The biological fate of orally administered mPEG-PDLLA polymeric micelles

Abstract

The biological fate of polymeric micelles (PMs) following oral administration was investigated in this study to better understand the contribution of transport of integral PMs to oral absorption. To track integral PMs, near-infrared fluorophores with aggregation-caused quenching properties were utilized to label PMs comprised of methoxy poly(ethylene glycol)-poly(D,L-lactic acid) (mPEG-PDLLA) copolymers and methoxy poly(ethylene glycol)-distearoyl phosphoethanolamine (DSPE-PEG). The particle size of PMs prepared from mPEG2.5k-PDLLA1.25k, mPEG2.5k-PDLLA2.5k, mPEG5k-PDLLA3k, mPEG5k-PDLLA5k and DSPE-PEG2k was 24.5, 29.5, 34.0, 41.4 and 15.6 nm, respectively. After oral administration by gavage to rats, PMs were retained in the gastrointestinal tract for at least 4 h, and the copolymer block chain lengths did not have significant influence. The emergence of fluorescence in the blood and liver served as direct evidence to support oral absorption of integral PMs. Approximately 1–2% of intact particles were absorbed via the lymphatic pathway, but the total amount of PMs that reach the systemic circulation await further elucidation. Confocal laser scanning microscopy added more evidence to support the penetration of integral PMs into the basolateral tissues of microvilli. Cellular uptake efficiency was about 4–7% in Caco-2 cell lines for all PM groups, but was reduced to 1–3% in Caco-2/HT29-MTX co-culture models due to the hindrance by the mucus layers. Approximately 6–12% of integral PMs were transported across Caco-2/HT29-MTX/Raji monolayers, whereas only approximately one-tenth of that amount was transported across Caco-2 and Caco-2/HT29-MTX monolayers. Differences, but not statistically significant, were observed between PM groups in lymphatic uptake, biodistribution, cellular uptake and trans-monolayer transport, possibly owing to difference in block chain lengths as well as particle size. In conclusion, evidence obtained in this study supports penetration of integral PMs across the enteric epithelia, but the total amount may be limited.