Squalenoyl nanomedicine of gemcitabine is more potent after oral administration in leukemia-bearing rats: study of mechanisms

Abstract

In an earlier report, we demonstrated the superior anticancer efficacy of orally administered squalenoyl gemcitabine (SQdFdC) nanomedicine over its parent drug gemcitabine on rats bearing RNK-16 large granular lymphocytic (LGL) leukemia. In the present communication, we investigated the mechanisms behind this observation both at the cell and tissue level. The mechanisms were investigated by performing cytotoxicity, cell uptake, and biodistribution experiments. In the presence of cytidine deaminase, SQdFdC nanoassemblies resisted deamination and exerted significant anticancer activity in vitro against RNK-16 LGL leukemia cells, whereas the cytotoxicity of free gemcitabine decreased by approximately 83-fold, indicating its degradation due to deamination. Additionally, the SQdFdC showed considerably higher intracellular accumulation and retention compared with gemcitabine (P<0.05). Unlike gemcitabine, the cellular access to SQdFdC was not influenced by nucleoside transporters. When administered orally to rats, unlike H-gemcitabine, the H-SQdFdC absorbed slowly, but exhibited an improved pharmacokinetics and tissue distribution profile, particularly in the lymphoid organs (the major organs of metastasis). The resistance to deamination, followed by the improved pharmacokinetic and tissue distribution, and greater accumulation and retention at the level of cancer cells, are the key factors for the superiority of SQdFdC nanoassemblies over free gemcitabine against RNK-16 LGL leukemia in rats.

Oral 4-(N)-stearoyl gemcitabine nanoparticles inhibit tumor growth in mouse models

“…Examples of gemcitabine prodrugs tested include the LY2334737 (an amide derivative of gemcitabine), CP-4126 (also known as CO-101, an ester derivative of gemcitabine), SL-01 (another amide derivative of gemcitabine, i.e. 3-(dodecyloxycarbonyl)pyrazine-2-carbonyl gemcitabine)), and amino acid derivatives of gemcitabine (as a substrate to the PEPT1 transporter) [ 2 , 3 , 8 ]. LY2334737 is a valproate amide prodrug of gemcitabine synthesized by conjugating gemcitabine in the N 4 -position with valproic acid [ 9 ], and oral LY2334737 has been tested in multiple phase 1 clinical trials [ 10 – 14 ].…”

“…Squalenoyl gemcitabine (SQdFdC) is another amide prodrug of gemcitabine synthesized by conjugating gemcitabine in the N 4 position with 1,1′,2-tris-norsqualenoic acid, and the resultant SQdFdC self-assemblies to nanoparticles of 100-300 nm in water [ 21 , 22 ]. Oral SQdFC showed potent antitumor activity in a rat leukemia model [ 8 , 23 ]. Besides the SQdFdC self-assembled nanoparticles, other nanoparticles have also been tested for oral administration of gemcitabine.…”

Synthesis, Characterization, and In Vitro and In Vivo Evaluations of 4-(N)-Docosahexaenoyl 2′, 2′-Difluorodeoxycytidine with Potent and Broad-Spectrum Antitumor Activity

“…Over the years, there have been reports showing that chemical modifications of this fluorinated deoxycytidine analogue may potentially improve its efficacy and/or safety profiles. For example, it was shown that conjugation of a fatty acid, such as stearic acid, to dFdC at the 4-NH 2 group decreases the sensitivity of the latter to deaminase; modifies its pharmacokinetics; and, in some cases, improves its in vivo antitumor activity [24] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] .…”

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

“…33,96 To protect gemcitabine from rapid deamination, many attempts have been made by chemically modifying gemcitabine. [177][178][179][180] For example, it was shown that conjugation of a fatty acid, such as stearic acid, to gemcitabine at the 4-N position decreases the sensitivity of the later to deaminase. 181,182 In addition, gemcitabine-fatty acid conjugates formulated into nanoparticles also become less sensitive to deamination, as they are no longer good substrates of CDAs.…”