Overcoming tumor cell chemoresistance using nanoparticles: lysosomes are beneficial for (stearoyl) gemcitabine-incorporated solid lipid nanoparticles

Abstract

Despite recent advances in targeted therapies and immunotherapies, chemotherapy using cytotoxic agents remains an indispensable modality in cancer treatment. Recently, there has been a growing emphasis in using nanomedicine in cancer chemotherapy, and several nanomedicines have already been used clinically to treat cancers. There is evidence that formulating small molecular cancer chemotherapeutic agents into nanomedicines significantly modifies their pharmacokinetics and often improves their efficacy. Importantly, cancer cells often develop resistance to chemotherapy, and formulating anticancer drugs into nanomedicines also helps overcome chemoresistance. In this review, we briefly describe the different classes of cancer chemotherapeutic agents, their mechanisms of action and resistance, and evidence of overcoming the resistance using nanomedicines. We then emphasize on gemcitabine and our experience in discovering the unique (stearoyl) gemcitabine solid lipid nanoparticles that are effective against tumor cells resistant to gemcitabine and elucidate the underlying mechanisms. It seems that lysosomes, which are an obstacle in the delivery of many drugs, are actually beneficial for our (stearoyl) gemcitabine solid lipid nanoparticles to overcome tumor cell resistance to gemcitabine.

Enhancing efficacy of gemcitabine in pancreatic patient-derived xenograft mouse models

“…The released Gem is actively converted to the metabolite, Gem triphosphate which blocks DNA synthesis when delivered to the appropriate intracellular compartment implicated in phosphorylation process ( Wonganan et al, 2013 ). In contrast, the weak cytotoxicity effect of GemHCl against 2D and 3D cultures could be attributed to inefficient transportation across cell membrane as a result of rapid deamination of GemHCl and under-expression of transporters ( Chen et al, 2018 ). Indeed, we admit that hydrolysis of 4NSG to release Gem can occur intracellularly outside the compartment for phosphorylation hence diminishing the efficacy of 4NSG as it suffers from possible intracellular deamination prior to phosphorylation to a certain degree after the release of Gem.…”

“…Indeed, we admit that hydrolysis of 4NSG to release Gem can occur intracellularly outside the compartment for phosphorylation hence diminishing the efficacy of 4NSG as it suffers from possible intracellular deamination prior to phosphorylation to a certain degree after the release of Gem. After the hydrolysis of the amide bond intracellularly, there is also the possibility of Gem efflux prior to delivery to phosphorylation enzymes ( Chen et al, 2018 ). The current study tentatively cast a new light on extensive cellular uptake and efficacy of 4NSG than GemHCl.…”

Application of Solid Lipid Nanoparticles to Improve the Efficiency of Anticancer Drugs

“…Cancer is a group of diseases that include the uncontrolled division of cells and resistance to cell death, as well as the ability of these cells to invade other tissues [2]. It represents one of the leading causes of death worldwide [30].…”

Biotin-Decorated PAMAM G4.5 Dendrimer Nanoparticles to Enhance the Delivery, Anti-Proliferative, and Apoptotic Effects of Chemotherapeutic Drug in Cancer Cells

“…Ideal nanocarriers are required to retain and selectively release the drug specifically in tumor cells and need to be compatible with the immune system and exhibit a long lifespan in the circulation [7,16]. A comprehensive range of nanocarriers with different nanostructures have been fabricated to enhance the therapeutic efficiency of gemcitabine, including polymersomes [17], liposomes [18], micelles [14,19], and polymeric nanoparticles, including dendrimers [15,20,21].…”