Polymer Micelle Formulation for the Proteasome Inhibitor Drug Carfilzomib: Anticancer Efficacy and Pharmacokinetic Studies in Mice

Carfilzomib (CFZ) is a peptide epoxyketone proteasome inhibitor approved for the treatment of multiple myeloma (MM). Despite the remarkable efficacy of CFZ against MM, the clinical trials in patients with solid cancers yielded rather disappointing results with minimal clinical benefits. Rapid degradation of CFZ in vivo and its poor penetration to tumor sites are considered to be major factors limiting its efficacy against solid cancers. We previously reported that polymer micelles (PMs) composed of biodegradable block copolymers poly(ethylene glycol) (PEG) and poly(caprolactone) (PCL) can improve the metabolic stability of CFZ in vitro. Here, we prepared the CFZ-loaded PM, PEG-PCL-deoxycholic acid (CFZ-PM) and assessed its in vivo anticancer efficacy and pharmacokinetic profiles. Despite in vitro metabolic protection of CFZ, CFZ-PM did not display in vivo anticancer efficacy in mice bearing human lung cancer xenograft (H460) superior to that of the clinically used cyclodextrin-based CFZ (CFZ-CD) formulation. The plasma pharmacokinetic profiles of CFZ-PM were also comparable to those of CFZ-CD and the residual tumors that persisted in xenograft mice receiving CFZ-PM displayed an incomplete proteasome inhibition. In summary, our results showed that despite its favorable in vitroperformances, the current CFZ-PM formulation did not improve in vivo anticancer efficacy and accessibility of active CFZ to solid cancer tissues over CFZ-CD. Careful consideration of the current results and potential confounding factors may provide valuable insights into the future efforts to validate the potential of CFZ-based therapy for solid cancer and to develop effective CFZ delivery strategies that can be used to treat solid cancers

Pharmacokinetic parameters of carfilzomib after the intravenous administration of polymeric micelle formulation containing carfilzomib (CFZ-PM) and cyclodextrin-based carfilzomib formulation (CFZ-CD) to ICR mice.

<p>Pharmacokinetic parameters of carfilzomib after the intravenous administration of polymeric micelle formulation containing carfilzomib (CFZ-PM) and cyclodextrin-based carfilzomib formulation (CFZ-CD) to ICR mice.</p

Physicochemical characterization of drug-free and carfilzomib (CFZ) loaded Polymeric Micelles (PM).

<p>Physicochemical characterization of drug-free and carfilzomib (CFZ) loaded Polymeric Micelles (PM).</p

Effects of polymeric micelle formulation containing carfilzomib (CFZ-PM) vs cyclodextrin-based carfilzomib formulation (CFZ-CD) on tumor growth in H460 xenograft mice.

<p>NOD/SCID mice harboring H460 xenograft tumors were randomized to 5 different groups and received respective intravenous injections on two consecutive days per week; CFZ-PM at the dose of 3 (□) or 6 (■) mg/kg, CFZ-CD at the dose of 3 (△) mg/kg, vehicle (citrate buffer ●) and empty PM (dissolved in normal saline <b>○</b>). The upper arrow symbol (<b>↑)</b> indicates the day of drug injection. <b>(A)</b> Tumor growth curves. <b>(B, C)</b> Weights and images of excised tumor tissues on day 18. <b>(D)</b> Body weights. Data are shown as means ± S.D. (n = 4–5). *, <i>p</i> < 0.05 vs. vehicle control using ANOVA followed by Dunnett’s <i>post hoc</i> test.</p

Plasma concentration-time profiles of carfilzomib after the intravenous administration of polymeric micelle formulation containing carfilzomib (CFZ-PM) or cyclodextrin-based carfilzomib formulation (CFZ-CD) to mice (A, 3 mg/kg and B, 6 mg/kg).

<p>Data are shown as means ± S.D. (n = 4–5). The inset figures show the plasma concentration-time profiles up to 2 h.</p