Toward understanding polymer micelle stability: Density ultracentrifugation offers insight into polymer micelle stability in human fluids

Abstract

Micelles, as a class of drug delivery systems, are underrepresented among United States Food and Drug Administration approved drugs. A lack of clinical translation of these systems may be due to, in part, to a lack of understanding of micelle interactions with biologic fluids following injection. Despite the limited clinical translation, micelles remain an active area of research focus and pre-clinical development. The goal of the present study was to examine the stability of amphiphilic block copolymer micelles in biologic fluids to identify the properties and components of biologic fluids that influence micelle stability. Micelle stability, measured via Förster resonance energy transfer-based fluorescent spectrometry, was complemented with density ultracentrifugation to reveal the colocalized, or dissociated, state of the dye cargo after exposure to human biologic fluids. Polymeric micelles composed of poly(ethylene glycol-block-caprolactone) (mPEG-CL) and poly(ethylene glycol-block-lactide) (mPEG-LA) were unstable in fetal bovine serum, human serum and synovial fluid, with varying levels of instability observed in ascites and pleural fluid. All polymeric micelles exhibited stability in cerebrospinal fluid, highlighting the potential for local cerebro-spinal administration of micelles. Interestingly, mPEG2.2k-CL3.1k and mPEG2k-LA2.7k micelles favored dissolution whereas mPEG5.4k-LA28.5k micelles favored stability. Taken together, our data offers both quantitative and qualitative evidence for micelle stability within human biologic fluids and offers evidence of polymer micelle instability in biologic fluids that is not explained by either total protein content or total unsaturated lipid content. The results help to identify potential sites for local delivery where stability is maintained.