine tumor models, versus parent anticancer drugs in conventional formulations. As a result, acyl and oligo(lactic acid) ester prodrugs are less toxic and induce durable antitumor responses. In summary, acyl and oligo(lactic acid) ester prodrugs widen the range of anticancer drugs that can be tested safely and effectively by using PEG-b-PLA and PEG-b-PCL nano-assemblies, and they display superior anticancer efficacy over parent anticancer drugs, which are often approved products. Oligo(lactic acid) ester taxane prodrugs are in pre-clinical development as novel drug combinations and immunotherapy combinations for cancer therapy.
聚乙二醇-嵌段-聚（D，L-乳酸）（PEG-b-PLA）和聚乙二醇-嵌段-聚（ε-己内酯）（PEG-b-PCL）形成纳米组装体，包括胶束和纳米颗粒，可提高注射用抗癌药物的水溶性。PEG-b-PLA 和 PEG-b-PCL 的毒性低于常用的注射用有机溶剂或增溶剂，如 Taxol®中的 Cremophor EL®。将紫杉醇制成 PEG-b-PLA 胶束（如 Genexol-PM®），可以在 Taxol®的基础上增加剂量，提高乳腺癌、肺癌和卵巢癌的抗肿瘤疗效。为了扩大注射用抗癌药物的种类，已经合成了酰基和低聚（乳酸）酯前药，用于 PEG-b-PLA 和 PEG-b-PCL 纳米组装体、相容性和新型注射用纳米药物。值得注意的是，通过 PEG-b-PLA 和 PEG-b-PCL 纳米组装体递送的酰基和低聚（乳酸）紫杉烷前药在小鼠肿瘤模型中表现出更高的血浆暴露度、降低主要器官的生物分布和增强肿瘤暴露度，与常规制剂中的母体抗癌药物相比。因此，酰基和低聚（乳酸）酯前药的毒性更低，并诱导持久的抗肿瘤反应。总之，酰基和低聚（乳酸）酯前药拓宽了可以使用 PEG-b-PLA 和 PEG-b-PCL 纳米组装体安全有效地测试的抗癌药物范围，并且与母体抗癌药物相比显示出更好的抗肿瘤疗效，而母体抗癌药物通常是已批准的产品。低聚（乳酸）酯紫杉烷前药正在进行临床前开发，作为癌症治疗的新型药物组合和免疫治疗组合。
