Thiomer-coated liposomes harbor permeation enhancing and efflux pump inhibitory properties

Abstract

An ideal oral drug carrier should facilitate drug delivery to the gastrointestinal tract and its absorption into the systemic circulation. To meet these requirements, we developed a thiomer-coated liposomal delivery system composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and a maleimide-functionalized lipid, to which chitosan-thioglycolic acid (CS-TGA) was covalently coupled. In addition to conventional 77 kDa CS-TGA (CS-TGA77), we tested the 150 kDa homologue (CS-TGA150) as well as an S-protected version of this polymer (CS-TGA150-MNA), in which some of the free SH-groups are conjugated with 6-mercaptonicotinamide to protect them from oxidation. Coupling of CS-TGA to the liposomal surface led to an increase in the particle size of at least 150 nm and an increase in the zeta potential from approximately − 33 mV to a maximum of about + 36 mV, depending on the polymer. As revealed by fluorescence dequenching the formulations have a storage stability of at least two weeks without releasing any encapsulated compounds. In simulated gastric fluid, the system was shown to be stable over 24 h, while in simulated intestinal fluid, a slow, sustained release of encapsulated compounds was observed. According to our experiments, thiomer-coated liposomes did not induce immunogenic reactions after an oral administration to mice. To evaluate the permeation enhancing and efflux pump inhibiting properties of CS-TGA coated liposomes we monitored the transport of fluoresceinisothiocyanate-dextran (FD4) and rhodamine-123 (Rho-123), respectively, through rat small intestine. Permeation studies showed a 2.8-fold higher permeation of FD4 in the presence of CS-TGA77 coated liposomes and an even 4-fold higher permeation in the presence of CSA-TGA150-MNA coated liposomes. The latter also performed best when we evaluated P-glycoprotein inhibiting properties by monitoring the transport of Rho-123, revealing a 4.2-fold enhancement respective to the buffer control. Taken together, thiomer-coated liposomes were shown to protect encapsulated drugs in the stomach, slowly release them in the small intestine and enhance their absorption through the intestinal tissue by opening tight junctions and inhibiting efflux pumps.

Hydrogel-assisted functional reconstitution of human P-glycoprotein (ABCB1) in giant liposomes

“…These results indicate that the presence of P-gp in the membrane increased the passive membrane permeability of Rho123, even when active transport was not enabled. The median P s of Rho123 across GUV membranes without P-gp (9.9 × 10 −10 m s −1 ) is approximately one order of magnitude smaller than a previously reported P s value of Rho123 diffusion across liposome membranes [55] and approximately two orders of magnitude smaller than the P s value across basolateral membranes of MDCK cells (1 × 10 −7 m s −1 ) [56] as well as the reported P s values of other known P-gp substrates. For example, P s values for vincristine, vinblastin, and verapamil across the apical membrane of Caco-2 cells were 3.3 × 10 −9 , 1.8 × 10 −7 , and 5.2 × 10 −6 m s −1 , respectively [57].…”

“…1B. Formation of liposomes from a film of ultra-low melting agarose hence led to giant liposomes with comparable, low-permeability-characteristics than liposomes prepared by other methods [55,58]. …”

Nanostructured Lipid Carriers: Versatile Oral Delivery Vehicle

“…These have found wider application in drug delivery as they can resist GIT peristalsis movements due to stronger covalent binding of thiol groups of polymers with cysteine-rich components of mucus [89]. Thiomers also possess the capability to bind to the transmembrane domain of P-gp and thus enabling higher delivery of P-gp substrate drugs [90]. In vitro studies revealed that thiomer (cysteine) conjugation onto the surface of docetaxel-loaded NLCs using postinsertion technique led to higher mucoadhesion (81.6%) with mucin in comparison to unconjugated NLCs (51.9%) [76].…”

Cysteine-Functionalized Nanostructured Lipid Carriers for Oral Delivery of Docetaxel: A Permeability and Pharmacokinetic Study

“…20 Secondly, thiomers produced increased permeation, which can improve drug transport across the intestinal epithelial cells. 21 Thirdly, they can inhibit the P-gp activity in the intestinal epithelium, due to the interaction of the thiol groups with the transmembrane domain of the efflux pump, 22,23 which is very important for the influx of the majority of anticancer drugs into intestinal epithelium cells.…”