LAUSR

Bortezomib (BTZ) is a proteasome inhibitor as approved by US FDA for the treatment of multiple myeloma. It exhibits significant anti-cancer properties including against solid tumors; but lacks aqueous solubility, chemical stability which hinders its successful formulation development. The present study is an attempt to deliver BTZ using N-(2-hydroxypropyl) methacrylamide (HPMA) based copolymeric conjugates and biotinylated PNPs in an effective manner. Study describes a systematic synthetic pathway to synthesize functional polymeric conjugates such as HPMA-Biotin (HP-BT) HPMA-Polylactic acid (HPLA) and HPMA-PLA-Biotin (HPLA-BT) followed by exhaustive characterization both spectroscopically and microscopically. Our strategy yielded polymeric nanoparticles (PNPs) of narrow size range of 199.7±1.32 nm. Release studies were performed at pH 7.4 and 5.6. PNPs were 2-folds less hemolytic (p<0.0001) than pure drug. BTZ loaded PNPs of HPLA-BT demonstrated significant anti-cancer activity against MCF-7 cells. IC50 values of these PNP was 56.06 ± 0.12 nM, which was approximately two folds less than BTZ (p<0.0001). Cellular uptake study confirmed that higher uptake of formulations might be an outcome of biotin surface tethering characteristics that enhanced selectivity and targeting of formulations efficiently. In vivo pharmacokinetics evidenced increased bioavailability (AUC0 t-∞) of DL-HPLA-BT PNPs (drug loaded) than BTZ with an improved half-life. Overall developed PNPs led to improved and effective BTZ delivery.