pH-Sensitive carboxymethyl chitosan-modified cationic liposomes for sorafenib and siRNA co-delivery

Abstract

Combination of chemotherapeutic drug and small interfering RNA (siRNA) can affect multiple disease pathways and has been proven effective in suppressing tumor progression. Co-delivery of drug and siRNA within a same nanocarrier is a vital means in this field. The present study aimed at the development of a pH-sensitive liposome to co-deliver drug and siRNA to tumor region. Driven by the electrostatic interaction, the pH-sensitive material, carboxymethyl chitosan (CMCS), was coated onto the surface of the cationic liposome (CL) preloaded with sorafenib (Sf) and siRNA (Si). To evaluate whether the resulting CMCS-modified Sf and siRNA co-delivery cationic liposome (CMCS-SiSf-CL) enhanced antitumor efficiency after systematic administration, in vitro and in vivo experiments were evaluated in HepG2 cells and the H22 cells-bearing Kunming mice model. The experimental results demonstrated that CMCS-SiSf-CL was able to condense siRNA efficiently and protect siRNA from being degraded by serum and RNase. The release rate of Sf from CMCS-modified liposome exhibited pH-sensitive release behavior. Furthermore, in vitro cellular uptake results showed that CMCS-SiSf-CL yielded higher fluorescence intensity at pH 6.5 than at pH 7.4, and that siRNA could be delivered to tumor site by CMCS-SiSf-CL in vivo. The in vivo antitumor efficacy showed that CMCS-Sf-CL inhibits tumor growth effectively when compared with free Sf solution. In current experimental conditions, this liposomal formulation did not show significant toxicity both in vitro and in vivo. Therefore, co-delivering Sf with siRNA by CMCS-SiSf-CL might provide a promising approach for tumor therapy.

Pharmacokinetics and biodistribution of polymeric micelles containing miRNA and small-molecule drug in orthotopic pancreatic tumor-bearing mice

“…Co-delivery systems may ensure similar biodistribution of the drugs and have been shown to exert synergistic antitumor effects. For example, liposomes containing anti-BCR-ABL siRNA and imatinib mesylate, micelles encapsulating doxorubicin and Bcl-2 siRNA, and β-cyclodextrin-functionalized quantum dots containing doxorubicin and mdr1 siRNA were more effective than their monotherapies 17 . However, one of the major challenges in co-delivering nucleic acids and small molecules is their diverse physicochemical properties.…”

Combinatorial therapeutic approaches with RNAi and anticancer drugs using nanodrug delivery systems

“…Simple PEGylated liposomes [51], advanced stimuli-responsive liposomes [52,53], and targeting liposomes [54,55] have all been constructed for siRNA/chemotherapeutic co-delivery in cancer. Using a PEGylated liposome to co-deliver, BCL2 siRNA with docetaxel successfully inhibited lung cancer in vitr o and in vivo [51].…”

“…Synergism was reported between these therapeutic molecules in an A549 xenograft model upon successful co-delivery using liposomes [51]. Another study by Yao et al [53] used a pH-sensitive liposome to co-deliver sorafenib and a therapeutic siRNA in cell culture and a mouse model of liver cancer. The pH-sensitive liposome was constructed by modifying pH-sensitive carboxymethyl chitosan onto a liposome preloaded with siRNA and sorafenib.…”

Non-viral siRNA and shRNA Delivery Systems in Cancer Therapy

“…The targeting and prolonged circulation half-life of liposomes allow for the enhanced permeability of tumor vasculature, increased delivery to tumor tissue, and reduced side effects [34,82]. Cationic liposomes containing siRNA targeting tumor-associated genes have been used to inhibit tumor growth and proliferation, induce apoptosis, and enhance the radiosensitivity of tumor cells [83][84][85].…”