高分子键合康普瑞汀A4血管阻断剂纳米药物

Polymeric Nanodrug of Vascular Disrupting Agent Combretastatin A4

血管阻断剂(VDAs)因其在实体肿瘤治疗中的巨大潜力而引起人们的广泛关注.本文针对本课题组近年来在高分子血管阻断剂纳米药物抗肿瘤治疗方面的基础研究进行了总结.首先发现了纳米药物的瘤内低渗透性可显著提高血管阻断剂的肿瘤血管靶向性和抑瘤能力,进而构建了高分子血管阻断剂纳米药物;其次针对高分子血管阻断剂纳米药物治疗所引起的不利宿主反应,引入小分子抑制剂或激动剂进行联合治疗;然后利用其调控肿瘤微环境并创建肿瘤选择性药物激活递送系统;最后针对其治疗所产生的肿瘤凝血微环境提出了新的主动靶向策略——链式自放大肿瘤靶向,实现了高效的肿瘤靶向药物递送.这项工作突出了高分子血管阻断剂纳米药物在肿瘤治疗中的潜力,并对其未来研究方向作了简要展望,以促进其临床转化.

Vascular disrupting agents(VDAs)have aroused increasing interest due to their great potential in tumor therapy.In this work,recent progresses of our group in the polymeric nanodrug of VDAs are reviewed.As compared to combretastatin A4 phosphate(CA4P),a small-molecule prodrug of combretastatin A4 which has entered PhaseⅢclinical trials,poly(L-glutamic acid)-g-methoxy poly(ethylene glycol)/combretastatin A4(PLGCA4 or CA4-NPs)shows significantly improved the tumor blood vessels targeting and enhanced therapeutic effect due to the low permeability of nanodrug in solid tumors.However,the tumor microenvironment changes significantly after CA4-NPs treatment,which can lead to a series of host responses,such as the increased expression of VEGF-A,CXCR4 as well as the polarization of tumor-associated macrophages toward a M2-like phenotype.Several small molecule inhibitors or antagonists were used to combine with CA4-NPs for inhibiting tumor growth and metastasis.As a result,a significant reduction in tumor volume and prolonged survival time of tumor-bearing mice were observed.In addition,the levels of hypoxia and MMP-9 were regulated by using CA4-NPs,and thereby drug controlled release systems with high selectivity to tumor-microenvironment were constructed to achieve drug activation with high tumor selectivity.This significantly enhanced the therapeutic effect of MMP9-activated prodrugs and hypoxia-activated prodrugs.Based on the tumor-specific coagulation microenvironment created by the VDAs,a coagulation targeting peptide(GNQEQVSPLTLLKXC,termed A15)-decorated poly(L-glutamic acid)-graft-maleimide poly(ethylene glycol)/combretastatin A4 conjugate(A15-PLGCA4)was constructed as a self-amplifying nanotherapeutic tumor homing platform working through a chain reaction mechanism.After administration to tumor-bearing mice,A15-PLG-CA4 started a chain reaction cycle consisting of intratumoral hemorrhage,target FXIIIa amplification,blood clot binding and CA4 release in tumors to achieve a high tumor targeting efficiency.Furthermore,this self-amplifying tumor-targeting platform can be used for the selective delivery of other drugs to tumors.This work highlights the potential of the polymeric nanodrug of combretastatin A4 for tumor therapy.A brief perspective is also provided for future research directions about the VDAs nanodrug.