Nanocarriers for pancreatic cancer imaging, treatments, and immunotherapies

Abstract

Pancreatic tumors are highly desmoplastic and immunosuppressive. Delivery and distribution of drugs within pancreatic tumors are compromised due to intrinsic physical and biochemical stresses that lead to increased interstitial fluid pressure, vascular compression, and hypoxia. Immunotherapy-based approaches, including therapeutic vaccines, immune checkpoint inhibition, CAR-T cell therapy, and adoptive T cell therapies, are challenged by an immunosuppressive tumor microenvironment. Together, extensive fibrosis and immunosuppression present major challenges to developing treatments for pancreatic cancer. In this context, nanoparticles have been extensively studied as delivery platforms and adjuvants for cancer and other disease therapies. Recent advances in nanotechnology have led to the development of multiple nanocarrier-based formulations that not only improve drug delivery but also enhance immunotherapy-based approaches for pancreatic cancer. This review discusses and critically analyzes the novel nanoscale strategies that have been used for drug delivery and immunomodulation to improve treatment efficacy, including newly emerging immunotherapy-based approaches. This review also presents important perspectives on future research directions that will guide the rational design of novel and robust nanoscale platforms to treat pancreatic tumors, particularly with respect to targeted therapies and immunotherapies. These insights will inform the next generation of clinical treatments to help patients manage this debilitating disease and enhance survival rates.

Keywords: Pancreatic ductal adenocarcinoma; drug delivery; immunotherapy; nanoparticles; solid tumors; tumor microenvironment.

Figure 1

Therapeutic and immunological challenges in pancreatic cancer. (A) Therapeutic approaches, including chemotherapies, antibody-based therapeutics, and vaccines, have different challenges related to their delivery and in vivo stability. Chemotherapies undergo systemic clearance, metabolize in the liver, and show poor tumor-specific delivery. Similarly, pancreatic cancer is poorly immunogenic, and there is a lack of tumor-specific high-quality antigens to induce a clinically relevant anti-tumor immune response, which causes poor efficacies of vaccine-based immunotherapies in pancreatic cancer. (B) Pancreatic tumor microenvironment includes both the physical and biochemical components in the stroma, such as high ECM deposition and disrupted vasculature, which lead to poor drug delivery and interfere in immune infiltration. (C) Cellular crosstalk between cancer cells and stromal cell populations leads to various pathological hallmarks of PDAC, including PC progression, metastasis, drug resistance, and immunosuppression. Different cell types of pancreatic tumor microenvironment have been mentioned in the figure (lower panel). Major challenges and hallmarks of PDAC are mentioned in blue color. The colored dots represent various cytokines and chemokines that are present in the pancreatic TME and participate in cellular crosstalk in the local milieu. ECM: Extracellular matrix; TAM: Tumor-associated macrophage; CAFs: Cancer-associated fibroblasts; DCs: Dendritic cells.

Figure 2

Engineered nanocarriers for PDAC drug delivery and immunotherapy. This figure provides schematic illustrations of major types and multiple subtypes of nanocarriers and their characteristic features that have been employed for drug/theranostic payload delivery and immunotherapy against PDAC. Clockwise from left: Polymeric, lipidic, nano/micro vesicle-based, and inorganic materials-based nanocarriers. The schematic structure of each nanocarrier subtype is depicted in the top and bottom rows. The most commonly observed features of each nanocarrier class are mentioned in the middle. NPs: Nanoparticles.

Figure 3

Advantages of polymeric nanoadjuvants for PDAC immunotherapy. Clockwise from the top, the figure shows how polymeric NPs: enhance exogenous antigen internalization by DCs, which can promote antigen transportation to secondary lymphoid organs and increase antigen persistence; improve antigen cross-presentation by increasing cytosolic delivery of encapsulated payloads in DCs, thus leading to more effective antigen-specific CD8+ T cell activation; enhance ICD and sensitize PDAC to immune cell recognition; induce higher levels of CD8+ T cell activation by licensed DCs or ICD based on in situ vaccination; enable more efficient removal of stroma, and enhance the reversal of immunosuppressive TME. NPs: Nanoparticles; ECM: Extracellular matrix; CAFs: Cancer-associated fibroblasts; DCs: Dendritic cells.