Gemcitabine (GMT) is a generic pyrimidine antimetabolite drug marketed as hydrochloride salt (Gemzar®) and approved for use alone or in combination (by intravenous infusion) for the treatment of several types of tumors including pancreatic, lung, breast, bladder, testicular and ovarian cancer [1]. Although GMT is quite effective in the treatment of solid tumors, there are several issues related to its parenteral administration. Firstly, GMT is rapidly and extensively deaminated by cytidine deaminase to the inactive metabolite 2’,2’-difluorodeoxiuridine, and excreted in the urine. This leads to a very short plasma half-life (8–17 min). Additionally, tumor cells often develop resistance to GMT by decreasing expression of nucleoside transporters and deoxycytidine kinase, and/or decreasing expression of ribonucleotide reductase. There are several reports showing that these issues may be overcome by formulating N-acyl-GMT prodrugs into solid lipid nanoparticles (SLNs) [2-5]. In line with prior literature, we designed and synthesized N-acyl-GMT prodrugs with selected alkyl chains of proper length and biological function such as stearic acid, α-linolenic acid and vitamin E succinate with the ultimate goal of formulating those new compounds into SLNs suitable for local lung delivery. Compounds were synthesized by mixed-anhydride method and characterized by 1H and 13C NMR, and HRMS.
Lipophilic gemcitabine (GMT) prodrugs for solid lipid nanoparticles (SLNs) preparation
Nicola Micale
;
2023-01-01
Abstract
Gemcitabine (GMT) is a generic pyrimidine antimetabolite drug marketed as hydrochloride salt (Gemzar®) and approved for use alone or in combination (by intravenous infusion) for the treatment of several types of tumors including pancreatic, lung, breast, bladder, testicular and ovarian cancer [1]. Although GMT is quite effective in the treatment of solid tumors, there are several issues related to its parenteral administration. Firstly, GMT is rapidly and extensively deaminated by cytidine deaminase to the inactive metabolite 2’,2’-difluorodeoxiuridine, and excreted in the urine. This leads to a very short plasma half-life (8–17 min). Additionally, tumor cells often develop resistance to GMT by decreasing expression of nucleoside transporters and deoxycytidine kinase, and/or decreasing expression of ribonucleotide reductase. There are several reports showing that these issues may be overcome by formulating N-acyl-GMT prodrugs into solid lipid nanoparticles (SLNs) [2-5]. In line with prior literature, we designed and synthesized N-acyl-GMT prodrugs with selected alkyl chains of proper length and biological function such as stearic acid, α-linolenic acid and vitamin E succinate with the ultimate goal of formulating those new compounds into SLNs suitable for local lung delivery. Compounds were synthesized by mixed-anhydride method and characterized by 1H and 13C NMR, and HRMS.Pubblicazioni consigliate
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