Menachem Rotem, Nudelman Igor, Vorontsova Avital, Livneh Ido, Sela Mor, Benguigui Madeleine, Manobla Bar, Shammai Yael, Deo Abhilash, Buxbaum Chen, Bessler Ron, Raviv Ziv, Shklover Jeny, Sznitman Josué, Ciechanover Aaron, Schroeder Avi, Shaked Yuval
Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525422, Israel.
Rappaport Technion Integrated Cancer Center, Technion - Israel Institute of Technology, Haifa 3525422, Israel.
ACS Nano. 2025 Apr 1;19(12):11684-11701. doi: 10.1021/acsnano.4c10597. Epub 2025 Mar 21.
Multiple myeloma (MM) poses a significant therapeutic challenge due to its persistent progression and low survival rate. Although the proteasome inhibitor bortezomib has revolutionized MM treatment, MM aggressiveness and drug resistance remain critical concerns. To tackle this problem, we developed AMD3100-targeted Bortezomib Liposomes (ATBL) designed for the targeted delivery of bortezomib to MM cells. Uptake of ATBL into MM cells was dependent on CXCR4 and was enhanced compared to nontargeted liposomes, both and . Treating MM-bearing mice with ATBL achieved superior therapeutic efficacy compared to treatment with free bortezomib or nontargeted bortezomib-loaded liposomes. Notably, the therapeutic activity of ATBL was limited in mice inoculated with CXCR4-knockdown MM cells, highlighting CXCR4 as a potential biomarker for ATBL response. Importantly, ATBL was effective against an aggressive and bortezomib-resistant MM clone both and . Toxicity and biodistribution profiles demonstrated the safety and bone marrow-targeting ability of ATBL. Collectively, this study highlights ATBL as a promising next-generation proteasome inhibitor-based therapy that incorporates bone marrow-targeting ability and sensitizing elements to overcome drug resistance in MM.
多发性骨髓瘤（MM）由于其持续进展和低生存率而构成了重大的治疗挑战。尽管蛋白酶体抑制剂硼替佐米彻底改变了MM的治疗方式，但MM的侵袭性和耐药性仍然是关键问题。为了解决这个问题，我们开发了靶向AMD3100的硼替佐米脂质体（ATBL），其设计用于将硼替佐米靶向递送至MM细胞。ATBL被MM细胞摄取依赖于CXCR4，并且与非靶向脂质体相比摄取增强，体内和体外均如此。用ATBL治疗荷MM小鼠比用游离硼替佐米或非靶向载硼替佐米脂质体治疗具有更高的治疗效果。值得注意的是，ATBL的治疗活性在接种CXCR4基因敲低MM细胞的小鼠中受到限制，这突出了CXCR4作为ATBL反应潜在生物标志物的作用。重要的是，ATBL在体内和体外均对侵袭性和硼替佐米耐药的MM克隆有效。毒性和生物分布情况证明了ATBL的安全性和骨髓靶向能力。总体而言，本研究突出了ATBL作为一种有前景的基于蛋白酶体抑制剂的下一代疗法，其兼具骨髓靶向能力和增敏元件以克服MM中的耐药性。
