VLA4-Targeted Nanoparticles Hijack Cell Adhesion-Mediated Drug Resistance to Target Refractory Myeloma Cells and Prolong Survival.
VLA4-Targeted Nanoparticles Hijack Cell Adhesion-Mediated Drug Resistance to Target Refractory Myeloma Cells and Prolong Survival.
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DOI：
10.1158/1078-0432.ccr-20-2839
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发表时间：
2021-04-01
期刊：
影响因子：
--
通讯作者：
Lanza GM
中科院分区：
文献类型：
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作者：
Fontana F;Scott MJ;Allen JS;Yang X;Cui G;Pan D;Yanaba N;Fiala MA;O'Neal J;Schmieder-Atteberry AH;Ritchey J;Rettig M;Simons K;Fletcher S;Vij R;DiPersio JF;Lanza GM
在多发性骨髓瘤(MM)中，耐药细胞是化疗后复发或进展的基础。细胞黏附介导的耐药(CAM-DR)是MMC在化疗后生存的一种既定机制，其标志物在残留疾病中表达上调。整合素VLA4(α4β1)是细胞间黏附分子DR的关键调节因子，其表达影响丝裂原细胞对药物的敏感性。与其试图抑制其功能，我们在这里假设，耐药的MMC上调VLA4可以被用于靶向递送药物，这将提高治疗的安全性和有效性。我们合成了20 nm VLA4靶向胶束纳米粒(V-NP)，携带用于示踪的DiI或一种新型喜树碱前药(V-CP)。人或小鼠MMC，单独或有基质，以及免疫活性小鼠的原位MM被用来跟踪NP的传递和对治疗的反应。V-NP在体外和体内选择性地将它们的有效载荷输送到MMC，化疗通过存活MMC来增加它们的摄取。V-CP单独或与马法兰联合应用在骨髓瘤荷瘤小鼠中耐受性良好，并延长了存活时间。V-CP还降低了马法兰的剂量需求，在不增加总体毒性的情况下，降低了与次优剂量相关的肿瘤负担。V-CP可能是预防或治疗复发或难治性骨髓瘤的一种安全有效的策略。V-NP靶向耐药细胞可能为癌症的环境诱导耐药提供了一种新的途径。
In multiple myeloma (MM), drug resistant cells underlie relapse or progression following chemotherapy. Cell adhesion mediated-drug resistance (CAM-DR) is an established mechanism used by MMC to survive chemotherapy and its markers are upregulated in residual disease. The integrin VLA4 (α4β1) is a key mediator of CAM-DR and its expression affects drug sensitivity of MMC. Rather than trying to inhibit its function, we here hypothesized that up-regulation of VLA4 by resistant MMC could be exploited for targeted delivery of drugs, which would improve safety and efficacy of treatments. We synthetized 20 nm VLA4-targeted micellar nanoparticles (V-NP) carrying DiI for tracing or a novel camptothecin prodrug (V-CP). Human or murine MMC, alone or with stroma, and immunocompetent mice with orthotopic MM were used to track delivery of NP and response to treatments. V-NP selectively delivered their payload to MMC in vitro and in vivo, and chemotherapy increased their uptake by surviving MMC. V-CP, alone or in combination with melphalan, were well tolerated and prolonged survival in myeloma-bearing mice. V-CP also reduced the dose requirement for melphalan, reducing tumor burden in association to sub-optimal dosing without increasing overall toxicity. V-CP may be a safe and effective strategy to prevent or treat relapsing or refractory myeloma. V-NP targeting of resistant cells may suggest a new approach to environment-induced resistance in cancer.