Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) , Tianjin 300072 , China.
Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering , Chinese Academy of Medical Sciences and Peking Union Medical College , Tianjin 300192 , China.
ACS Appl Mater Interfaces. 2019 Jun 5;11(22):19700-19711. doi: 10.1021/acsami.9b01987. Epub 2019 May 22.
High locoregional recurrence of breast cancer after surgery remains a clinically appealing challenge. Local chemotherapy, especially sustainable delivery of chemotherapeutics at tumor sites by implantable hydrogels, has shown great potential to prevent cancer recurrence. However, the applications of conventional hydrogels are often limited by their intrinsic poor drug penetration into solid tumors and nonspecific drug accumulation in adjacent normal tissues. Herein, we developed a novel modular coassembly strategy to prepare a kind of pH-sensitive, tumor-specific targeting, and penetrating peptide (CRGDK)-modified doxorubicin-based prodrug nanoparticles (PDNPs), whose aqueous dispersion can undergo sol-gel transition after in vivo injection by thermo-induced self-aggregation to in situ form biodegradable hydrogel depot (PDNPs-gel), anchoring high amounts of PDNPs at tumor sites. Because of CRGDK-mediated targeting to overexpressed neuropilin-1 receptors on tumor vessels and tumor cells, PDNPs released from PDNPs-gel can effectively penetrate into tumor tissues, specifically enter tumor cells and finally realize intracellular acid-triggered drug release. In an in vivo incomplete resection of breast cancer model, a single peritumoral administration of PDNP-gel can achieve high inhibition efficacy against tumor recurrence. In addition, the administration of PDNP-gel only involves simple redispersion of PDNPs in water without any pretreatment for gelation, providing great convenience for storage, dosage, and prescription in practical use. Collectively, the reported multifunctional nanoparticles self-aggregated hydrogel system possesses great potential for efficient postsurgical prevention of tumor recurrence.
手术后乳腺癌局部区域复发仍然是一个具有临床吸引力的挑战。局部化疗，特别是通过可植入水凝胶在肿瘤部位可持续输送化疗药物，已显示出预防癌症复发的巨大潜力。然而，传统水凝胶的应用通常受到其内在的药物在实体瘤中渗透不良和在相邻正常组织中非特异性药物积累的限制。在此，我们开发了一种新的模块化共聚组装策略来制备一种 pH 敏感、肿瘤特异性靶向和穿透肽（CRGDK）修饰的阿霉素前药纳米颗粒（PDNPs），其水分散体在体内注射后通过热诱导自组装可以进行溶胶-凝胶转变，原位形成可生物降解的水凝胶库（PDNPs-凝胶），将大量 PDNPs 固定在肿瘤部位。由于 CRGDK 介导的对肿瘤血管和肿瘤细胞上过表达的神经纤毛蛋白-1 受体的靶向作用，从 PDNPs-凝胶中释放的 PDNPs 可以有效地穿透肿瘤组织，特异性进入肿瘤细胞，最终实现细胞内酸触发的药物释放。在乳腺癌不完全切除的体内模型中，单次瘤周给药 PDNPs-凝胶即可实现对肿瘤复发的高抑制效果。此外，PDNPs-凝胶的给药仅涉及将 PDNPs 在水中简单再分散，无需进行任何凝胶化预处理，为实际应用中的储存、剂量和处方提供了极大的便利。总之，所报道的多功能纳米颗粒自组装水凝胶系统具有高效预防术后肿瘤复发的巨大潜力。
