Dendrimers for cancer immunotherapy: Avidity-based drug delivery vehicles for effective anti-tumor immune response

Abstract

Cancer immunotherapy, or the utilization of a patient's own immune system to treat cancer, has shifted the paradigm of cancer treatment. Despite meaningful responses being observed in multiple studies, currently available immunotherapy platforms have only proven effective to a small subset of patients. To address this, nanoparticles have been utilized as a novel carrier for immunotherapeutic drugs, achieving robust anti-tumor effects with increased adaptive and durable responses. Specifically, dendrimer nanoparticles have attracted a great deal of scientific interest due to their versatility in various therapeutic applications, resulting from their unique physicochemical properties and chemically well-defined architecture. This review offers a comprehensive overview of dendrimer-based immunotherapy technologies, including their formulations, biological functionalities, and therapeutic applications. Common formulations include: (1) modulators of cytokine secretion of immune cells (adjuvants); (2) facilitators of the recognition of tumorous antigens (vaccines); (3) stimulators of immune effectors to selectively attack cells expressing specific antigens (antibodies); and (4) inhibitors of immune-suppressive responses (immune checkpoint inhibitors). On-going works and prospects of dendrimer-based immunotherapies are also discussed. Overall, this review provides a critical overview on rapidly growing dendrimer-based immunotherapy technologies and serves as a guideline for researchers and clinicians who are interested in this field. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Keywords: dendrimers; drug delivery; immune checkpoint inhibitors; immunotherapy; nanoparticles.

Figure 1.

Schematic illustration of a dendrimer structure with examples of common types utilized for various applications.

Figure 2:

Schematic representation of the mechanism of immunogene therapy by lipid-dendrimer NPs containing siRNA against the immune checkpoint PD-L1 and pDNA encoding the immunostimulating cytokine IL-2. Reprint from Huang et al. 2020.

Figure 3:

Components of dendrimer-based vaccines. Vaccine platforms can be paired with several types of dendrimers, including PAMAM, MAP, and glycodendrimers, which can target multiple antigens. These systems offer the possibility of improving the bioavailability and pharmacokinetic properties of immunotherapeutic vaccines.

Figure 4:

Schematic illustration of the dendrimer-mAb conjugates. (a) mAb-mediated immune cell functional assays. (b) Design and formulation of the dendrimer-mAb conjugates.

Figure 5:

Schematic illustration of the dendrimer-ICI conjugates. (a) Immune checkpoint molecules for cancer immunotherapy. The thickness of arrows is proportional to the reported binding affinities between the molecules. (b) Enhanced PD-1/PD-L1 blockade due to the integration of aPD-L1 antibodies to dendrimers. Reprint from Bu et al., 2020. (c) The conjugation of PD-1 derived peptide to dendrimers for PD-L1 blockade. Reprint from Jeong et al., 2020.