Gemcitabine Combination Nano Therapies for Pancreatic Cancer

Abstract

Pancreatic cancer is one of the deadliest causes of cancer-related death in the United States, with a 5-year overall survival rate of 6 to 8%. These statistics suggest that immediate medical attention is needed. Gemcitabine (GEM) is the gold standard first-line single chemotherapy agent for pancreatic cancer but, after a few months, cells develop chemoresistance. Multiple clinical and experimental investigations have demonstrated that a combination or co-administration of other drugs as chemotherapies with GEM lead to superior therapeutic benefits. However, such combination therapies often induce severe systemic toxicities. Thus, developing strategies to deliver a combination of chemotherapeutic agents more securely to patients is needed. Nanoparticle-mediated delivery can offer to load a cocktail of drugs, increase stability and availability, on-demand and tumor-specific delivery while minimizing chemotherapy-associated adverse effects. This review discusses the available drugs being co-administered with GEM and the limitations associated during the process of co-administration. This review also helps in providing knowledge of the significant number of delivery platforms being used to overcome problems related to gemcitabine-based co-delivery of other chemotherapeutic drugs, thereby focusing on how nanocarriers have been fabricated, considering the modes of action, targeting receptors, pharmacology of chemo drugs incorporated with GEM, and the differences in the physiological environment where the targeting is to be done. This review also documents the focus on novel mucin-targeted nanotechnology which is under development for pancreatic cancer therapy.

Keywords: Gemcitabine; chemotherapy; combination therapy; drug resistance; nanoparticles.

Figure 1

Peer-reviewed publications, book chapters, comments, and reviews, related to Gemcitabine co-administration with various other drugs to treat pancreatic cancer. The number of publications was obtained from archived data in PubMed (up to December 2018).

Figure 2

A detailed analysis of GEM co-administration outcomes with other drug candidate in terms of (A) overall survival and (B) progression-free survival of patients through various clinical trials.

Figure 3

Different nanoparticle mechanisms of delivering therapeutic agents: (1) nab-PTX causes cell cycle arrest by inhibiting polymerization of microtubules during mitosis within recipient cells [34], (2) nanogel releases the drug within the cell in stimulation to suitable pH and temperature as the pH and temperature of cancer cells are higher than normal cells [35], (3) metal-based magnetic nanoparticle checks drug resistance by inhibiting and blocking the P-gp drug efflux mechanism when they are taken up by cancer cells via micropinocytosis, which further obstructs P-gp because of the large size of the nanoparticles [36], (4) liposomes cross the lipid bilayer to target the cancer cells directed by biomarkers aberrantly expressed in PanCa [37], and (5) a micelle encapsulated drug acts as a ligand to target receptors which are specific to GEM-based co-therapy [38].

Figure 4

Passive (EPR) and active (ligand/receptor-based) targeting of Gemcitabine-based co-formulation.