Nanoparticle-based delivery systems modulate the tumor microenvironment in pancreatic cancer for enhanced therapy

Abstract

Pancreatic cancer is one of the most lethal malignant tumors with a low survival rate, partly because the tumor microenvironment (TME), which consists of extracellular matrix (ECM), cancer-associated fibroblasts (CAFs), immune cells, and vascular systems, prevents effective drug delivery and chemoradiotherapy. Thus, modulating the microenvironment of pancreatic cancer is considered a promising therapeutic approach. Since nanoparticles are one of the most effective cancer treatment strategies, several nano-delivery platforms have been developed to regulate the TME and enhance treatment. Here, we summarize the latest advances in nano-delivery systems that alter the TME in pancreatic cancer by depleting ECM, inhibiting CAFs, reversing immunosuppression, promoting angiogenesis, or improving the hypoxic environment. We also discuss promising new targets for such systems. This review is expected to improve our understanding of how to modulate the pancreatic cancer microenvironment and guide the development of new therapies.

Keywords: Cancer-associated fibroblasts; Extracellular matrix; Immunosuppression; Nano-delivery systems; Pancreatic cancer; Tumor microenvironment.

Fig. 1

The tumor microenvironment (TME) in pancreatic cancer. The expanded extracellular matrix increases interstitial stress, while collapse of blood vessels reduces oxygen levels and acidifies the pH. Low infiltration by immune cells and their phenotypic transformation inhibit anti-tumor immune responses. Various activation pathways generate cancer-associated fibroblasts (CAFs), key cellular components of the TME. MMPs, matrix metalloproteinases; TAMs, tumor-associated macrophages; Tregs, regulatory T cells

Fig. 2

Nanoparticle delivery systems used to target the extracellular matrix in the tumor microenvironment

Fig. 3

Different nanoparticle optimization strategies used to block the activation and proliferation of cancer-associated fibroblasts (CAFs). GNPs, gold nanoparticles

Fig. 4

Nanoparticle optimization strategies used to reverse immunosuppression in the tumor microenvironment. a Some nanoparticles are used to target M2 TAMs. b Indoleamine 2,3-dioxygenase-1 (IDO1) siRNA-loaded lipid nanoparticles enhance immunogenic cell death (ICD) to promote immunogenic death of tumor cells. Reprinted by permission from [73]. c Co-encapsulation of the ICD inducer oxaliplatin and the IDO inhibitor indomethacin in mesoporous silica nanoparticles (MSNPs) coated with lipid bilayers. Reprinted by permission from [74]. DCs dendritic cells, CTLs cytotoxic T lymphocytes, OXA oxaliplatin, CRT calreticulin, HMGB-1 high-mobility group box 1, IND indoximod

Fig. 5

Cilengitide encapsulated in a doxorubicin (DOX)-loaded thermosensitive liposome via a MT1-MMP-cleavable peptide improves tumor blood perfusion and drug delivery in pancreatic cancer. Cilengitide is released through MT1-MMP cleavage on tumor endothelial cells (ECs), promoting EC migration and angiogenesis. MT1-MMP, membrane type 1-matrix metalloproteinase; MC, MT1-MMP-activated cilengitide. Reprinted by permission from [79]

Fig. 6

Nanoparticle-based strategies used to target hypoxia in pancreatic cancer