Folate-Modified Chitosan Nanoparticles Coated Interferon-Inducible Protein-10 Gene Enhance Cytotoxic T Lymphocytes' Responses to Hepatocellular Carcinoma

Abstract

Adoptive therapy using tumor antigen-specific cytotoxic T lymphocytes (CTLs) is a promising approach for treatment of human cancers. Due to immune suppression in cancer patients, it is difficult for tumor antigen-specific CTLs to arrive at tumor tissues. Interferon-inducible protein-10 (IP-10) is a powerful chemokine that effectively attracts CTLs to tumor tissues and improves their anti-tumor activity. Increase over expression of IP-10 in tumor tissues can efficiently promote efficacy of adoptive therapy. Folate-modified chitosan nanoparticles coating the human IP-10 gene (FA-CS-hIP-10) were therefore developed in this study. The FA-CS-hIP-10 nanoparticles were specifically bound to folate receptors on hepatoma cells and promoted the expression of IP-10, to improve the activity of pMAGE-A1(278-286) specific CTLs. Combination of the FA-CS-hIP-10 and pMAGE-A1(278-286) specific CD8+ CTLs efficiently increased secretion of IFN-γ, inhibited tumor growth and extended survival of nude mice with subcutaneously transplanted human hepatocellular carcinoma. Our results demonstrated that the mechanism behind this novel therapeutic approach involved inhibition of angiogenesis and proliferation, and also promoted apoptosis of tumor cells. Our study provides a potentially novel approach for treatment of human hepatocellular carcinoma by improving the activity of tumor antigen-specific CTLs.

Functionalization of chitosan with carboxylic acids and derivatives of them: Synthesis issues and prospects of practical use: A review

“…In addition, chitosan possesses good adhesion to the stromal cells; this is important for the design of the scaffolds [4,15,16]. Chitosan derivatives are used as hydrogels or nanoparticles for the design of the carriers of drugs, the agents for diagnostics of food additives or cancer, as well as for the design of materials for the extraction of toxic heavy metals from wastewaters [17][18][19][20][21][22]. The functional groups of chitosan, especially the amino groups, give an opportunity of the chemical functionalization of this aminopolysaccharide; this permits one to extent a range of the materials on base of chitosan as well as improving characteristic properties of them.…”

Opportunities and Challenges of Nanoparticles in Digestive Tumours as Anti-Angiogenic Therapies

“…After intravenous injection of GX1-DGC-DCT, tumour growth in xenograft gastric cancer models showed a tumour inhibition rate of 67.05% compared with the single DCT group (145). Some similar studies in gastric cancer reported that chitosan oligosaccharide (COS)-conjugated selenium (Se) and carboxymethyl chitosan (CMCS)-conjugated norcantharidin (NCTD) could remarkably enhance its antitumour efficacy (153)(154)(155)(156). PEG, polylactic acid (PLA), and polycaprolactone (PCL) are FDA-approved commercially available biodegradable copolymers that are widely used to prepare nanoparticles for drug delivery (157).…”

The effects of dendritic cell-based vaccines in the tumor microenvironment: Impact on myeloid-derived suppressor cells

“…In cancer, chitosan is mainly used in chemotherapeutic delivery and as an immunoadjuvant in vaccines (102). Folate (FA)-modified chitosan has demonstrated to enhance tumor targeting and cytotoxic T-cell responses in some oncological settings (103)(104)(105)(106). FA-modified chitosan nanoparticles carrying a plasmid of the mouse interferon-induced protein-10 (mIP-10) gene, a chemoattractant for cytotoxic T cells, reduced MDSCs from spleen, tumor, and bone marrow in combination with a DC/tumor cell fusion vaccine in hepatocellular carcinomabearing mice (67).…”