Key Lab of Biobased Polymer Materials, Shandong Provincial Education Department, School of Polymer Science and Engineering, Qingdao University of Science and Technology, Qingdao, 266042, PR China.
School of Material Science and Engineering, Qingdao University of Science and Technology, Qingdao, 266042, PR China.
Acta Biomater. 2022 Aug;148:142-151. doi: 10.1016/j.actbio.2022.06.007. Epub 2022 Jun 9.
Photothermal therapy has been extensively studied to improve the light-to-heat efficiency for tumor ablation, but could cause severe damage to adjacent healthy tissue due to the thermal transfer, the random distribution of photothermal agents (PTAs), or combination hereof. Herein, we solve this dilemma with a material design strategy to develop a P(AAm-co-AN)-b-P(NIPAM-co-DMAa)-b-P(AAm-co-AN) ABA triblock copolymer by RAFT polymerization, which exhibits both UCST and LCST dual thermo-responsive behaviors in aqueous solution. The P(AAm-co-AN) block with appropriate AN content allows to finely tune its UCST to ∼ 43°C, which can effectively co-assemble with camptothecin (CPT) and Cy7-TCF, a near-infrared (NIR) PTA, realizing the photo-activated "on-demand" release of CPT and Cy7-TCF. The LCST of P(NIPAM-co-DMAa) segment is adjusted to ∼ 53°C by varying DMAa content, enabling an irreversible sol-to-gel transition. The heat transfer in hydrogel and heat dissipation at the interface of hydrogel-adjacent tissue are limited, resulting in selectively cell killing in tumor, with little hyperthermia in adjacent tissues. Moreover, the hydrogel continues to release CPT to enhance the synergistic efficacy of PTT with chemotherapy. These results suggest that dual thermo-responsive polymer can contribute PTT with high selectivity and negligible side effects for precise medicine. STATEMENT OF SIGNIFICANCE: Photothermal therapy exploits the susceptibility of tumor cells toward external light-induced hyperthermia, but can cause severe damage to adjacent healthy tissue due to thermal transfer, random distribution of photothermal agents (PTAs), or combination hereof. Here, we solve this dilemma by developing a P(AAm-co-AN)-b-P(NIPAM-co-DMAa)-b-P(AAm-co-AN) triblock copolymer with UCST and LCST dual thermo-responsive behaviors, realizing the sequential micelle-unimer-hydrogel phase transitions. The polymer can effectively encapsulate PTA/drug, achieve long systemic circulation, accumulate in tumor through EPR effect, regulate drug release by controlling tumor temperature above UCST via irradiation, and finally exhibit a sol-gel transition, eradicating the heat transfer to adjacent tissue. This represents a practicable strategy to guide the design of next-generation polymeric vector that can contribute PTT with negligible side effects.
光热疗法已被广泛研究以提高肿瘤消融的光热效率，但由于热传递、光热剂（PTAs）的随机分布或两者的结合，会对相邻的健康组织造成严重的损伤。在这里，我们通过 RAFT 聚合开发了一种 P(AAm-co-AN)-b-P(NIPAM-co-DMAa)-b-P(AAm-co-AN)ABA 嵌段共聚物的材料设计策略来解决这一困境，该共聚物在水溶液中表现出 UCST 和 LCST 双重热响应行为。具有适当 AN 含量的 P(AAm-co-AN)嵌段可以精细地将其 UCST 调节至约 43°C，这可以有效地与喜树碱（CPT）和近红外（NIR）PTA Cy7-TCF 共组装，实现光激活的“按需”CPT 和 Cy7-TCF 释放。通过改变 DMAa 含量，将 P(NIPAM-co-DMAa)段的 LCST 调节至约 53°C，实现不可逆的溶胶-凝胶转变。水凝胶中的热传递和水凝胶-相邻组织界面的热耗散受到限制，导致肿瘤中选择性细胞杀伤，相邻组织中很少发生过热。此外，水凝胶继续释放 CPT 以增强 PTT 与化疗的协同疗效。这些结果表明，双重热响应聚合物可为精确医学提供高选择性和可忽略的副作用的光热治疗。
光热疗法利用肿瘤细胞对外部光诱导的高热的敏感性，但由于热传递、光热剂（PTAs）的随机分布或两者的结合，会对相邻的健康组织造成严重的损伤。在这里，我们通过开发具有 UCST 和 LCST 双重热响应行为的 P(AAm-co-AN)-b-P(NIPAM-co-DMAa)-b-P(AAm-co-AN)三嵌段共聚物来解决这一困境，实现了胶束-无规线团-水凝胶相转变的顺序。该聚合物可以有效地包封 PTA/药物，实现系统循环时间长，通过 EPR 效应在肿瘤中积累，通过照射将肿瘤温度控制在 UCST 以上来控制药物释放，最后发生溶胶-凝胶转变，消除向相邻组织的传热。这代表了一种可行的策略，可以指导下一代聚合物载体的设计，为光热治疗提供可忽略副作用的可能性。
