光热疗法已被广泛研究,以提高肿瘤消融的光热效率,但由于热传递可能会对邻近的健康组织造成严重损害,光热剂(PTAs)的随机分布,或组合。在这里,我们通过RAFT聚合开发P(AAm-co-AN)-b-P(NIPAM-co-DMAA)-b-P(AAm-co-AN)ABA三嵌段共聚物,在水溶液中表现出UCST和LCST双重热响应行为。具有适当AN内容的P(AAm-co-AN)块允许将其UCST微调至〜43°C,可以有效地与喜树碱(CPT)和Cy7-TCF共组装,近红外(NIR)PTA,实现CPT和Cy7-TCF的照片激活“按需”发布。P(NIPAM-co-DMAA)段的LCST通过改变DMAA含量调整至~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-邻近组织界面处的热耗散是有限的,导致肿瘤细胞选择性杀伤,邻近组织几乎没有热疗。此外,水凝胶继续释放CPT以增强PTT与化疗的协同功效。这些结果表明,双热响应聚合物可以以高选择性和可忽略的副作用为精确药物提供PTT。重要性声明:光热疗法利用肿瘤细胞对外部光诱导的热疗的敏感性,但由于热传递会对邻近的健康组织造成严重损害,光热剂(PTAs)的随机分布,或组合。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难题,实现顺序胶束-unimer-水凝胶相变。该聚合物可以有效地包封PTA/药物,实现长期的全身循环,通过EPR效应积聚在肿瘤中,通过辐射控制肿瘤温度高于UCST来调节药物释放,最后表现出溶胶-凝胶转变,根除向邻近组织的热传递。这代表了指导下一代聚合物载体设计的可行策略,该载体可以贡献PTT,副作用可忽略不计。
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.