Construction Of A Novel Silica-lipid Based Delivery System For Oral Delivery Of Anticancer Drugs

Liposomes are lipid vesicles that constituted by a phospholipid bilayer, which has a similar structure with the cell membrane. Different classes of drug molecules can be encapsulated by liposomes, with hydrophobic drugs typically inserted into the lipid bilayers and hydrophilic drugs loaded within the aqueous interior. Although liposomes have been extensively studied as drug carriers for parenteral administration, their potential application in oral drug delivery has also been studied.Oral liposome carriers may provide increased solubility and protection of encapsulated drugs from the harsh environment of the gastrointestinal tract. The fluidity of the lipid bilayers and the relatively small size of the liposomes greatly facilitate oral absorption. However, the instability of conventional liposomes under the physiological conditions typically found in the gastrointestinal tract has hindered clinical applications. Therefore, the aim of this study is to construct a novel oral delivery system with silica-lipid structure to improve the stability of liposome and the bioavailability of the encapsulated drug.In the first chapter, we investigated the feasibility of silica-coated ethosome as a novel oral delivery system using curcumin (poorly water-soluble) as a model drug. The silica-coated ethosomes loading curcumin (CU-SE) were prepared by alcohol injection method with homogenization, followed by the formation of a silica shell by the sol-gel process. The microstructures of the drug system were analyzed by transmission electron microscope (TEM) and fourier transform infrared (FT-IR) spectroscopy, it shows that the silica-coated ethosome is modified successful. CU-SE had a mean diameter of (478.5±80.3) nm and a polydispersity index of0.285±0.042, while the apparent entrapment efficiency was (80.77±2.19)%.In vitro release of curcumin from CU-SE and curcumin-loaded ethosomes (CU-ET) were evaluated by dynamic dialysis. Compared with CU-ET without silica-coatings, CU-SE had significantly higher stability as determined by in vitro release assays. The bioavailability of CU-SEs and CU-ETs was11.86-and2.25-fold higher, respectively, than that of crcumin suspensions (CU-SUs). Silica coating markedly improved the stability of ethosomes, and CU-SE increase in bioavailability compared with CU-ET, indicating that silica-coated ethosomes may be employed as a potential carrier to deliver drugs with poor water solubility via the oral route with improved bioavailability.Then in the second chapter, we explored to develope a novel hybrid liposome-silica nano-carrier for tumor combination therapy via oral route, using palictaxel (P-glycoprotein substrates) and cyclosporine (P-glycoprotein inhibitors) as a model drug pair. Co-delivery system was obtained by incubation with silica-coated liposomes loading paclitaxel and cyclosporine liposomes at25℃by1:3(v/v).And characterized the c-delivery system by TEM, FT-IR and confocal scanning microscopy.The obtained formulation has a mean diameter of100.2±15.2nm, the polydispersity index was0.251±0.018, and high encapsulation efficiency (90.15±2.47)%and (80.64±3.52)%for palictaxel and cyclosporine respectively.Dnamic dialysis was used to investigate the co-delivery system and other formulations at two different release medium for in vitro release. In the artificial gastric fluid, the amount of drug release from co-delivery system and silica-coated liposome loading paclitaxel was significantly reduced when encapsulated by the silica shell. In the artificial intestinal fluid, a sequential drug release trend of cyclosporine prior to paclitaxel was observed, which is conducive to improve the oral bioavailability of paclitaxel.Then pharmacokinetic study of various formulations (paclitaxel liposome, paclitaxel liposome/cyclosporine liposome mixture, co-delivery system) were investigated. The Cmax were163.4,298.1and543.9ng·mL-1,tmax were2,2and4h respectively. Compared with paclitaxel liposome and paclitaxel liposome/cyclosporine liposome mixture, the relative bioavailability of co-delivery system was up to405.27%and266.7%, indicating that the priority of sequential release of co-delivery system and synchronous release.In the pharmacodynamic study, the hybrid liposome-silica nano-carriers was investigated.The results showed that it could significantly inhibit tumor growth with good biocompatibility in vivo,which laid the foundation for further application of the delivery system.In this study, we developed a novel liposome-silica nano-carrier for tumor combination therapy via oral route.Compared with conventional liposomes, the stability of co-delivery system was significantly improved,In vivo assays showed enhanced oral bioavailability of drug by the co-delivery system and with good biocompatibility. Indicating that the promising potential of co-delivery system for multi-drug therapy against tumor and other serious diseases via oral route.