Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China.
J Control Release. 2022 May;345:610-624. doi: 10.1016/j.jconrel.2022.03.042. Epub 2022 Mar 24.
Increasing knowledge of drug delivery properties, tumor profiles and their relationship promotes precise administration regimens, representing a promising pattern to personalized tumor treatment. Herein, we propose a regulatory hydrogel depot toward metastatic cancer by establishing mathematical models between tumor characteristics and administration regimens. Specifically, a thermo-sensitive PLGA-PEG-PLGA polymer is introduced as injectable hydrogel matrix, of which the administration volume and frequency are manipulated elaborately according to tumor size and gel-degradation kinetics. Structurally, doxorubicin (Dox) and arginine-terminated nanoparticles containing KIAA1199 specific shRNA (RPDNs) are incorporated into hydrogels, thereby formulating a topical and sustained drug depot to achieve synergy treatment. For dual-targeting therapy, Dox interdicts DNA replication/transcription, and shKIAA persistently silences KIAA1199 protein to modulate aggressive phenotypes. After individual peritumoral injection, Gel/RPDNs/Dox demonstrates desirable distribution patterns and gel degradation kinetics with enhanced tumor penetration. Moreover, a preferable inhibition of tumor proliferation and metastasis is confirmed after twice treatment in 12 days, indicating better therapeutic efficacy with less dosage and frequency. Consequently, the controllable administration regimen inspired mathematical models of thermosensitive hydrogel provides an intelligent platform for personalized treatment to metastatic cancer.
提高药物传递特性、肿瘤特征及其关系的认识，促进了精准给药方案的制定，为肿瘤个体化治疗提供了一种有前景的模式。在此，我们通过建立肿瘤特征与给药方案之间的数学模型，提出了一种针对转移性癌症的调控水凝胶库。具体而言，我们引入了一种温敏性 PLGA-PEG-PLGA 聚合物作为可注射水凝胶基质，根据肿瘤大小和凝胶降解动力学，精心控制给药体积和频率。结构上，阿霉素（Dox）和含有 KIAA1199 特异性 shRNA 的精氨酸末端纳米粒（RPDNs）被包埋在水凝胶中，从而形成一种局部和持续的药物库，以实现协同治疗。对于双重靶向治疗，Dox 抑制 DNA 复制/转录，shKIAA 持续沉默 KIAA1199 蛋白，从而调节侵袭表型。单次瘤周注射后，Gel/RPDNs/Dox 表现出理想的分布模式和凝胶降解动力学，并增强了肿瘤穿透性。此外，经过 12 天两次治疗后，肿瘤增殖和转移得到了更好的抑制，表明在减少剂量和频率的情况下具有更好的治疗效果。因此，基于温度敏感水凝胶的可控给药方案为转移性癌症的个体化治疗提供了一个智能平台。
