ROS-Responsive Glycopolymeric Nanoparticles for Enhanced Drug Delivery to Macrophages.

Macrophages play a diverse, key role in many pathologies, including inflammatory diseases, cardiovascular diseases, and cancer. However, many therapeutic strategies targeting macrophages suffer from systemic off-target toxicity resulting in notoriously narrow therapeutic windows. To address this shortcoming, the development of poly(propylene sulfide)-b-poly(methacrylamidoglucopyranose) [PPS-b-PMAG] diblock copolymer-based nanoparticles (PMAG NPs) capable of targeting macrophages and releasing drug in the presence of reactive oxygen species (ROS) is reported. PMAG NPs have desirable physicochemical properties for systemic drug delivery, including slightly negative surface charge, ≈100 nm diameter, and hemo-compatibility. Additionally, due to the presence of PPS in the NP core, PMAG NPs release drug cargo preferentially in the presence of ROS. Importantly, PMAG NPs display high cytocompatibility and are taken up by macrophages in cell culture at a rate ≈18-fold higher than PEGMA NPs-NPs composed of PPS-b-poly(oligoethylene glycol methacrylate). Computational studies indicate that PMAG NPs likely bind with glucose transporters such as GLUT 1/3 on the macrophage cell surface to facilitate high levels of internalization. Collectively, this study introduces glycopolymeric NPs that are uniquely capable of both receptor-ligand targeting to macrophages and ROS-dependent drug release and that can be useful in many immunotherapeutic settings.

Immunostimulatory biomaterials to boost tumor immunogenicity.

Cancer immunotherapy is exhibiting great promise as a new therapeutic modality for cancer treatment. However, immunotherapies are limited by the inability of some tumors to provoke an immune response. These tumors with a 'cold' immunological phenotype are characterized by low numbers of tumor-infiltrating lymphocytes, high numbers of immunosuppressive leukocytes (e.g. regulatory T cells, tumor-associated macrophages), and high production of immune-dampening signals (e.g. IL-10, TGF-ß, IDO-1). Strategies to boost the aptitude of tumors to initiate an immune response (i.e. boost tumor immunogenicity) will turn 'cold' tumors 'hot' and augment the anti-tumor efficacy of current immunotherapies. Approaches to boost tumor immunogenicity already show promise; however, multifaceted delivery and immunobiology challenges exist. For instance, systemic delivery of many immune-stimulating agents causes off-target toxicity and/or the development of autoimmunity, limiting the administrable dose below the threshold needed to achieve efficacy. Moreover, once administered in vivo, molecules such as the nucleic acid-based agonists for many pattern recognition receptors are either rapidly cleared or degraded, and don't efficiently traffic to the intracellular compartments where the receptors are located. Thus, these nucleic acid-based drugs are ineffective without a delivery system. Biomaterials-based approaches aim to enhance current strategies to boost tumor immunogenicity, enable novel strategies, and spare dose-limiting toxicities. Here, we review recent progress to improve cancer immunotherapies by boosting immunogenicity within tumors using immunostimulatory biomaterials.