Huaxi MR Research Center (HMRRC), Department of Radiology, Functional and Molecular Imaging Key Laboratory of Sichuan Province, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, People's Republic of China.
Research Institute for Biomaterials, Tech Institute for Advanced Materials, College of Materials Science and Engineering, NJTech-BARTY Joint Research Center for Innovative Medical Technology, Nanjing Tech University, Nanjing, 211816, People's Republic of China.
J Nanobiotechnology. 2021 Apr 19;19(1):111. doi: 10.1186/s12951-021-00854-z.
Nanocarriers-derived antitumor therapeutics are often associated with issues of limited tumor penetration and dissatisfactory antitumor efficacies. Some multistage delivery systems have been constructed to address these issues, but they are often accompanied with complicated manufacture processes and undesirable biocompatibility, which hinder their further application in clinical practices. Herein, a novel dual-responsive multi-pocket nanoparticle was conveniently constructed through self-assembly and cross-linking of amphiphilic methoxypolyethylene glycol-lipoic acid (mPEG-LA) conjugates to enhance tumor penetration and antitumor efficacy.
The multi-pocket nanoparticles (MPNs) had a relatively large size of ~ 170 nm at physiological pH which results in prolonged blood circulation and enhanced accumulation at the tumor site. But once extravasated into acidic tumor interstices, the increased solubility of PEG led to breakage of the supramolecular nanostructure and dissolution of MPNs to small-sized (< 20 nm) nanoparticles, promoting deep penetration and distribution in tumor tissues. Furthermore, MPNs exhibited not only an excellent stable nanostructure for antitumor doxorubicin (DOX) loading, but rapid dissociation of the nanostructure under an intracellular reductive environment. With the capacity of long blood circulation, deep tumor penetration and fast intracellular drug release, the DOX-loaded multi-pocket nanoparticles demonstrated superior antitumor activities against large 4T1 tumor (~ 250 mm) bearing mice with reduced side effect.
Our facile fabrication of multi-pocket nanoparticles provided a promising way in improving solid tumor penetration and achieving a great therapeutic efficacy.
纳米载体衍生的抗肿瘤治疗药物常存在肿瘤穿透性有限和抗肿瘤疗效不理想的问题。一些多阶段递药系统已被构建用于解决这些问题，但它们通常伴随着复杂的制造工艺和不理想的生物相容性，这阻碍了它们在临床实践中的进一步应用。在此，通过两亲性甲氧基聚乙二醇-硫辛酸（mPEG-LA）缀合物的自组装和交联，方便地构建了一种新型的双响应多口袋纳米粒子，以增强肿瘤穿透性和抗肿瘤疗效。
多口袋纳米粒子（MPNs）在生理 pH 下具有约 170nm 的相对较大尺寸，这导致其在血液循环中延长，并增强在肿瘤部位的积累。但一旦渗出到酸性肿瘤间隙中，PEG 的溶解度增加会导致超分子纳米结构的破裂和 MPNs 的溶解成小尺寸（<20nm）纳米粒子，促进在肿瘤组织中的深层穿透和分布。此外，MPNs 不仅表现出优异的稳定的纳米结构用于载抗肿瘤阿霉素（DOX），而且在细胞内还原环境下能够快速解离纳米结构。具有长血液循环、深层肿瘤穿透和快速细胞内药物释放的能力，载 DOX 的多口袋纳米粒子对具有大 4T1 肿瘤（约 250mm）的荷瘤小鼠表现出优异的抗肿瘤活性，同时降低了副作用。
我们简便的多口袋纳米粒子的制备方法为提高实体瘤穿透性和实现良好的治疗效果提供了一种有前景的方法。
