Phospho‐ibuprofen (MDC‐917) incorporated in nanocarriers: anti‐cancer activity in vitro and in vivo

Abstract

BACKGROUND AND PURPOSEPhospho-ibuprofen (P-I; MDC-917) inhibits the growth of colon cancer in mice. Here, we investigated the use of nanocarriers to improve its pharmacokinetics (PKs) and anti tumour efficacy. EXPERIMENTAL APPROACHThe cellular uptake and cytotoxicity of P-I encapsulated into liposomes and micelles, and its in vitro metabolic stability, were determined in cultures of human colon adenocarcinoma cells. The performance of liposomal P-I was further evaluated in PK studies in mice, and in a model of colon cancer xenografts in nude mice. KEY RESULTSLiposomal P-I and micellar P-I showed significantly enhanced cellular uptake in the colon cancer cells. Liposomal P-I also demonstrated increased cytotoxicity in vitro. Free P-I was metabolized rapidly to ibuprofen in the presence of purified esterases. In contrast, liposomal P-I, and to a lesser extent micellar P-I, was resistant to esterase-mediated hydrolysis. In mice, liposomal P-I partially protected P-I from hydrolysis in the circulation, and improved the biodistribution of intact P-I and its metabolites compared to free P-I. Liposomal P-I was more effective at inhibiting the growth of human colon cancer xenografts in mice, which may be explained on the basis of its improved PK profile compared to free P-I. CONCLUSIONS AND IMPLICATIONSLiposome encapsulation of P-I partially protected P-I from esterase-mediated hydrolysis in mice, enhanced the cytotoxicity and bioavailability of P-I and increased its efficacy at inhibiting the growth of human colon cancer xenografts. These results indicate that liposomes are suitable nanocarriers for the delivery of P-I, and that the anti-tumour potential of liposomal P-I merits further evaluation.

Phospho-NSAIDs Have Enhanced Efficacy in Mice Lacking Plasma Carboxylesterase: Implications for their Clinical Pharmacology

“…Given the impact of murine Ces1c on the pharmacological activity of phospho-NSAIDs and that the human plasma does not have carboxylesterase activity, our findings provide a biological rationale for the use of Ces1c knockout mice for the pharmacokinetic and efficacy evaluation of this class of anticancer agents, as these mice may represent a more accurate model of human drug metabolism. Phospho-NSAIDs are a novel class of anticancer drugs that have demonstrated strong inhibitory effects in preclinical models of human cancers (6,13,16, 23). A common structural feature of these phospho-modified drugs is the presence of a carboxylic ester bond linking the parent NSAIDs to a phospho-head group via a linker; and the integrity of this linkage is critical for the pharmacological activity of the drugs.…”

“…In each experiment, we randomized the mice such that the starting tumor volumes between vehicle and treatment groups were within 10 mm 3 . Tumor dimensions (n ≥ 8 per group) were measured at designated time points with a digital caliper twice a week, and tumor volumes were calculated using the following formula: tumor volume = [length × width × (length + width/2) × 0.56] (6). At the end of the treatment period, the animals were sacrificed and their tumors were excised and weighed.…”

“…We have developed a series of novel phospho-modified NSAIDs (6–9), consisting of an NSAID attached to a diethyl-phosphate group via a linker. The benefits of such a modification are two-fold: enhanced therapeutic efficacy and improved safety.…”

When Is It Important to Measure Unbound Drug in Evaluating Nanomedicine Pharmacokinetics?

“…In cases where the carrier delivers the active drug directly to the target cell (e.g., tumor), the significance of the unbound drug fraction with regard to efficacy is greatly diminished, although still having importance for off-target exposure-toxicity relationships. An example of such targeted delivery systems includes nanomicelles and nanoliposomes that bind to amphipathic peptide and small-molecule drugs, thereby protecting these compounds from rapid metabolic clearance, although paradoxically also increasing drug potency (Kirchherr et al, 2009;Banerjee and Onyuksel, 2012b;Nie et al, 2012). To illustrate, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (poly-[ethylene glycol])-2000] micelles of pancreatic polypeptide and vasoactive intestinal polypeptide show resistance to proteases in vitro, an increase in total drug exposure (i.e., total drug AUC), and a marked improvement in in vivo potency Onyuksel, 2012a, 2013;Sethi et al, 2013).…”

Topical phospho-sulindac (OXT-328) is effective in the treatment of non-melanoma skin cancer

“…However, their use is limited by gastrointestinal toxicity that does not justify prolonged use in healthy individuals (7). Prompted by these concerns, our group has synthesized novel phospho-derivatives of conventional NSAIDs (8–18). Phospho-NSAIDs show superior anticancer efficacy and reduced gastrointestinal toxicity compared to conventional NSAIDs in preclinical models.…”