title: Just getting into cells is not enough: mechanisms underlying 4-(N)-stearoyl gemcitabine solid lipid nanoparticle's ability to overcome gemcitabine resistance caused by RRM1 overexpression.
abstract: Gemcitabine is a deoxycytidine analog that is widely used in the chemotherapy of many solid tumors. However, acquired tumor cell resistance often limits its use. Previously, we discovered that 4-(N)-stearoyl gemcitabine solid lipid nanoparticles (4-(N)-GemC18-SLNs) can overcome multiple acquired gemcitabine resistance mechanisms, including RRM1 overexpression. The present study was designed to elucidate the mechanisms underlying the 4-(N)-GemC18-SLNs' ability to overcome gemcitabine resistance. The 4-(N)-GemC18 in the 4-(N)-GemC18-SLNs entered tumor cells due to clathrin-mediated endocytosis of the 4-(N)-GemC18-SLNs into the lysosomes of the cells, whereas the 4-(N)-GemC18 alone in solution entered cells by diffusion. We substantiated that it is the way the 4-(N)-GemC18-SLNs deliver the 4-(N)-GemC18 into tumor cells that allows the gemcitabine hydrolyzed from the 4-(N)-GemC18 to be more efficiently converted into its active metabolite, gemcitabine triphosphate (dFdCTP), and thus more potent against gemcitabine-resistant tumor cells than 4-(N)-GemC18 or gemcitabine alone. Moreover, we also showed that the RRM1-overexpressing tumor cells were also cross-resistant to cytarabine, another nucleoside analog commonly used in cancer therapy, and 4-(N)-stearoyl cytarabine carried by solid lipid nanoparticles can also overcome the resistance. Therefore, formulating the long-chain fatty acid amide derivatives of nucleoside analogs into solid lipid nanoparticles may represent a platform technology to increase the antitumor activity of the nucleoside analogs and to overcome tumor cell resistance to them.
authors.affiliation: Pharmaceutics Division, The University of Texas at Austin, College of Pharmacy, Austin, TX 78712, USA.
authors.forename: Piyanuch
authors.initials: P
authors.lastname: Wonganan
authors.forename: Dharmika S P
authors.initials: DS
authors.lastname: Lansakara-P
authors.forename: Saijie
authors.initials: S
authors.lastname: Zhu
authors.forename: Melisande
authors.initials: M
authors.lastname: Holzer
authors.forename: Michael A
authors.initials: MA
authors.lastname: Sandoval
authors.forename: Mangalika
authors.initials: M
authors.lastname: Warthaka
authors.forename: Zhengrong
authors.initials: Z
authors.lastname: Cui
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004058:Diffusion; D004337:Drug Carriers / Q000737:chemistry*; D019008:Drug Resistance, Neoplasm; D004705:Endocytosis; D005260:Female; D006868:Hydrolysis; D008055:Lipids / Q000737:chemistry; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry; D012262:Ribonucleoside Diphosphate Reductase; D012264:Ribonucleotide Reductases / Q000235:genetics*; D015854:Up-Regulation
chemical_list: C525761:4-(N)-stearoylgemcitabine; D000964:Antimetabolites, Antineoplastic; D004337:Drug Carriers; D008055:Lipids; D003841:Deoxycytidine; D012264:Ribonucleotide Reductases; D012262:Ribonucleoside Diphosphate Reductase; C498690:Rrm1 protein, mouse