Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Biomedical Engineering, Washington University, St. Louis, MO, USA.
Nat Commun. 2020 Nov 27;11(1):6037. doi: 10.1038/s41467-020-19932-1.
Drug resistance and dose-limiting toxicities are significant barriers for treatment of multiple myeloma (MM). Bone marrow microenvironment (BMME) plays a major role in drug resistance in MM. Drug delivery with targeted nanoparticles have been shown to improve specificity and efficacy and reduce toxicity. We aim to improve treatments for MM by (1) using nanoparticle delivery to enhance efficacy and reduce toxicity; (2) targeting the tumor-associated endothelium for specific delivery of the cargo to the tumor area, and (3) synchronizing the delivery of chemotherapy (bortezomib; BTZ) and BMME-disrupting agents (ROCK inhibitor) to overcome BMME-induced drug resistance. We find that targeting the BMME with P-selectin glycoprotein ligand-1 (PSGL-1)-targeted BTZ and ROCK inhibitor-loaded liposomes is more effective than free drugs, non-targeted liposomes, and single-agent controls and reduces severe BTZ-associated side effects. These results support the use of PSGL-1-targeted multi-drug and even non-targeted liposomal BTZ formulations for the enhancement of patient outcome in MM.
耐药性和剂量限制毒性是多发性骨髓瘤（MM）治疗的重大障碍。骨髓微环境（BMME）在 MM 耐药性中起主要作用。靶向纳米颗粒的药物输送已被证明可提高特异性和疗效，降低毒性。我们旨在通过以下方法改善 MM 的治疗效果：（1）利用纳米颗粒输送来提高疗效和降低毒性；（2）针对肿瘤相关内皮细胞，将货物特异性递送至肿瘤区域；（3）同步递化疗药物（硼替佐米；BTZ）和破坏骨髓微环境的药物（ROCK 抑制剂），以克服骨髓微环境诱导的耐药性。我们发现，用 P-选择素糖蛋白配体-1（PSGL-1）靶向 BTZ 和 ROCK 抑制剂负载的脂质体靶向 BMME 比游离药物、非靶向脂质体和单药对照更有效，并且降低了严重的 BTZ 相关副作用。这些结果支持使用 PSGL-1 靶向多药物甚至非靶向脂质体 BTZ 制剂来提高 MM 患者的治疗效果。
