Modulating the Therapeutic Activity of Nanoparticle Delivered Paclitaxel by Manipulating the Hydrophobicity of Prodrug Conjugates

Abstract

A series of paclitaxel prodrugs designed for formulation in lipophilic nanoparticles are described. The hydrophobicity of paclitaxel was increased by conjugating a succession of increasingly hydrophobic lipid anchors to the drug using succinate or diglycolate cross-linkers. The prodrugs were formulated in well defined block copolymer-stabilized nanoparticles. These nanoparticles were shown to have an elimination half-life of approximately 24 h in vivo. The rate at which the prodrug was released from the nanoparticles could be controlled by adjusting the hydrophobicity of the lipid anchor, resulting in release half-lives ranging from 1 to 24 h. The diglycolate and succinate cross-linked prodrugs were 1-2 orders of magnitude less potent than paclitaxel in vitro. Nanoparticle formulations of the succinate prodrugs showed no evidence of efficacy in HT29 human colorectal tumor xenograph models. Efficacy of diglycolate prodrug nanoparticles increased as the anchor hydrophobicity increased. Long circulating diglycolate prodrug nanoparticles provided significantly enhanced therapeutic activity over commercially formulated paclitaxel at the maximum tolerated dose.

Development and optimization of oil-filled lipid nanoparticles containing docetaxel conjugates designed to control the drug release rate in vitro and in vivo

“…Many studies have reported the reduction of PX or DX activity by conjugating fatty acid chains to 2′-OH. 21,23,24 This study is consistent with previous reports that in general, all three DX-lipid conjugates were less potent than DX against DU-145 cells, and increasing the lipid chain length decreased the cell growth inhibitory activity in vitro. It has been previously demonstrated that esterification at 2′-OH or 7-OH abolished the microtubule binding affinity of the conjugates but not the total toxicity.…”

“…21 It has been previously reported that the conjugation of fatty acids to DX and PX occurs preferentially on 2′-OH. 21,23,24 By controlling the molar ratio of the fatty acid chloride to DX carefully, 2′-mono substituted DX conjugates were obtained with minimal formation of 2′,7-di substituted byproducts and unreacted DX. In the case of C22-DX, only the 2′-OH ester derivative was obtained after washing with 5% HCl and brine as determined by thin layer chromatography and nuclear magnetic resonance, without further chromatography required.…”

“…In a previous study, 23 a series of PX prodrugs with various linkers and lipid anchors were synthesized. Among the lipophilic prodrugs of PX, the most potent compound (compound 7) in vivo showed only moderate in vitro cytotoxicity.…”

Temperature‐Sensitive Nanocapsules for Controlled Drug Release Caused by Magnetically Triggered Structural Disruption

“…An estimate of the half life (t 50 ) required to reach 50% release may be obtained by replotting Figure 7 in a log-log form to extrapolate it to M t /M 1 ¼ 0.5 (figure not shown). [9] These half lives are listed in Table 2, and they range from 40 to 400 h indicating good (4 8C) storage stability. It is also clear that crosslinking the double-layer improves the stability, as reflected in both the half life and the apparent diffusivity D e in Table 2.…”

Antitumor effect of iRGD-modified liposomes containing conjugated linoleic acid–paclitaxel (CLA-PTX) on B16-F10 melanoma

“…[17][18][19] Modification of PTX with fatty acid derivatives is one potential approach. It has been reported that docosahexaenoic acid-PTX is currently in Phase III clinical trials.…”