Doxorubicin and CpG loaded liposomal spherical nucleic acid for enhanced Cancer treatment

Abstract

Chemotherapeutics that can trigger immunogenic cell death (ICD) and release tumor-specific antigens are effective on treating a variety of cancers. The codelivery of chemotherapeutics with adjuvants is a promising strategy to achieve synergistic therapeutic effect. However, low drug loading and complicated preparation of current delivery systems lead to carrier-associated toxicity and immunogenicity. Herein, we developed a facile approach to construct liposomal spherical nucleic acids (SNA) by the self-assembly of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)-doxorubicin conjugate and DOPE-matrix metalloproteinases-9 (MMP-9) responsive peptide-CpG conjugate (DOPE-MMP-CpG). Liposomal SNAs efficiently co-delivered DOX and CpG into tumors and released the two drugs upon biological stimuli of MMP-9 enzyme in tumor microenvironment (TME) and high concentration of endogenous glutathione in tumor cells. We demonstrated that liposomal SNA enhanced activation of dendritic cells (DCs), promoted expansion of CD8+ and CD4+ T cells in both tumors and spleen, inhibited tumor growth, and extended animal survival. This work provided a simple strategy of delivering chemotherapeutics and adjuvants to tumors with synergistic therapeutic effect and reduced side effect. Graphical Abstract

Spherical nucleic acids: emerging amplifiers for therapeutic nanoplatforms

“…82 Liu designed a liposome SNA containing Dox and CpG response peptide coupling, which can enhance the activation of dendritic cells and promote the amplification of CD8 + and CD4 + T cells. 116 Subsequently, Liu constructed a spherical nucleic acid using CpG-ODN and monophosphoryl lipid A double adjuvants, and Dox was radially surrounded as the shell, which can enhance ICD-induced immune responses, achieving synergistic therapeutic effects of chemotherapy and immunotherapy. 87 Mirkin et al enhanced T cell responses by hybridizing antigen peptides onto SNAs.…”

When Natural Compounds Meet Nanotechnology: Nature-Inspired Nanomedicines for Cancer Immunotherapy

“…DOX-encapsulated liposomes were also co-loaded with anti-PD-L1 antibody in the gel for the elimination of postoperative immunosuppression through multi-step activation of the cancer-immunity cycle [104]. In addition to single drug-loaded liposomes, two-in-one liposomes have become more predominant for combination immunotherapy through the co-delivery of two chemotherapeutics or chemotherapeutics with adjuvants [105]. For example, Wang et al constructed neurotransmitter analogs-modified liposomes for codelivery of camptothecin (CPT) and Cur to glioma and found that Cur could effectively downregulate the CPT-induced elevated expression of PD-L1 and thus prevent the inactivation of T cells and achieve enhanced chemo-immunotherapy [106].…”

CD16 CAR-T cells enhance antitumor activity of CpG ODN-loaded nanoparticle-adjuvanted tumor antigen-derived vaccinevia ADCC approach

“…Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs have been identified as TLR-9 agonists, which could trigger innate and adaptive immunity. Until now, various CpG ODN has been studied in different stage clinical trials for cancer combinatorial immunotherapy [ 33 – 35 ]. For example, SD-101 was effective in 78% of patients with unresectable melanoma in combination with PD-1 inhibitors [ 36 ].…”