NTU-Northwestern Institute for Nanomedicine, Interdisciplinary Graduate School , Nanyang Technological University , 50 Nanyang Drive , Singapore 637553.
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences , Nanyang Technological University , 21 Nanyang Link , Singapore 637371.
ACS Appl Mater Interfaces. 2019 May 8;11(18):16391-16401. doi: 10.1021/acsami.9b04557. Epub 2019 Apr 26.
Nanomedicine has emerged as a promising strategy for effective cancer treatment. A useful approach is to develop carrier-free nanodrugs via a facile supramolecular self-assembly process. To achieve high therapeutic effect, integrating photodynamic therapy with chemotherapy has been sought after. In this work, we designed a nanocarrier (PEG-Por-CD: oxliPt(IV)-ada) assembled with oxaliplatin prodrug (oxliPt(IV)-ada) and porphyrin photosensitizer (PEG-Por-CD) through host-guest interaction to achieve stimulus-responsive combination therapy. Contributed by excellent spatial control of the binding ratio between host and guest molecules, porphyrin and oxaliplatin were separately modified with β-cyclodextrin and adamantane to prepare the amphiphilic host-guest complex for subsequent self-assembly into therapeutic nanoparticles. The obtained PEG-Por-CD: oxliPt(IV)-ada nanoparticles exhibited good colloidal stability with an average hydrodynamic size of 164 nm while undergoing the disassembly under reductive environment to release active therapeutic species. Confocal imaging demonstrated the ability of PEG-Por-CD: oxliPt(IV)-ada to effectively accumulate in the cells and produce reactive oxygen species in vitro upon 630 nm light irradiation. As compared with the monotherapy, the PEG-Por-CD: oxliPt(IV)-ada nanoparticles exhibited 3-fold enhanced cytotoxicity and 2-fold increase in the apoptosis. In vivo experiments using 4T1 tumor-bearing mice confirmed that the nanoparticles were efficient in suppressing the tumor growth without eliciting systemic toxicity. The present self-delivery nanosystem constructed from the self-assembly approach not only allows precise control over the drug and photosensitizer loading ratio but also eliminates systemic toxicity concern of the drug carriers, providing a solution for further development of combinational cancer treatment.
纳米医学已成为癌症治疗的一种很有前途的策略。一种有用的方法是通过简便的超分子自组装过程开发无载体纳米药物。为了达到高治疗效果，已经寻求将光动力疗法与化学疗法相结合。在这项工作中，我们通过主客体相互作用设计了一种纳米载体（PEG-Por-CD：oxliPt(IV)-ada），该载体由奥沙利铂前药（oxliPt(IV)-ada）和卟啉光敏剂（PEG-Por-CD）组装而成，以实现刺激响应性联合治疗。由于主体和客体分子之间结合比的空间控制出色，因此将卟啉和奥沙利铂分别用β-环糊精和金刚烷进行修饰，以制备两亲性主客体配合物，随后自组装成治疗性纳米颗粒。所获得的 PEG-Por-CD：oxliPt(IV)-ada 纳米颗粒在还原环境下发生解组装以释放活性治疗物质时，表现出良好的胶体稳定性，平均水动力粒径为 164nm。共聚焦成像表明，PEG-Por-CD：oxliPt(IV)-ada 能够有效地在细胞中积累，并在 630nm 光照射下在体外产生活性氧。与单一疗法相比，PEG-Por-CD：oxliPt(IV)-ada 纳米颗粒表现出 3 倍的细胞毒性增强和 2 倍的细胞凋亡增加。使用 4T1 荷瘤小鼠的体内实验证实，纳米颗粒能够有效地抑制肿瘤生长而不会引起全身毒性。本研究使用自组装方法构建的自递送纳米系统不仅可以精确控制药物和光敏剂的载药量，而且还可以消除药物载体的全身毒性问题，为进一步开发联合癌症治疗提供了一种解决方案。
