Carfilzomib Delivery by Quinic Acid-Conjugated Nanoparticles: Discrepancy Between Tumoral Drug Accumulation and Anticancer Efficacy in a Murine 4T1 Orthotopic Breast Cancer Model.

Despite being a major breakthrough in multiple myeloma therapy, carfilzomib (CFZ, a second-generation proteasome inhibitor drug) has been largely ineffective against solid cancer, possibly due to its pharmacokinetic drawbacks including metabolic instability. Recently, quinic acid (QA, a low-affinity ligand of selectins upregulated in peritumoral vasculature) was successfully utilized as a surface modifier for nanoparticles containing paclitaxel. Here, we designed QA-conjugated nanoparticles containing CFZ (CFZ@QANP; the surface of poly(lactic-co-glycolic acid) nanoparticles modified by conjugation with a QA derivative). Compared to the clinically used cyclodextrin-based formulation (CFZ-CD), CFZ@QANP enhanced the metabolic stability and in vivo exposure of CFZ in mice. CFZ@QANP, however, showed little improvement in suppressing tumor growth over CFZ-CD against the murine 4T1 orthotopic breast cancer model. CFZ@QANP yielded no enhancement in proteasomal inhibition in excised tumors despite having a higher level of remaining CFZ than CFZ-CD. These results likely arise from delayed, incomplete CFZ release from CFZ@QANP as observed using biorelevant media in vitro. These results suggest that the applicability of QANP may not be predicted by physicochemical parameters commonly used for formulation design. Our current results highlight the importance of considering drug release kinetics in designing effective CFZ formulations for solid cancer therapy.

Expanding therapeutic utility of carfilzomib for breast cancer therapy by novel albumin-coated nanocrystal formulation.

Carfilzomib (CFZ) is the second-in-class proteasome inhibitor with much improved efficacy and safety profiles over bortezomib in multiple myeloma patients. In expanding the utility of CFZ to solid cancer therapy, the poor aqueous solubility and in vivo instability of CFZ are considered major drawbacks. We investigated whether a nanocrystal (NC) formulation can address these issues and enhance anticancer efficacy of CFZ against breast cancer. The surface of NC was coated with albumin in order to enhance the formulation stability and drug delivery to tumors via interactions with albumin-binding proteins located in and near cancer cells. The novel albumin-coated NC formulation of CFZ (CFZ-alb NC) displayed improved metabolic stability and enhanced cellular interactions, uptake and cytotoxic effects in breast cancer cells in vitro. Consistently, CFZ-alb NC showed greater anticancer efficacy in a murine 4T1 orthotopic breast cancer model than the currently used cyclodextrin-based formulation. Overall, our results demonstrate the potential of CFZ-alb NC as a viable formulation for breast cancer therapy.

Quinic Acid-Conjugated Nanoparticles Enhance Drug Delivery to Solid Tumors via Interactions with Endothelial Selectins.

Current nanoparticle (NP) drug carriers mostly depend on the enhanced permeability and retention (EPR) effect for selective drug delivery to solid tumors. However, in the absence of a persistent EPR effect, the peritumoral endothelium can function as an access barrier to tumors and negatively affect the effectiveness of NPs. In recognition of the peritumoral endothelium as a potential barrier in drug delivery to tumors, poly(lactic-co-glycolic acid) (PLGA) NPs are modified with a quinic acid (QA) derivative, synthetic mimic of selectin ligands. QA-decorated NPs (QA-NP) interact with human umbilical vein endothelial cells expressing E-/P-selectins and induce transient increase in endothelial permeability to translocate across the layer. QA-NP reach selectin-upregulated tumors, achieving greater tumor accumulation and paclitaxel (PTX) delivery than polyethylene glycol-decorated NPs (PEG-NP). PTX-loaded QA-NP show greater anticancer efficacy than Taxol or PTX-loaded PEG-NP at the equivalent PTX dose in different animal models and dosing regimens. Repeated dosing of PTX-loaded QA-NP for two weeks results in complete tumor remission in 40-60% of MDA-MB-231 tumor-bearing mice, while those receiving control treatments succumb to death. QA-NP can exploit the interaction with selectin-expressing peritumoral endothelium and deliver anticancer drugs to tumors to a greater extent than the level currently possible with the EPR effect.

Next-generation proteasome inhibitors for cancer therapy.

Over 2 decades ago, the proteasome was considered a risky or even untenable therapeutic target. Today, proteasome inhibitors are a mainstay in the treatment of multiple myeloma (MM) and have sales in excess of 3 billion US dollars annually. More importantly, the availability of proteasome inhibitors has greatly improved the survival and quality of life for patients with MM. Despite the remarkable success of proteasome inhibitor therapies to date, the potential for improvement remains, and the development and optimal use of proteasome inhibitors as anticancer agents continues to be an active area of research. In this review, we briefly discuss the features and limitations of the 3 proteasome inhibitor drugs currently used in the clinic and provide an update on current efforts to develop next-generation proteasome inhibitors with the potential to overcome the limitations of existing proteasome inhibitor drugs.

Inhibition of Organic Anion Transporting Polypeptide 1B1 and 1B3 by Betulinic Acid: Effects of Preincubation and Albumin in the Media.

Betulinic acid (BA), a plant-derived pentacyclic triterpenoid, may interact with the members of the organic anion transporting polypeptide 1B subfamily. Here, we investigated the interactions of BA and its analogs with OATP1B1/3 and rat Oatp1b2 in vitro and in vivo. BA inhibited the activity of OATP1B1/3 and rat Oatp1b2 in vitro. Systemic exposure of atorvastatin was substantially altered with the intravenous co-administration of BA (20 mg/kg). Preincubation (incubation with inhibitors, followed by washout) with BA led to a sustained inhibition of OATP1B3, which recovered rapidly in the media containing 10% fetal bovine serum. The addition of albumin to the media decreased intracellular concentrations of BA and expedited the recovery of OATP1B3 activity following preincubation. For asunaprevir and cyclosporin A (previously known to inhibit OATP1B3 upon preincubation), the addition of albumin to the media shortened recovery time with asunaprevir, but not with cyclosporin A. Overall, our results showed that BA inhibits OATP1B transporters in vitro and may incur hepatic transporter-mediated drug interactions in vivo. Our results identify BA as another OATP1B3 inhibitor with preincubation effect and suggest that the preincubation effect and its duration is impacted by altered equilibrium of inhibitors between intracellular and extracellular space (e.g., albumin in the media).