Ta Terence, Bartolak-Suki Elizabeth, Park Eun-Joo, Karrobi Kavon, McDannold Nathan J, Porter Tyrone M
Department of Biomedical Engineering, Boston University, 44 Cummington Street, Boston, MA 02215, USA.
Department of Radiology, Harvard Medical School, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115, USA.
J Control Release. 2014 Nov 28;194:71-81. doi: 10.1016/j.jconrel.2014.08.013. Epub 2014 Aug 23.
Thermosensitive liposomes have emerged as a viable strategy for localized delivery and triggered release of chemotherapy. MR-guided focused ultrasound (MRgFUS) has the capability of heating tumors in a controlled manner, and when combined with thermosensitive liposomes can potentially reduce tumor burden in vivo. However, the impact of this drug delivery strategy has rarely been investigated. We have developed a unique liposome formulation modified with p(NIPAAm-co-PAA), a polymer that confers sensitivity to both temperature and pH. These polymer-modified thermosensitive liposomes (PTSL) demonstrated sensitivity to focused ultrasound, and required lower thermal doses and were more cytotoxic than traditional formulations in vitro. A set of acoustic parameters characterizing optimal release from PTSL in vitro was applied in the design of a combined MRgFUS/PTSL delivery platform. This platform more effectively reduced tumor burden in vivo when compared to free drug and traditional formulations. Histological analysis indicated greater tumor penetration, more extensive ECM remodeling, and greater cell destruction in tumors administered PTSL, correlating with improved response to the therapy.
热敏脂质体已成为一种可行的局部给药和触发化疗药物释放的策略。磁共振引导聚焦超声（MRgFUS）能够以可控方式加热肿瘤，与热敏脂质体联合使用时，有可能在体内减轻肿瘤负担。然而，这种药物递送策略的影响很少被研究。我们开发了一种独特的脂质体制剂，用聚（N-异丙基丙烯酰胺-共-丙烯酸）（p(NIPAAm-co-PAA)）进行修饰，该聚合物对温度和pH均具有敏感性。这些聚合物修饰的热敏脂质体（PTSL）对聚焦超声表现出敏感性，在体外比传统制剂需要更低的热剂量且具有更强的细胞毒性。在设计联合MRgFUS/PTSL递送平台时，应用了一组表征PTSL在体外最佳释放的声学参数。与游离药物和传统制剂相比，该平台在体内更有效地减轻了肿瘤负担。组织学分析表明，给予PTSL的肿瘤中肿瘤穿透性更强、细胞外基质重塑更广泛且细胞破坏更严重，这与治疗反应的改善相关。
