A Multifunctional Polymeric Micelle for Targeted Delivery of Paclitaxel by the Inhibition of the P-Glycoprotein Transporters

Abstract

P-glycoprotein (P-gP) efflux-mediated multidrug resistance is a fundamental aspect of chemotherapeutic failure in oncology. The current study aims to deliver paclitaxel (PTX) specifically at the target site with improved in vivo efficacy of poorly permeable PTX against solid tumors. Multifunctional polymeric micelles as targeted delivery have been devised for loading and release of PTX. Mucoadhesion, permeation enhancement, oral pharmacokinetics, biodistribution, and toxicological studies were carried out to fully elucidate the therapeutic outcomes of the polymeric micelles. Ex vivo permeation studies indicated a 7.89-fold enhancement in the permeation of PTX with mucopermeating papain functionalized thiolated redox micelles (PT-R-Ms) compared to the pure PTX. Moreover, PT-R-Ms exhibited a higher percentage of apoptotic cells (42.9 ± 0.07%) compared to pure PTX. Biodistribution studies revealed that fluorotagged PT-RMs accumulated in excised tumors and organs. The higher fluorescence intensity indicated the mucopermeation of micelles across the intestine. The orally administered PT-R-Ms efficiently overcome intestinal barriers and inhibit the P-gP efflux pump, resulting in increased bioavailability of PTX (up to 8-fold) in comparison to pure PTX. The enhanced anti-tumor efficacy and reduced toxic effects are key aspects of efficient cancer therapy. This study demonstrates that the use of mucopermeating PT-R-Ms is an encouraging approach to overwhelm the permeation barrier in cancer treatment.

Mucus interaction to improve gastrointestinal retention and pharmacokinetics of orally administered nano-drug delivery systems

“…Efiana et al [ 234 ] modified self-emulsifying drug delivery systems (SEDDS) with 0.5% papain-palmitate and found a threefold increase in mucus permeability when compared to unmodified SEDDS. Razzaq et al [ 235 ] synthesized papain-functionalized thiolated redox multifunctional polymeric micelles for delivery of paclitaxel to solid tumors and demonstrated a 7.89-fold improvement in mucus penetration when compared to pure paclitaxel.…”

Multidrug Resistance in Cancer Cells: Focus on a Possible Strategy Plan to Address Colon Carcinoma Cells

“…Based on the affinity of the transporter protein, the toxicity of the protein to the normal cells, and the side effects, the modulators are selected. Anticancer drugs are administered along with the inhibitors so that the transporter proteins are kept occupied and the drug is allowed to accumulate in the cancer cells at an effective lethal concentration, as the inhibitors, when considered on a chemical basis, cause intrinsic toxicity or produce undesired effects [ 44 ]. Recent research supports the use of natural products as MDR modulators.…”

Smart Nanocarriers as an Emerging Platform for Cancer Therapy: A Review

“…P-glycoprotein (P-gp) is an efflux transporter, The efflux of diffused intracellular anticancer medicines is mostly caused by overexpression of P-gp in tumour cells, resulting in low bioavailability of the drug. Razzaq, S et al developed a mucopermeating papain functionalized thiolated redox micelle for site-specific administration of paclitaxel, that the developed formulations can inhibit P-gp efflux pump, improve oral bioavailability, higher penetration and enhanced efficacy compared to conventional paclitaxel formulation [ 61 ]. The different types of polymeric micelle for cancer therapy used in clinical trials are shown in Table 3 .…”