Carrier-Free Supramolecular Hydrogel Composed of Dual Drugs for Conquering Drug Resistance

Abstract

The resistance of tumor cells to anticancer drugs has become one of the principal causes of the failure in clinical chemotherapy. To overcome this issue, developing feasible drug delivery systems for effective cancer therapy is urgently needed. In this work, we construct an amphiphilic drug self-delivery system consisting of Taxol and tyroservatide (YSV) to overcome drug resistance. The carrier-free supramolecular hydrogel composed of nanofibers is formed by the involved ester bond self-hydrolysis process, which has high drug loading efficiency and facilitates the delivery of both the hydrophobic Taxol and hydrophilic YSV. Because of the dual inhibitory function of YSV on histone deacetylase and P-glycoprotein, an improved combinational anticancer effect of the molecule against drug-resistant tumor cells in vitro is achieved. Furthermore, the designed drug self-delivery system exhibited enhanced antitumor efficiency and favorable biocompatibility in vivo when administered by tail vein injection. Our study provides a new strategy for fabricating a carrier-free supramolecular hydrogel to overcome drug resistance, which might open up an alternative avenue for the tumor combinational therapy.

Self-Motivated Supramolecular Combination Chemotherapy for Overcoming Drug Resistance Based on Acid-Activated Competition of Host–Guest Interactions

“…To fabricate the acid-responsive self-motivated drug delivery system, PCB and mPEG-PLL(AF-CAA) were first synthesized based on published methods (Supporting Information). Subsequently, the anticancer drug OxPt and the mitochondria-targeting cytotoxic peptide N-Phe-KLAK with a sequence of FGG D (KALKALK) 2 were encapsulated in PCB with a molar ratio of OxPt:N-Phe-Page 8 of 28 CCS Chemistry 9 KLAK:CB [7] as 85:15:100 using a vortex mixer with a speed of 2500 rpm stirring for 1 min at the ambient temperature. As shown in Figure 1a and 1b, the host-guest interaction between OxPt or N-Phe-KLAK and PCB was explored by ITC measurement, and the apparent binding constant (K a ) was determined to be 6.94 × 10 5 M -1 and 2.64 × 10 5 M -1 , respectively, indicating the stable encapsulation of the two drugs in PCB.…”

“…The apparent binding constant was determined to be 5.32 × 10 6 M -1 at pH 6.5, which was an order of magnitude higher than those between drugs and PCB. The competitive replacement rate from CB [7] by aminomethyl phenylalanine was calculated to be 95.7% (Supporting Information). These results suggest that the drugs loaded nanoparticles SCC-NPs are successfully constructed and the mPEG-PLL(AF-CAA) is theoretically effective in competitively replacing OxPt and N-Phe-KLAK encapsulated in PCB-NPs under acidic condition.…”

“…Notably, as shown in Figure 5a, in contrast to OxPt that was highly toxic to NCM460 cells (IC 50 : 15.7 μM), SCC-NPs showed moderate toxicity with cell viabilities > 80% in the concentration range of 0~200 μM, suggesting its reduced side effects to normal cells. This advantage of reduced side effect was ascribed to the stable encapsulation by CB [7], which displayed a strong host-guest interaction with OxPt. As to HT29R cells, as shown in Figure 5b, the anticancer activity of SCC-NPs was significantly increased, with an IC 50 value of 28.6 μM, which was similar to that of OxPt (17.9 μM).…”

“…Considering that the polyethylene glycol (PEG)-based poly-cucurbit [7]uril (PCB) is effective in delivering platinum-based drugs and N-terminal phenylalanine (N-Phe)-containing therapeutic peptides, it should be an ideal carrier to achieve stable and safe combination chemotherapy. [38][39][40][41][42][43][44] Notably, the oxaliplatin (OxPt) and N-Phe-containing peptide are comparable in binding constants upon cucurbit [7]uril (CB [7]) (ca. 2 × 10 6 M -1 ), indicating the possibility of precise control of dosage ratio between different drugs.…”

Recent Progress in the Design and Application of Supramolecular Peptide Hydrogels in Cancer Therapy

“…In another example, Liu and colleagues developed a novel prodrug, namely Taxol-EYSV, which could from SPH in the tumor after intravenous injection. [167] The Taxol-EYSV molecule was synthesized by conjugating Taxol to a tripeptide tyroservatide (YSV, histone deacetylase and P-glycoprotein inhibitor) through an ester bond that could be cleaved under hydrolysis. The YSV peptide then formed hydrogel for Taxol deposition, and inhibited histone deacetylase and P-glycoprotein.…”