Surnar Bapurao, Jayakannan Manickam
Department of Chemistry, Indian Institute of Science Education and Research (IISER) Pune , Dr. Homi Bhabha Road, Pune 411008, Maharashtra, India.
Biomacromolecules. 2016 Dec 12;17(12):4075-4085. doi: 10.1021/acs.biomac.6b01608. Epub 2016 Nov 23.
A unique biodegradable triple block nanocarrier (TBN) is designed and developed for synergistic combination therapy of antagonistic drugs for cancer treatment. The TBN was built with hydrophilic polyethylene glycol (PEG) outer shell; a middle hydrophobic and biodegradable polycaprolactone (PCL) block for encapsulating anthracycline anticancer drug like doxorubicin (DOX), and an inner carboxylic-functionalized polycaprolactone (CPCL) core for cisplatin (CP) drug conjugation. TBN-cisplatin drug conjugate self-assembled as stable nanoparticles in saline (also in PBS) wherein the hydrophobic PCL block functions as a shield for Pt-drug stability against GSH detoxification. Enzymatic-biodegradation of TBN exclusively occurred at the intracellular environment to deliver both cisplatin (CP) and doxorubicin (DOX) simultaneously to the nucleus. As a result, the TBN-cisplatin conjugate and its DOX-loaded nanoparticles accomplished 100% cell growth inhibition in GSH overexpressed breast cancer cells. Combination therapy revealed that free drugs were antagonistic to each other, whereas the dual drug-loaded TBN exhibited excellent synergistic cell killing at much lower drug concentrations in breast cancer cells. Confocal microscopic analysis confirmed the localization of drugs in the cytoplasm and at peri-nuclear site. Flow cytometry analysis revealed that the drugs were taken up 4-fold better while delivering them from TBN platform compared to free form. The TBNs approach is a perfect platform to overcome the GSH detoxification in Pt-drugs and enable the codelivery of antagonistic drugs like cisplatin and DOX from single polymer dose to accomplish synergistic killing in breast cancer cells.
一种独特的可生物降解三嵌段纳米载体（TBN）被设计并开发用于癌症治疗中拮抗药物的协同联合治疗。TBN由亲水性聚乙二醇（PEG）外壳构建而成；中间是疏水性且可生物降解的聚己内酯（PCL）嵌段，用于封装多柔比星等蒽环类抗癌药物（如阿霉素（DOX）），内部是用于顺铂（CP）药物偶联的羧基功能化聚己内酯（CPCL）核心。TBN - 顺铂药物偶联物在盐溶液（也在磷酸盐缓冲液中）中自组装成稳定的纳米颗粒，其中疏水性PCL嵌段起到保护Pt - 药物稳定性以抵抗谷胱甘肽解毒的作用。TBN的酶促生物降解仅在细胞内环境中发生，以同时将顺铂（CP）和阿霉素（DOX）递送至细胞核。结果，TBN - 顺铂偶联物及其负载DOX的纳米颗粒在谷胱甘肽过表达的乳腺癌细胞中实现了100%的细胞生长抑制。联合治疗表明游离药物相互拮抗，而负载双药的TBN在乳腺癌细胞中以低得多的药物浓度表现出优异的协同细胞杀伤作用。共聚焦显微镜分析证实了药物在细胞质和核周部位的定位。流式细胞术分析表明，与游离形式相比，从TBN平台递送药物时药物的摄取量提高了4倍。TBN方法是一个完美的平台，可克服Pt - 药物中的谷胱甘肽解毒作用，并能够从单一聚合物剂量实现顺铂和DOX等拮抗药物的共递送，以在乳腺癌细胞中实现协同杀伤。
