Bufalin-loaded vitamin E succinate-grafted-chitosan oligosaccharide/RGD conjugated TPGS mixed micelles demonstrated improved antitumor activity against drug-resistant colon cancer

Abstract

BackgroundMultidrug resistance (MDR) is the major reason for the failure of chemotherapy in colon cancer. Bufalin (BU) is one of the most effective antitumor active constituents in Chansu. Our previous study found that BU can effectively reverse P-glycoprotein (P-gp)-mediated MDR in colon cancer. However, the clinical application of BU is limited due to its low solubility in water and high toxicity. In the present study, a multifunctional delivery system based on vitamin-E- succinate grafted chitosan oligosaccharide (VES-CSO) and cyclic (arginine-glycine-aspartic acid peptide) (RGD)-modified d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) was prepared by emulsion solvent evaporation method for targeted delivery of BU to improve the efficacy of drug-resistant colon cancer therapy.MethodsThe cytotoxicity of BU-loaded micelles against drug-resistant colon cancer LoVo/ADR and HCT116/LOHP cells was measured by CCK-8 assay. The cellular uptake, Rho123 accumulation, and cell apoptosis were determined by flow cytometry. The expression of apoptosis-related protein and P-gp was measured by Western blot assay. The antitumor activity of BU-loaded micelles was evaluated in LoVo/ADR-bearing nude mice.ResultsBU-loaded VES-CSO/TPGS-RGD mixed micelles (BU@VeC/T-RGD MM) were 140.3 nm in diameter with zeta potential of 8.66 mV. The BU@VeC/T-RGD MM exhibited good stability, sustained-release pattern, higher intracellular uptake, and greater cytotoxicity in LoVo/ADR cells. Furthermore, the mechanisms of the BU@VeC/T-RGD MM to overcome MDR might be due to enhanced apoptosis rate and P-gp efflux inhibition. Subsequently, in vivo studies confirmed an enhanced therapeutic efficiency and reduced side effects associated with BU@VeC/T-RGD MM compared with free BU, owing to the enhanced permeation and retention effect, improved pharmacokinetic behavior, and tumor targeting, which lead to MDR-inhibiting effect in LoVo/ADR-bearing nude mice.ConclusionOur results demonstrated that VeC/T-RGD MM could be developed as a potential delivery system for BU to improve its antitumor activity against drug-resistant colon cancer.

Nanomedicine to Overcome Multidrug Resistance Mechanisms in Colon and Pancreatic Cancer: Recent Progress

“…Recently, bufalin (BU), an antitumor drug that blocks P-GP-mediated resistance in CRC [ 62 ], was associated with vitamin E succinate-grafted-chitosan oligosaccharide with RGD peptide (arginine-glycine-aspartic acid) and TPGS. Compared to free BU, this combination showed improved antitumor activity (43% tumor volume reduction), pharmacokinetic profile and toxicity in resistant-CRC (LoVo/ADR cells)-bearing nude mice [ 31 ]. Moreover, the nanoformulation alone (i.e., without P-GP inhibitors) can overcome the P-GP-mediated MDR.…”

Novel Strategies for Solubility and Bioavailability Enhancement of Bufadienolides

“…Yuan et al prepared vitamin E succinate grafted oligosaccharides (VES-CSO) and a cyclic (arginine-glycine-aspartic acid) (RGD) modified TPGS multifunctional drug delivery system ( Figure 11 B) to improve the efficacy of drug-resistant colon cancer. The results showed that BF-loaded VES-CSO/TPGS-RGD mixed micelles (BF@VEC/T-RGD MM) had higher treatment efficiency and fewer side effects compared with free BF, as well as tumor targeting due to a stronger penetration and retention effect [ 131 , 132 ]. Shi et al prepared a polymeric prodrug with BF, a tumor-targeting polypeptide (RGD), and endosomal escape polymer poly ( N , N -diethylaminoethyl methacrylate-co-butyl methacrylate) (P(DEA-co-BMA)) as carriers (BUF-NP-RGD, Figure 11 C).…”

“…Schematic for process of tumor-targeting micellar nanoparticles assembled from amphiphilic brush-type copolymers, P(OEGMA-co-BF-co-RGD)-g-P(DEA-co-BMA) ( D ). Adapted from [ 131 ].…”

Combination of Chinese and western medicine to prevent and reverse resistance of cancer cells to anticancer drugs

“…在肝癌中, 蟾毒灵可通过抑制Akt信号通 路逆转肝细胞性肝癌对索拉非尼的耐药, 同时具有逆 转多药耐药潜能 [65,66] . 在大肠癌中, 蟾毒灵与5-FU合用 具有协同增敏的作用, 且能够逆转大肠癌细胞对阿霉 素和奥沙利铂的耐药 [67,68] . 因此, 蟾毒灵具有逆转耐药 的潜在临床应用价值, 值得进一步研究.…”