Design and Development of a New Type of Hybrid PLGA/Lipid Nanoparticle as an Ursolic Acid Delivery System against Pancreatic Ductal Adenocarcinoma Cells

Abstract

Despite many attempts, trials, and treatment procedures, pancreatic ductal adenocarcinoma (PDAC) still ranks among the most deadly and treatment-resistant types of cancer. Hence, there is still an urgent need to develop new molecules, drugs, and therapeutic methods against PDAC. Naturally derived compounds, such as pentacyclic terpenoids, have gained attention because of their high cytotoxic activity toward pancreatic cancer cells. Ursolic acid (UA), as an example, possesses a wide anticancer activity spectrum and can potentially be a good candidate for anti-PDAC therapy. However, due to its minimal water solubility, it is necessary to prepare an optimal nano-sized vehicle to overcome the low bioavailability issue. Poly(lactic-co-glycolic acid) (PLGA) polymeric nanocarriers seem to be an essential tool for ursolic acid delivery and can overcome the lack of biological activity observed after being incorporated within liposomes. PLGA modification, with the addition of PEGylated phospholipids forming the lipid shell around the polymeric core, can provide additional beneficial properties to the designed nanocarrier. We prepared UA-loaded hybrid PLGA/lipid nanoparticles using a nanoprecipitation method and subsequently performed an MTT cytotoxicity assay for AsPC-1 and BxPC-3 cells and determined the hemolytic effect on human erythrocytes with transmission electron microscopic (TEM) visualization of the nanoparticles and their cellular uptake. Hybrid UA-loaded lipid nanoparticles were also examined in terms of their stability, coating dynamics, and ursolic acid loading. We established innovative and repeatable preparation procedures for novel hybrid nanoparticles and obtained biologically active nanocarriers for ursolic acid with an IC50 below 20 µM, with an appropriate size for intravenous dosage (around 150 nm), high homogeneity of the sample (below 0.2), satisfactory encapsulation efficiency (up to 70%) and excellent stability. The new type of hybrid UA-PLGA nanoparticles represents a further step in the development of potentially effective PDAC therapies based on novel, biologically active, and promising triterpenoids.

Optimization of an Injectable Hydrogel Depot System for the Controlled Release of Retinal-Targeted Hybrid Nanoparticles

“…The optimized biodegradable NPs, composed of PLGA, Dotap, and hyaluronic acid, hold especially high potential to encapsulate, adsorb, or incorporate a variety of therapeutic molecules. The hydrophobic matrix of PLGA and Dotap will aid in the ability to incorporate small lipophilic molecules [ 68 , 69 , 70 ], while the cationic charge of Dotap could be advantageous to enhance the loading efficiency of anionic molecules. Finally, the presence of HA enhanced the biocompatibility and mobility of NPs in the vitreous humor, as demonstrated by the fact that uncoated NPs became trapped and did not move through the vitreous, while the HA coating allowed for diffusion towards the retina.…”

Ursolic acid loaded tri-block copolymer nanoparticles based on triphenylphosphine for mitochondria-targeted cancer therapy

“…In recent years, there have been more reports on UA nanoparticles for therapeutic anti-tumor and anti-inflammatory studies [42][43][44]. Among them, for anti-tumor studies, they mostly use PLGA or lipid materials, which are prepared into nanoparticles.…”

The development of nanocarriers for natural products

“…This nanocarrier elevated the bloodstream stability, bioavailability and cytotoxic impact of UA, particularly against pancreatic cancer cells. The exceptionally stable NPs displayed high EE (up to 70%) and low IC 50 values (below 20 μM), making them potential agents for combating pancreatic cancer (Markowski et al, 2022).…”