Bortezomib-loaded lipidic-nano drug delivery systems; formulation, therapeutic efficacy, and pharmacokinetics.

AIM: Nano drug delivery systems can provide the opportunity to reduce side effects and improve the therapeutic aspect of a variety of drugs. Bortezomib (BTZ) is a proteasome inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma. Severe side effects of BTZ are the major dose-limiting factor. Particulate drug delivery systems for BTZ are polymeric and lipidic drug delivery systems. This review focussed on lipidic-nano drug delivery systems (LNDDSs) for the delivery of BTZ. RESULTS: LNDDSs including liposomes, solid lipid nanoparticles, and self-nanoemulsifying drug delivery systems showed reduce systemic side effects, improved therapeutic efficacy, and increased intestinal absorption. Besides LNDDSs were used to target-delivery of BTZ to cancer. CONCLUSION: Overall, LNDDSs can be considered as a novel delivery system for BTZ to resolve the treatment-associated restrictions.

Eradicating acute myeloid leukemia in a Mll(PTD/wt):Flt3(ITD/wt) murine model: a path to novel therapeutic approaches for human disease.

The coexpression of the MLL partial tandem duplication (PTD) and the FLT3 internal tandem duplication (ITD) mutations associate with a poor outcome in cytogenetically normal acute myeloid leukemia (AML). In mice, a double knock-in (dKI) of Mll(PTD/wt) and Flt3(ITD/wt) mutations induces spontaneous AML with an increase in DNA methyltransferases (Dnmt1, 3a, and 3b) and global DNA methylation index, thereby recapitulating its human AML counterpart. We determined that a regulator of Dnmts, miR-29b, is downregulated in bone marrow of dKI AML mice. Bortezomib exerted a dose-dependent increase in miR-29b expression in AML blasts ex vivo, followed by decreased Dnmts, reduced proliferation, and increased apoptosis. In vivo, bortezomib was not active against dKI AML, yet liposomal-encapsulated bortezomib, as a single agent, reversed downregulation of miR-29b in vivo and induced a long-term (90-day) disease-free remission in 80% of dKI AML mice that exhibited high leukemic burden at the start of therapy, yet showed no signs of relapse at autopsy. Taken together, these data support that liposomal bortezomib, as a single agent, eradicates Mll(PTD/wt):Flt3(ITD/wt) AML in mouse and may represent a powerful and potentially curative approach to high-risk human disease.

Utilization of Lipid-based Nanoparticles to Improve the Therapeutic Benefits of Bortezomib.

Cancer is a condition where there is an uncontrolled growth of cells resulting in high mortality. It is the second most frequent cause of death worldwide. Bortezomib (BTZ) is a Proteasome Inhibitor (PI) that is used for the treatment of a variety of cancers. It is the first PI that has received the approval of the US Food and Drug Administration (FDA) to treat mantle cell lymphoma and multiple myeloma. High incidence of sideeffects, limited dose, low water solubility, fast clearance, and drug resistance are the significant limitations of BTZ. Therefore, various drug delivery systems have been tried to overcome these limitations of BTZ in cancer therapy. Nanotechnology can potentially enhance the aqueous solubility of BTZ, increase its bioavailability, and control the release of BTZ at the site of administration. The lipid-based nanocarriers, such as liposomes, solid lipid NPs, and microemulsions, are some of the developments in nanotechnology, which could potentially enhance the therapeutic benefits of BTZ.

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 vitro performances, 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.

Final Results of a Phase 1 Study of Vorinostat, Pegylated Liposomal Doxorubicin, and Bortezomib in Relapsed or Refractory Multiple Myeloma.

INTRODUCTION/BACKGROUND: Deacetylase inhibitors have synergistic activity in combination with proteasome inhibitors and anthracyclines in preclinical models of multiple myeloma (MM). We therefore evaluated the safety and efficacy of the deacetylase inhibitor vorinostat in combination with pegylated liposomal doxorubicin (PLD) and bortezomib in relapsed/refractory MM. PATIENTS AND METHODS: Thirty-two patients were treated with PLD and bortezomib in combination with escalating doses of vorinostat on days 4 to 11 or 1 to 14. RESULTS: The maximum tolerated dose of vorinostat was 400 mg on days 4 to 11. Neutropenia and thrombocytopenia attributable to protocol therapy were seen in 59% and 94% of patients, of which 37% and 47% were of grade 3 or higher severity, respectively. Constitutional and gastrointestinal adverse events of all grades were common, the majority of which were less than grade 3 in severity. The overall response rate (partial response rate or better) was 65% and the clinical benefit rate (minimal response rate or better) 74%. The overall response rate was 83%, 71%, and 45% for patients with bortezomib-naive, -sensitive, and -refractory MM, respectively. The median progression-free survival was 13.9 months and the 3-year overall survival 77%. Whole blood proteasome activity assays demonstrated a potential impact of vorinostat on the chymotryptic-like activity of the proteasome. CONCLUSION: Further evaluation of PLD, bortezomib, and deacetylase inhibitor combinations is warranted, with special attention directed toward strategies to improve tolerability.

