Drug Delivery Strategies for the Treatment of Pancreatic Cancer

Abstract

Pancreatic cancer is fast becoming a global menace and it is projected to be the second leading cause of cancer-related death by 2030. Pancreatic adenocarcinomas, which develop in the pancreas' exocrine region, are the predominant type of pancreatic cancer, representing about 95% of total pancreatic tumors. The malignancy progresses asymptomatically, making early diagnosis difficult. It is characterized by excessive production of fibrotic stroma known as desmoplasia, which aids tumor growth and metastatic spread by remodeling the extracellular matrix and releasing tumor growth factors. For decades, immense efforts have been harnessed toward developing more effective drug delivery systems for pancreatic cancer treatment leveraging nanotechnology, immunotherapy, drug conjugates, and combinations of these approaches. However, despite the reported preclinical success of these approaches, no substantial progress has been made clinically and the prognosis for pancreatic cancer is worsening. This review provides insights into challenges associated with the delivery of therapeutics for pancreatic cancer treatment and discusses drug delivery strategies to minimize adverse effects associated with current chemotherapy options and to improve the efficiency of drug treatment.

Keywords: desmoplasia; drug-conjugate; extracellular matrix; immunotherapy; nanotechnology; pancreatic adenocarcinoma; pancreatic cancer.

Figure 1

Anatomy of the pancreas and different pancreatic parts where cancer occurs. Created with BioRender.com (accessed on 14 April 2023).

Figure 2

The pancreatic tumor microenvironment showing abnormal vascularity and excessive desmoplasia. Created with BioRender.com (accessed on 14 April 2023).

Figure 3

Representation of cross-interaction of different cells in the pancreatic tumor microenvironment (TME). The cancer cells, through cell surface molecules and soluble cytokines such as transforming growth factor (TGF-β) and interleukin (IL-10), establish immunosuppressive TME by recruiting and activating immunosuppressive cells such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs). In addition, interaction between programmed cell death protein ligand-1 (PD-L1) on the cancer cells and programmed cell death protein-1 (PD-1) expressed on T cells induces T cell apoptosis, resulting in immune system evasion. These immunosuppressive cells and their associated molecules are targets for cancer immunotherapy. Created with BioRender.com. Accessed on 14 April 2023. Adapted from [113].

Figure 4

Photodynamic therapy using gallium–indium nanoparticles that have been modified with hyaluronic acid (targeting agent) and a benzoporphyrin derivative photosensitizer. Created with BioRender.com (accessed on 14 April 2023). Adapted from [139].

Figure 5

Nanoparticulate drug delivery systems. Created with BioRender.com (accessed on 14 April 2023).

Figure 6

Different types of drug conjugates that are used in cancer therapy. Created with BioRender.com (accessed on 24 February 2023).

Figure 7

Multistage delivery strategy. The primary nanoparticle delivers the secondary nanoparticles containing the cytotoxic payloads to the tumor microenvironment via the EPR effect. Exposure of the primary nanoparticles to acidic pH or specific enzymes in the tumor microenvironment leads to their breakdown into secondary nanoparticles and subsequent drug release in the tumor. Created with BioRender.com (accessed on 24 February 2023).