Hyaluronic acid shell and disulfide-crosslinked core micelles for in vivo targeted delivery of bortezomib for the treatment of multiple myeloma

Bortezomib (BTZ) provides one of the best treatments for multiple myeloma (MM). The efficacy of BTZ is, nevertheless, restricted by its fast clearance, low selectivity, and dose limiting toxicities. Here, we report on targeted BTZ therapy of MM in vivo by hyaluronic acid-shelled and core-disulfide-crosslinked biodegradable micelles (HA-CCMs) encapsulating lipophilized BTZ, bortezomib-pinanediol (BP). HA-CCMs loaded with 7.3 BTZ equiv. wt% exhibited a small size of 78 nm, good stability in 10% FBS, and glutathione-triggered drug release. MTT assays in CD44 positive LP-1 multiple myeloma cells revealed that BP encapsulated in HA-CCMs caused enhanced antiproliferative effect compared with free BP. Flow cytometry, confocal microscopy and MTT assays indicated BP-loaded HA-CCMs (HA-CCMs-BP) could actively target to LP-1 cells and induce high antitumor effect. Proteasome activity assays in vitro showed HA-CCMs-BP had a similar Proteasome activity inhibition as compared to free BTZ at 18 h. The fluorescence imaging using Cy5-labeled HA-CCMs showed that HA-CCMs had a long elimination half-life and enhanced tumor accumulation via HA-mediated uptake mechanism. The therapeutic studies in LP-1 MM-bearing mice revealed better treatment efficacy of HA-CCMs-BP compared with free BTZ, in which HA-CCMs-BP at 3 mg BTZ equiv./kg brought about significant tumor growth inhibition and survival benefits. Loading of lipophilized BTZ into HA-shelled multifunctional micelles has emerged as an exciting approach for bortezomib therapy of MM. STATEMENT OF SIGNIFICANCE: Multiple myeloma (MM) is the second most common hematological malignancy. Bortezomib (BTZ), a potent Proteasome Inhibitor, provides one of the best treatments for MM. The clinical efficacy of BTZ is, however, limited by its quick clearance, poor selectivity, and significant side effects including myelosuppression and peripheral neuropathy. Here, we report on targeted BTZ therapy of MM in vivo by hyaluronic acid-shelled and core-disulfide-crosslinked biodegradable micelles (HA-CCMs) encapsulating lipophilized BTZ, bortezomib-pinanediol (BP). Our results showed that BP-loaded HA-CCMs exhibit markedly enhanced toleration, broadened therapeutic window, and significantly more effective growth suppression of CD44-overexpressed multiple myeloma in nude mice than free bortezomib. Lipophilized BTZ-loaded HA-CCMs has opened a new avenue for targeted bortezomib therapy of multiple myeloma.

CD44; Micelles; Multiple myeloma; Proteasome inhibitor; Reduction-sensitive; Targeted delivery.