Poly(d,l-lactide-co-glycolide) Nanoparticles as Delivery Platforms for TLR7/8 Agonist-Based Cancer Vaccine

Abstract

Targeted drug delivery can significantly influence the efficacy of a drug. In the past decades, diverse drug-delivery technologies, including nano-and microparticles, co-crystals, and microneedles have been developed to maximize therapeutic efficacy and minimize undesired side effects of therapeutics. Nanoparticles-submicron-sized drug carriers-have been actively investigated for the delivery of antibiotics, nucleic acids, peptide/proteins, and chemotherapeutics. Recently, nanoparticles have gained attention as a vaccine delivery platform for tumor-associated antigens (TAAs) and/or vaccine adjuvants. Agonists of imidazoquinoline-based Toll-like receptor (TLR) 7/8 are potent cytokine inducers that are used as cancer vaccine adjuvants to elicit robust T-cell response by activating dendritic cells (DCs). Despite their in vitro potency, the translation of TLR7 agonists as cancer vaccine adjuvants in the clinic has been limited by their poor retention at the injection site. Therefore, a formulation that could improve the availability of TLR7/8 agonists to DCs via conventional vaccine administration routes (subcutaneous, intramuscular) can broaden the application of TLR7/8 agonists for cancer immunotherapy. Polymeric nanoparticles fabricated with poly(D,Llactide-co-glycolide) (PLGA) can be an efficient TLR7/8 agonist delivery platform. PLGA is a biocompatible polymer, and nanoparticles prepared from this polymer are stable in saline and are small enough to be administered by subcutaneous or intramuscular injections. Furthermore, nanoparticulate TLR7/8 delivery can enhance DC uptake and facilitate lymphatic drainage, both of which can enhance the adjuvanticity of TLR7/8 agonists compared with soluble forms. In this review, we discuss the use of PLGA nanoparticles with TLR7/8 agonists for improving cancer immunotherapy.

Development of a novel TLR8 agonist for cancer immunotherapy

“…DN052 is currently advancing in phase 1 trials in cancer patients in the US (ClinicalTrials.gov Identifier: NCT03934359) and both the safety and efficacy will be rigorously tested in the clinic. It is noteworthy that besides cancer indications, TLR8 agonists such as DN052 can be used for other indications including cancer vaccines [50] and the treatment of viral infections including HBV.…”

Delivery of cancer therapies by synthetic and bio-inspired nanovectors

“…Contrary to transgene vectorization by OVs, nanoparticles usually transport proteins, which does not allow spatial and temporal treatment amplification. Nevertheless, inhibitors of IL-10, TGF-β, indoleamine 2,3-dioxygenase immunosuppressive molecules [273], TLR agonists [302][303][304] or pro-inflammatory cytokines (e.g. IL-2, IL-15, TNF-α, IFN-γ) [15,[305][306][307][308] have been successfully addressed to the TME in preclinical models using different types of nanoparticles [275,309].…”

Protamine – A Review on an Oligonucleotide-Binding Peptide Applied in Nanopharmaceuticals including Vaccines

“…In order for a tumor-specific T-cell response to be elicited, T-cells need to be stimulated by an antigen and a costimulatory molecule by DCs. PLGA NPs were successful to co-deliver tumor-associated antigens (TAAs) and TLR7/8 agonists, such as CpG-ODN, since it can encapsulate both hydrophobic and hydrophilic compounds (Kim, Griffith, and Panyam 2019). When it comes to SARS-CoV-2 therapy, computational simulation design has been used to predict the possibility of incorporating two drugs with different solubility in PLGA NPs.…”