Drug delivery methods for cancer immunotherapy

Abstract

Despite the fact that numerous immunotherapy-based drugs have been approved by the FDA for the treatment of primary and metastatic tumors, only a small proportion of the population can benefit from them because of primary and acquired resistances. Moreover, the translation of immunotherapy from the bench to the clinical practice is being challenging because of the short half-lives of the involved molecules, the difficulties to accomplish their delivery to the target sites, and some serious adverse effects that are being associated with these approaches. The emergence of drug delivery vehicles in the field of immunotherapy is helping to overcome these difficulties and limitations and this review describes how, providing some illustrative examples. Moreover, this article provides an exhaustive review of the studies that have been published to date on the particular case of hematological cancers. (Created with BioRender).

Keywords: Cancer; Drug delivery; Hematologic cancers; Hydrogels; Immunotherapy; Nanocarriers.

Fig. 1

Examples of the capability of liposomes to accommodate all components of a therapeutic vaccine. A Peptide-based vaccine formulated as a cationic liposomal formulation composed of DOTAP, cholesterol, and DOPE that includes a HER2/neu-derived peptide (AE36) inside and an adjuvant (CpG-ODN) in the surface [18]. Created with BioRender.com. B Liposomal peptide-based cancer vaccine composed of DSPC, DSPG, DSPE, DOPE, and cholesterol that includes the AE36, E75, and E75-AE36 peptides in the surface and the PADRE peptide inside [19]. Created with BioRender.com. C Liposomal vaccine for the codelivery of two nucleic acid-based adjuvants, CpG ODN and Poly(I:C), which target TLR9 and TLR3, and the OVA antigen. Reprinted from reference [20] with modifications with permission. D Liposomal pH-sensitive vaccine for the codelivery of two nucleic acid-based adjuvants, CpG ODN and cGAMP, which target TLR9 and STING. Reprinted with modifications from reference [21] with permission

Fig. 2

Scheme of the preparation of the OVA/CL264-loaded pH-sensitive micelles reported by Li et al. and hypothesis of the mechanism of the codelivery of the OVA antigen and the TLR-7 agonist CL264 to the dendritic cells in the lymph nodes and their internalization in dendritic cells by scavenger receptor-mediated endocytosis. Reprinted from reference [56] with permission

Fig. 3

Examples of some hybrid structures that are able to accommodate all the components of cancer vaccines in the same vehicle, using the different composition of its core and the layers of its structure. A Synthesis procedure of gold nanocages coated with liposomes to deliver a melanoma antigen and the adjuvant MPLA to DCs. The antigen is loaded in the hollow core of the gold nanocages, and the adjuvant is incorporated in the liposomal coating that allows the conjugation of the targeting moiety. Reprinted from reference [80] with permission. B Hybrid polymersomes based on PCL-PEG-PCL and DOTAP that includes the OVA antigen (in the inner PEG cavity and the DOTAP coating), and two adjuvants, imiquimod (in the PCL membrane) and MPLA (in the DOTAP coating). Reprinted from reference [81] with permission. C Synthesis procedure of hybrid nanovaccines composed of a core of PLGA that includes the adjuvant, imiquimod, and a lipid membrane of DMPC that incorporates the antigen (αOVA) and the targeting ligand, apolipoprotein E3. Reprinted with major modifications from reference [82] with permission

Fig. 4

CAR T cell-loaded biomimetic fibrin-based hydrogels reported by Ogunnaike et al. that enables the controlled release of CAR T cells and sustain their viability, achieving superior antitumor activity compared to naked CAR T cell inoculations. A Implementation of the hydrogel into the tumor resection cavity. B Cryo-SEM imaging of the CAR-T cells-loaded fibrin-based hydrogel. C Confocal imaging of the CAR-T cells-loaded fibrin-based hydrogel (CAR T cells labelled with green fluorescein). D Confocal imaging of live/dead CAR T cells in the hydrogel for 5 days (live cells were labelled with green fluorescein; dead cells were labelled with red fluorescein). E Quantification of live CAR T cells in the hydrogel for 5 days, using different concentrations of fibrin. No significant differences were found. Reprinted from reference [111] with permission

Fig. 5

Injectable self-assembled PEG-PLA/HPMC-C₁₂-based hydrogel reported by Grosskopf et al. that permits the direct administration of CAR T cells in combination with cytokines in the brain, creating a temporary inflammatory niche. A Comparison between the local administration of the combined immunotherapy by using the hydrogel and the conventional intravenous administration. B Synthesis of the PEG-PLA/HPMC-C₁₂-based hydrogels that include the CAR T cells and the cytokines. Reprinted with modifications from reference [116] with permission