Polyester Nanoparticles with Controlled Topography for Peroral Drug Delivery Using Insulin as a Model Protein.

Receptor-mediated polyester drug delivery systems have tremendous potential for improving the clinical performance of existing pharmaceutical drugs. Despite significant progress made in this area, it remains unclear how and to what extent the polyester nanoparticle surface topography would affect the in vitro, ex vivo and in vivo performance of a drug, and if there exists a correlation between in vitro and in vivo, as well as healthy versus pathophysiological states. Herein, we report a systematic investigation of the interactions between ligands and receptors as a function of the linker length, two-carbon (2C) versus four-carbon (4C). The in vitro, ex vivo and in vivo in healthy models validate the hypothesis that 4C has better reach and binding to the receptors. The results indicate that 4C offered better performance over 2C in vivo in improving the oral bioavailability of insulin (INS) by 1.1-fold (3.5-fold compared to unfunctionalized nanoparticles) in a healthy rat model. Similar observations were made in pathophysiological models; however, the effects were less prominent compared to those in healthy models. Throughout, ligand decorated nanoparticles outperformed unfunctionalized nanoparticles. Finally, a semimechanistic pharmacokinetic and pharmacodynamic (PKPD) model was developed using the experimental data sets to quantitatively evaluate the effect of P2Ns-GA on oral bioavailability and efficacy of insulin. The study presents a sophisticated oral delivery system for INS or hydrophilic therapeutic cargo, highlighting the significant impact on bioavailability that minor adjustments to the surface chemistry can have.

Rationally Designed Naringenin-Conjugated Polyester Nanoparticles Enable Folate Receptor-Mediated Peroral Delivery of Insulin.

Receptor-mediated transcytosis of nanoparticles is paramount for the effective delivery of various drugs. Here, we report the design and synthesis of highly functional nanoparticles with specific targeting toward the folate receptor (FR) for the peroral delivery of insulin. In doing so, we demonstrate naringenin (NAR), a citrous flavonoid, as a targeting ligand to FR, with a similar affinity as folic acid. The NAR-decorated nanoparticles indicated a 4-fold increase in FR colocalization compared to unfunctionalized nanoparticles. The NAR-conjugated precision polyester allows for high insulin loading and entrapment efficiencies. As a result, insulin-laden NAR-functional nanoparticles offered a 3-fold higher bioavailability in comparison to unfunctionalized nanoparticles. This work generated a promising contribution to folate-receptor-mediated peroral delivery of insulin, utilizing polymeric nanoparticles decorated with a natural ligand, NAR.