Review of preclinical studies of multifunctional nanosystems in combination with other drugs targeting pancreatic ductal adenocarcinoma for tumor volume reduction

Pancreatic ductal adenocarcinoma (PDAC), commonly known as pancreatic cancer, is among the leading causes of cancer-related deaths in the Western world due to advanced stage disease presentation, early metastases, and generally very limited response to chemotherapy or radiotherapy [1]. PDAC is an aggressive tumor with a poor prognosis, as it is difficult to predict, detect and diagnose in early stages [2]. Recent advances in nanotechnology-based drug delivery systems have aimed to increase cellular uptake, improve pharmacokinetics and effectiveness of anticancer drugs, which have helped to potentiate the activity of specific agents for effective pancreatic cancer (PC) therapy [3]. Polyethylene glycol (PEG) is produced from the polymerization of ethylene oxide, ethylene glycol or diethylene glycol in the presence of alkaline catalysts and the reaction is terminated by neutralizing the catalyst when the polymer reaches the desired molecular weight. In 2018, they were employed the anticancer drug, doxorubicin, conjugated to PEGylated nanotubes, decreased tumor size in mice. The release was measured for 42 days, with the majority released during the first seven days and much lower in the following days [4], [5]. In 2019, a superparamagnetic iron oxide nanoparticle (SPION) formulation of curcumin (SP-CUR), which is a non-toxic bioactive anti-inflammatory/anti-cancer agent was developed for improved delivery into tumors. Results in a 6- to 8-week-old male mouse model evidenced enhanced accumulation of SP-CUR in the pancreas, which potentiated gemcitabine (GEM) to reduce tumor growth rate and metastasis [6]. On the other hand, fucoidan (FCD) is a natural sulfated polysaccharide extracted from brown algae, which was included in the fabrication of a nanosystem through its polyelectrolyte interaction with positively charged lactoferrin to enhance its cellular uptake and internalization. In 2020, in vitro studies performed on the pancreatic cancer cell line PANC-1 demonstrated superior cytotoxicity and inhibition of migration and invasion as a result of enhanced cellular uptake and internalization [7], [8]. In addition, in vivo studies in male mice revealed a greater reduction in tumor volume with a higher survival rate with no noticeable signs of toxicity for dual targeted drug-loaded nanoparticles compared to free drug-loaded or drug-loaded nanoparticles without active targeting moieties [8]. In the same year, they used for active targeting drug lactoferrin (LF) and hyaluronic acid by adding them to the surface of nanoparticles through layer-by-layer coating technique. In vivo studies revealed that the nanoparticles showed greater tumor volume reduction with superior survival without any major organ toxicity [7]. Nanotechnology offers the resources to directly target the drug to the tumor site, thus improving the therapeutic efficacy of current treatment modalities [8]. This review focuses on determining the most effective composition in tumor shrinkage as well as the importance of nanotechnology for the treatment of pancreatic ductal adenocarcinoma (PDAC) and target site delivery