VLA4-nanoparticles hijack cell adhesion mediated drug resistance (CAM-DR) to target refractory myeloma cells and prolong survival.

Background 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 (a4b1) 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. Methods 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. Results 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. Conclusions 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. Conclusions 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.