Polymeric micelles loaded with carfilzomib increase tolerability in a humanized bone marrow-like scaffold mouse model.

Carfilzomib-loaded polymeric micelles (CFZ-PM) based on poly(ethylene glycol)-b-poly(N-2-benzoyloxypropyl methacrylamide) (mPEG-b-p(HPMA-Bz)) were prepared with the aim to improve the maximum tolerated dose of carfilzomib in a "humanized" bone marrow-like scaffold model. For this, CFZ-PM were prepared and characterized for their size, carfilzomib loading and cytotoxicity towards multiple myeloma cells. Further, circulation and tumor & tissue distribution of fluorescently labeled micelles were determined. Tolerability of CFZ-PM versus the clinical approved formulation - Kyprolis® - was assessed. CFZ-PM presented small diameter below 55 nm and low PDI < 0.1. Cy7-labeled micelles circulated for extended periods of time with over 80% of injected dose in circulation at 24 h after intravenous injection and 1.3% of the injected dose of Cy7-labeled micelles accumulated in myeloma tumor-bearing scaffolds. Importantly, CFZ-PM were well tolerated whereas Kyprolis® showed adverse effects. Kyprolis® dosed at the maximum tolerated dose, as well as CFZ-PM, did not show therapeutic benefit, while multiple myeloma cells showed sensitivity in vitro, underlining the importance of the bone marrow crosstalk in testing novel formulations. Overall, this work indicates that PM are potential drug carriers of carfilzomib.

Liposomal dexamethasone inhibits tumor growth in an advanced human-mouse hybrid model of multiple myeloma.

Glucocorticoids are the cornerstone in the clinic for treatment of hematological malignancies, including multiple myeloma. Nevertheless, poor pharmacokinetic properties of glucocorticoids require high and frequent dosing with the off-target adverse effects defining the maximum dose. Recently, nanomedicine formulations of glucocorticoids have been developed that improve the pharmacokinetic profile, limit adverse effects and improve solid tumor accumulation. Multiple myeloma is a hematological malignancy characterized by uncontrolled growth of plasma cells. These tumors initiate increased angiogenesis and microvessel density in the bone marrow, which might be exploited using nanomedicines, such as liposomes. Nano-sized particles can accumulate as a result of the increased vascular leakiness at the bone marrow tumor lesions. Pre-clinical screening of novel anti-myeloma therapeutics in vivo requires a suitable animal model that represents key features of the disease. In this study, we show that fluorescently labeled long circulating liposomes were found in plasma up to 24 h after injection in an advanced human-mouse hybrid model of multiple myeloma. Besides the organs involved in clearance, liposomes were also found to accumulate in tumor bearing human-bone scaffolds. The therapeutic efficacy of liposomal dexamethasone phosphate was evaluated in this model showing strong tumor growth inhibition while free drug being ineffective at an equivalent dose (4 mg/kg) regimen. The liposomal formulation slightly reduced total body weight of myeloma-bearing mice during the course of treatment, which appeared reversible when treatment was stopped. Liposomal dexamethasone could be further developed as monotherapy or could fit in with existing therapy regimens to improve therapeutic outcomes for multiple myeloma.