Dendritic Glycopolymer as Drug Delivery System for Proteasome Inhibitor Bortezomib in a Calcium Phosphate Bone Cement: First Steps Toward a Local Therapy of Osteolytic Bone Lesions.

Establishment of drug delivery system (DDS) in bone substitute materials for local treatment of bone defects still requires ambitious solutions for a retarded drug release. We present two novel DDS, a weakly cationic dendritic glycopolymer and a cationic polyelectrolyte complex, composed of dendritic glycopolymer and cellulose sulfate, for the proteasome inhibitor bortezomib. Both DDS are able to induce short-term retarded release of bortezomib from calcium phosphate bone cement in comparison to a burst-release of the drug from bone cement alone. Different release parameters have been evaluated to get a first insight into the release mechanism from bone cements. In addition, biocompatibility of the calcium phosphate cement, modified with the new DDS was investigated using human mesenchymal stromal cells.

Selective intracellular delivery of proteasome inhibitors through pH-sensitive polymeric micelles directed to efficient antitumor therapy.

The ubiquitin-proteasome system is central in the regulation of cellular proteins controlling cell cycle progression and apoptosis, drawing much interest for developing effective targeted cancer therapies. Herein, we developed a novel pH-responsive polymeric-micelle-based carrier system to effectively deliver the proteasome inhibitor MG132 into cancer cells. MG132 is covalently bound to the block copolymer composed of polyethylene glycol (PEG) and polyaspartate through an acid-labile hydrazone bond. This bond is stable at physiological condition, but hydrolytically degradable in acidic compartments in the cell, such as late-endosomes and lysosomes, and thus, it was used for controlled release of MG132 after EPR-mediated preferential accumulation of the micelles into the tumor. MG132-loaded micelles have monodispersed size distribution with an average diameter of 45nm, and critical micelle concentration is well below 10(-7)M. In vitro studies against several cancer cell lines confirmed that MG132-loaded micelles retained the cytotoxic effect, and this activity was indeed due to the inhibition of proteasome by released MG132 from the micelles. Real-time in vitro confocal-microscopy experiments clearly indicated that MG132-conjugated micelles disintegrated only inside the target cells. By intravital confocal micro-videography, we also confirmed the prolonged circulation of MG132 loaded micelles in the bloodstream, which lead to tumor specific accumulation of micelles, as confirmed by in vivo imaging 24h after injection. These micelles showed significantly lower in vivo toxicity than free MG132, while achieving remarkable antitumor effect against a subcutaneous HeLa-luc tumor model. Our findings create a paradigm for future development of polymeric-micelle-based carrier system for other peptide aldehyde type proteasome inhibitors to make them effective cohort of the existing cancer therapeutic regiments.

Gold nanoparticle delivery-enhanced proteasome inhibitor effect in adenocarcinoma cells.

BACKGROUND: Proteasome inhibition is a current therapeutic strategy used in the treatment of multiple myeloma. Drugs controlling proteasome activity are ideally suited for unidirectional manipulation of cellular pathways such as apoptosis. The first proteasome inhibitor approved in clinics was bortezomib. This drug is currently used in combination with other anticancer agents. OBJECTIVES: In this study, the enhancement of bortezomib activity was evaluated using gold nanoparticles coated with poly(ethylene glycol). The uptake mechanism of the gold nanoparticles in pancreatic cell lines, S2-013 and hTERT-HPNE, was assessed by laser scanning confocal microscopy (LSCM). RESULTS: Pancreatic cancer cells internalized the nanoparticles together with the drug in few minutes through the formation of endocytic vesicles. This rapid uptake leads to an increase in the concentration and diffusion of bortezomib in the cytoplasm yielding an increased toxicity on the cells when compared to the drug alone. CONCLUSION: Gold nanoparticles can be used as effective delivery systems to increasing the permeation and retention of drugs in cancer cells.