Rational design of Polymeric Hybrid Micelles to Overcome Lymphatic and Intracellular Delivery Barriers in Cancer Immunotherapy

Abstract

Poor distribution of antigen/adjuvant to target sites and inadequate induction of T cell responses remain major challenges in cancer immunotherapy because of the lack of appropriate delivery systems. Nanocarrier-based antigen delivery systems have emerged as an innovative strategy to improve vaccine efficacy. Here we present polymeric hybrid micelles (PHMs) as a simple and potent antigen/adjuvant co-delivery system with highly tunable properties. PHMs consist of two amphiphilic diblock copolymers, polycaprolactone-polyethylenimine (PCL-PEI) and polycaprolactone-polyethyleneglycol (PCL-PEG). PHMs with different proportions of cationic PCL-PEI were prepared and loaded with tyrosinase-related protein 2 (Trp2) peptide and adjuvant CpG oligodeoxynucleotide to generate the Trp2/PHM/CpG co-delivery system. Lymphatic and intracellular antigen delivery as a function of PCL-PEI proportion was evaluated in vitro and in vivo. PHMs containing 10% (w/w) PCL-PEI (Trp2/PHM10/CpG) showed the optimal balance of good distribution to lymph nodes, strong immunization effect after subcutaneous administration, and low toxicity to dendritic cells. In a mouse model of B16F10 melanoma, Trp2/PHM10/CpG showed significantly higher antigen-specific cytotoxic T lymphocyte activity and greater anticancer efficacy than Trp2/PHM0/CpG without PCL-PEI or a mixture of free Trp2 and CpG. These results provide new insights into how cationic segments affect the efficiency of antigen delivery by cationic nanocarriers. They also suggest that PHMs can serve as a structurally simple and highly tunable platform for co-delivery of antigen and adjuvant in cancer immunotherapy.

Lymphatic changes in cancer and drug delivery to the lymphatics in solid tumors

“…Additionally, LyP-1 micelles had the most efficacy against tumors in vitro. In a study by Li et al, micelles composed of two amphiphilic diblock copolymers, polycaprolactonepolyethylenimine (PCL-PEI) and PCL-PEG, were loaded with Trp2 peptide and CpG oligodeoxynucleotide as an adjuvant [167]. Different ratios of cationic PCL-PEI were used, and it was determined that 10% w/w PCL-PEI had the best distribution into the lymph nodes and efficacy after subcutaneous administration.…”

Advanced biomaterials for cancer immunotherapy

“…Cui et al investigated polyplex micelles loaded with genes encoding the tumor-associated antigens SART3, GM-CSF, and CD40L and demonstrated that these micelles when administered subcutaneously may be safe and effective for tumor immunotherapy [139]. Researchers manufactured polymeric hybrid micelles (PHMs) loaded with Trp2 and CpG, and these PHMs consisted of polycaprolactone-polyethylene glycol (PCL-PEG) and 10% (w/w) PCL-PEI and were proven to have the ability to deliver antigen and adjuvant to lymph nodes and stimulate the CTL response, thus effectively inhibiting tumor growth [140]. Luo et al prepared poly(ethylene glycol)-b-poly(L-lysine)-b-poly(L-leucine) (PEG-PLL-PLLeu) micelles coloaded with OVA and STAT3 siRNA and proved that these micelles downregulate the expression of STAT3 and promote the maturation of DCs, thus improving the therapeutic efficacy of tumor vaccines [141].…”

Anti-GPC3 antibody-modified sorafenib-loaded nanoparticles significantly inhibited HepG2 hepatocellular carcinoma

“…Due to its unique properties, polycaprolactone (PCL) is one of the most widely used polymers. PCL is biodegradable, miscible with other polymers, nontoxic, and easy to crystallize (Li et al., 2017 ; Totaro et al., 2017 ). Copolymers of TPGS-b-PCL such as PCL plus d -α-tocopheryl polyethylene glycol 1000 succinate (TPGS) have been widely used to deliver antitumor drugs such as genistein and paclitaxel (Tang et al., 2014 ; Parikh et al., 2017 ).…”