Pancreatic Cancer: Challenges and Opportunities in Locoregional Therapies

Abstract

Pancreatic cancer (PC) remains the seventh leading cause of cancer-related deaths worldwide and the third in the United States, making it one of the most lethal solid malignancies. Unfortunately, the symptoms of this disease are not very apparent despite an increasing incidence rate. Therefore, at the time of diagnosis, 45% of patients have already developed metastatic tumours. Due to the aggressive nature of the pancreatic tumours, local interventions are required in addition to first-line treatments. Locoregional interventions affect a specific area of the pancreas to minimize local tumour recurrence and reduce the side effects on surrounding healthy tissues. However, compared to the number of new studies on systemic therapy, very little research has been conducted on localised interventions for PC. To address this unbalanced focus and to shed light on the tremendous potentials of locoregional therapies, this work will provide a detailed discussion of various localised treatment strategies. Most importantly, to the best of our knowledge, the aspect of localised drug delivery systems used in PC was unprecedentedly discussed in this work. This review is meant for researchers and clinicians considering utilizing local therapy for the effective treatment of PC, providing a thorough guide on recent advancements in research and clinical trials toward locoregional interventions, together with the authors' insight into their potential improvements.

Keywords: drug delivery; intra-arterial infusion chemotherapy; irreversible electroporation; isolated upper abdominal perfusion; localised therapy; pancreatic ductal adenocarcinoma; photodynamic therapy; stereotactic body radiotherapy; thermal ablation.

Figure 1

Graphical illustration of pancreatic tumour microenvironment. (A) Primary pancreatic tumour. (B) Enlarged pancreatic tumour environment: The cancerous cell cytokines induce the production of fibroblasts and stellate cells, leading to the build-up of the dense stroma compartment. The hostile dense and stromal structure increases intra-tumoral pressure, causing the hypo-vascularization or the collapse of blood vessels surrounding tumours. Due to the lack of a cancerous blood vessel matrix, EPR effects cannot be utilised efficiently for the delivery of systemic therapeutics.

Figure 2

Illustration of localised vs. systemic therapy for the treatment of PC. Systemically injectables are designed to kill cancer cells that have migrated outside of the pancreas to organs elsewhere in the body. Localised therapy, including injectable, implantable, and micro/nano-based formulations, affect a specific area of the pancreas to control a wide margin of tumours. Image adapted from Aquid et al. [77].

Figure 3

Schematic illustration demonstrating the mechanism of action of GEM/DDP-loaded thermal sensitive hydrogel. In water, the amphiphilic triblock copolymer (PDLLAPEG-PDLLA) underwent self-assembling into micelles at room temperature. GEM and DDP were dissolved into a predetermined amount of micelles solution to form a homogeneous (GEM-DDP/micelles) mixture. Upon exposure to body temperature, the resulting mixture spontaneously gelated into a cross-link hydrogel network (GEM-DDP/hydrogel). Following intra-tumoral injection, (GEM-DDP/hydrogel) dispersed around tumour sites, producing the sustained release of GEM and DPP, facilitating their synergic antitumour activity. Reprinted with permission from Shi et al. [91]. 2022, Springer Nature.

Figure 4

Graphical illustration of PTX-TRAP depots’ conceptual framework. (A) Synthesis scheme of TRAP PTX: PTX was dissolved in DCM and reacted with succinic anhydride in the presence of DMAP at room temperature to yield PTX succinic acid (PTX-SA). Purified PTX-SA was then reacted with EDC and sNHS in DMF at room temperature, yielding PTX-sNHS conjugate. (B) Following injection, PTX-sNHS conjugate reacted with the amines group on ECM, attaching PTX to the tumour tissues. After the linker moiety dissolved, PTX was released intratumorally. Reprinted and modified with permission from Pandit et al. [106]. 2022, Elsevier.

Figure 5

Schematic illustration of core-shell electrospun fibres containing GEM. GEM-HA-sol was firstly dispersed into PLA solution to form an electrospinning solution. Under the application of electrospinning technique, GEM-containing core-shell electrospun fibres are formed, namely GEM@PLA-HA. Reprinted with permission from Xia et al. [125]. 2022, John Wiley and Sons.