Department of Chemistry, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Department of Cardiovascular Diseases, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Molecules. 2022 May 28;27(11):3485. doi: 10.3390/molecules27113485.
Limited tissue selectivity and targeting of anticancer therapeutics in systemic administration can produce harmful side effects in the body. Various polymer nano-vehicles have been developed to encapsulate therapeutics and prevent premature drug release. Dually responsive polymeric vesicles (polymersomes) assembled from temperature-/pH-sensitive block copolymers are particularly interesting for the delivery of encapsulated therapeutics to targeted tumors and inflamed tissues. We have previously demonstrated that temperature-responsive poly(-vinylcaprolactam) (PVCL)--poly(dimethylsiloxane) (PDMS)--PVCL polymersomes exhibit high loading efficiency of anticancer therapeutics in physiological conditions. However, the in-vivo toxicity of these polymersomes as biocompatible materials has not yet been explored. Nevertheless, developing an advanced therapeutic nanocarrier must provide the knowledge of possible risks from the material's toxicity to support its future clinical research in humans. Herein, we studied pH-induced degradation of PVCL--PDMS--PVCL vesicles in-situ and their dually (pH- and temperature-) responsive release of the anticancer drug, doxorubicin, using NMR, DLS, TEM, and absorbance spectroscopy. The toxic potential of the polymersomes was evaluated in-vivo by intravenous injection (40 mg kg single dose) of PVCL-PDMS-PVCL vesicles to mice. The sub-acute toxicity study (14 days) included gravimetric, histological, and hematological analyses and provided evidence for good biocompatibility and non-toxicity of the biomaterial. These results show the potential of these vesicles to be used in clinical research.
在全身给药时，抗癌治疗药物的组织选择性和靶向性有限，会在体内产生有害的副作用。已经开发出各种聚合物纳米载体来封装治疗药物并防止药物过早释放。由温度/ pH 敏感嵌段共聚物组装而成的双重响应聚合物囊泡（聚合物囊泡）对于将封装的治疗药物递送到靶向肿瘤和炎症组织特别有趣。我们之前已经证明，温度响应性聚（-乙烯己内酯）（PVCL）-聚（二甲基硅氧烷）（PDMS）-PVCL 聚合物囊泡在生理条件下表现出高的抗癌治疗药物负载效率。然而，这些聚合物囊泡作为生物相容材料的体内毒性尚未得到探索。然而，开发先进的治疗性纳米载体必须提供材料毒性可能带来的风险的知识，以支持其未来在人类中的临床研究。在此，我们使用 NMR、DLS、TEM 和吸收光谱原位研究了 pH 诱导的 PVCL-PDMS-PVCL 囊泡的降解及其对阿霉素等抗癌药物的双重（pH 和温度）响应释放。通过静脉注射（40mgkg 单次剂量）PVCL-PDMS-PVCL 囊泡到小鼠体内来评估聚合物囊泡的潜在毒性。亚急性毒性研究（14 天）包括重量分析、组织学和血液学分析，并为生物材料的良好生物相容性和非毒性提供了证据。这些结果表明这些囊泡有潜力用于临床研究。
