Anti-CD38 targeted carfilzomib-loaded hybrid nanocomposites for multiple myeloma therapy: cytotoxicity and biodistribution.

Carfilzomib (CFZ), a second-generation proteasome inhibitor, offers potent activity against multiple myeloma (MM) but suffers from rapid clearance, short half-life (< 30 min), and poor in vivo stability, which limit its therapeutic efficacy. To overcome these challenges, we designed a targeted nanotherapeutic system i.e., anti-CD38 monoclonal antibody (mAb) functionalized carfilzomib loaded PCL nanocomposites (Ab-CFZ-PCL-NPs). Nanocomposites were fabricated using a nanoprecipitation method within a quality by design (QbD) framework and characterized by Fourier transformed infrared (FTIR), dynamic light scattering (DLS), and entrapment efficiency studies. DLS analysis showed that the mean hydrodynamic diameter and PDI of CFZ-PCL-NPs were 103.6 ± 0.134 nm and 0.113 ± 0.177, respectively. In contrast, the Anti-CD38 conjugated nanocomposites exhibited a significantly larger size of 189.9 ± 0.321 nm (p < 0.05, Student’s t-test) and a PDI of 0.135 ± 0.126, confirming the successful surface deposition of the Anti-CD38 antibody. The in vitro drug release demonstrated sustained drug diffusion at physiological pH(7.4) with 91.12 ± 1.058% DR (up to 10 days) while a significantly faster drug diffusion (96.78 ± 0.942% (up to 4 days) was observed at tumor stimulating pH(5.5) corroborating a pH responsively behavior of nanosystem .Antibody conjugation significantly improved cellular uptake (> 85%), cytotoxicity (> 90%) in multiple myeloma cells (MM cells), and high tumor growth inhibition(> 85%) compared to non-conjugated nanocomposites. This work highlights the novelty of combining proteasome inhibition with anti-CD38 targeting in a single nano-formulation, offering prolonged drug retention, improved tumor-specific delivery, and reduced systemic limitations of CFZ. The Ab-CFZ-PCL-NPs establish a promising theragnostic platform for advancing precision therapies in multiple myeloma beyond conventional nanoparticle approaches.