Dual Carfilzomib and Doxorubicin–Loaded Liposomal Nanoparticles for Synergistic Efficacy in Multiple Myeloma

Abstract

Here, we report the synthesis and evaluation of dual drugloaded nanoparticles as an effective means to deliver carfilzomib and doxorubicin to multiple myeloma tumor cells at their optimal synergistic ratio. First, various molar ratios of carfilzomib to doxorubicin were screened against multiple myeloma cell lines to determine the molar ratio that elicited the greatest synergy using the Chou-Talalay method. The therapeutic agents were then incorporated into liposomes at the optimal synergistic ratio of 1:1 to yield dual drug-loaded nanoparticles with a narrow size range of 115 nm and high reproducibility. Our results demonstrated that the dual drug-loaded liposomes exhibited synergy in vitro and were more efficacious in inhibiting tumor growth in vivo than a combination of free drugs, while at the same time reducing systemic toxicity. Taken together, this study presents the synthesis and preclinical evaluation of dual drug-loaded liposomes containing carfilzomib and doxorubicin for enhanced therapeutic efficacy to improve patient outcome in multiple myeloma.

Second-generation proteasome inhibitor carfilzomib enhances doxorubicin-induced cytotoxicity and apoptosis in breast cancer cells

“…In imatinib-sensitive and -resistant chronic myeloid leukemia models, CFZ showed a synergistic effect in combination with tyrosine kinase inhibitors [36]. Dual drug-loaded liposomes containing CFZ and DOX exhibited synergistic efficacy in multiple myeloma in vitro and were more efficacious in inhibiting tumor growth in vivo [37]. As shown, CIs for most combinations of CFZ and DOX were far lower than 1.0, indicating synergistic effects on breast cancer cells, and the combination of the lower doses of CFZ and DOX significantly and synergistically induced increasingly cytotoxic effects and apoptosis in breast cancer cells by preventing inhibitory factor κB αlpha (IκBα) degradation in the NF-κB signal pathway and activating JNK apoptosis signaling not p38 MAPK in our assays.…”

<p>CPX-351: a nanoscale liposomal co-formulation of daunorubicin and cytarabine with unique biodistribution and tumor cell uptake properties</p>

“…Due to their in vivo stability, liposomes allow for a greater regulation of drug release and prolonged drug exposure. Together, these properties overcome issues with differing pharmacokinetic and pharmacodynamic profiles and fluctuating molar ratios in vivo 6,7. In addition, liposomal encapsulation may allow preferential targeting of specific tissues, thereby enhancing drug concentrations at the site of disease while reducing exposure to healthy tissues 7.…”

Immunoproteasome Inhibitor–Doxorubicin Conjugates Target Multiple Myeloma Cells and Release Doxorubicin upon Low-Dose Photon Irradiation

“…19 Recent studies that demonstrate synergistic effect of proteasome inhibitors and doxorubicin when applied to tumor tissue further supported our conjugate design. 20 Furthermore, N-acylation renders doxorubicin inactive (and non-toxic), allowing its use in targeting conjugates. 21 We here opted to link doxorubicin ( Figure 1, red fragment 14) to LU-035i via two photolabile linkers: the oft-used bisfunctionalized 6-nitroveratryloxycarbonyl moiety 22 and one based on the recently reported 2-(4-nitrophenyl)benzofuran chromophore ( Figure 1, blue fragment, Scheme S1).…”