Apically targeted oral micelles exhibit highly efficient intestinal uptake and oral absorption

Abstract

IntroductionPolymeric micelles (PMs) hold promise for improving solubility and oral absorption of poorly soluble drugs. Unfortunately, the oral absorption of PMs is also limited by intestinal epithelium. To improve the oral delivery efficiency of micelles, transporter-mediated micelles could enhance the transport efficiency across the epithelial barrier, and they have attracted more attention.MethodsPeptide transporter 1 (PepT1)-mediated micelles (Val-PMs/Phe-PMs) were designed by grafting valine (or phenylalanine) onto the surface of curcumin (Cur)-loaded-D-α-tocopheryl polyethylene glycol 1000 succinate micelles (TP-PMs). The oral absorption mechanism and oral bioavailability were further investigated in vitro and in vivo.ResultsThe cellular study showed that Val-PMs/Phe-PMs had a high PepT1 affinity, resulting in a higher drug uptake and transcellular transport than TP-PMs. In rats, Val-PMs/Phe-PMs exhibited higher intestinal accumulation in the apical side of the intestinal epithelium than TP-PMs, promoting drug diffusion across epithelial barrier. The oral bioavailability of Cur was significantly improved by Val-PMs/Phe-PMs, which was about 10.50- and 3.40-fold greater than that of Cur-Sol and TP-PMs, respectively.ConclusionPepT-1-mediated micelles, using PepT1 as a target on intestinal epithelium, have unique functions with intestine and prove promising for oral delivery of poorly water-soluble drugs.

Nanoparticles Based on Chondroitin Sulfate from Tuna Heads and Chitooligosaccharides for Enhanced Water Solubility and Sustained Release of Curcumin

“…The in vitro release study showed sustained release of CU from CHCU and CHCSCU formulations compared with the free CU suspension, as illustrated in Figure 7 . It revealed a burst release in the first 3 h, followed by a sustained release of CU over 24 h. In contrast, approximately 80% of the free CU was found in the release medium, indicating that CU displayed a rather fast release, that the dialysis bag had no detention on drug release after 24 h, and that the CHCU and CHCSCU nanoparticles released less than 20% of their CU content after 3 h and approximately 40% after 24 h. This is in line with previous studies showing that about 20–40% of CU contents were released from nanoparticles, while about 80% of CU contents were released from free CU in the medium studied within 24 h [ 67 , 89 , 90 ]. The results suggest that CU molecules were well-encapsulated within the nanoparticles, hence enhancing CU stability, and were released in a controlled manner, hence providing sustained delivery.…”

Drug Delivery with Polymeric Nanocarriers—Cellular Uptake Mechanisms

“…However, despite the amount of research on polymeric micelles, data regarding the uptake mechanisms and intracellular trafficking of these micelles remains behind. Furthermore, most research that investigated the endocytic uptake of polymeric micelles only analyzed the uptake of the drug, hence, only providing indirect evidence for nanocarrier uptake [47,[93][94][95][96][97][98][99][100][101]. As will be discussed below, this assumption may not always be correct, as the carrier and the load can separate upon the uptake.…”

Beyond nanoparticle-based oral drug delivery: transporter-mediated absorption and disease targeting

“…Tu et al synthesized Val-α-tocopherol-PEG (TSPG) or Phe-TPGS by conjugating Val or Phe to TSPG, and made their 15 nmsized PMs (e.g., Val-PM or Phe-PM). 67 After Val-PM bound to PEPT1, the formed Val-PM-PEPT1 complexes were internalized into the cells via a combination of clathrin-mediated endocytosis, caveolae-mediated endocytosis, macropinocytosis, or clathrin-/caveolae-independent endocytosis in Caco-2 cells (Fig. 8A).…”

“…Nevertheless, various NDDSs have been investigated to target GI transporters/receptors for Fig. 8 Detailed mechanisms of the entry, intracellular trafficking, and exocytosis of (A) some AA (Phe or Val)-or (B) some zwitterion-decorated NDDSs (Phe-PM, Phe-conjugated PM; 67 Val-PM, Val-conjugated PM; 67 GS-PP-PM, Gly-Sar-conjugated PM; 68 PLGA@PPP4K, PLGA/CB-PPO-PCB NP 69 ). CV, caveolae-mediated endocytosis; LR, lipid-raft-mediated endocytosis; MP, macropinocytosis; CL, clathrin-mediated endocytosis; CCI, clathrin/caveolae-independent endocytosis; ER, endoplasmic reticulum; GA, Golgi apparatus; AAT, amino acid transporter; LAT2, L-type amino acid transporter 2.…”