Linifanib – a multi-targeted receptor tyrosine kinase inhibitor and a low molecular weight gelator

Abstract

In this study we demonstrate that linifanib, a multi-targeted receptor tyrosine kinase inhibitor, with a key urea containing pharmacophore, self-assembles into a hydrogel in the presence of low amounts of solvent. We demonstrate the role of the urea functional group and that of fluorine substitution on the adjacent aromatic ring in promoting self-assembly. We have also shown that linifanib has superior mechanical strength to two structurally related analogues and hence increased potential for localisation at an injection site for drug delivery applications.

Developing a self-healing supramolecular nucleoside hydrogel

“…[1][2][3] There already exist examples of low molecular weight gelating entities with potential for use in drug delivery, whether they be therapeutic molecular gels, such as the recent linifinib 4 and benzothiazole 5 examples or inert gelator matrices such as the extensively studied tri-/dipeptide gelators. [6][7][8] Whilst there is extensive literature describing the applications of LMWGs in drug delivery, there are only a few published examples of these inert matrix gelators that possess self-healing properties i.e.…”

Rationally Developed Organic Salts of Tolfenamic Acid and Its β‐Alanine Derivatives for Dual Purposes as an Anti‐Inflammatory Topical Gel and Anticancer Agent

“…However,t he IC 50 value (250 mm) for > 50 %k ill rate of cancerc ells, compared with those of existing anticancer drugs (doxorubicin (0.60 mm), tamoxifen (25.84 mm), cisplatin (4.72 mm), dotaxel (66.4 mm), and 5-fluorouracil( 90.6 mm)) is much higher, [89,90] and therefore, not expected to be useful in traditional chemotherapy.N evertheless, at opical gel formulation of S7 can be used to treat postoperative conditions, such as preventing the possibility of relapse of malignant tumors after surgery; the local concentrationo ft he gelator drug and its slow and sustained releasef rom the topical gel can be very effectivei nt reatings uch conditions. [92][93][94]63] [91] Several groups are trying to develop supramolecular gels for anticancer drug encapsulationa nd controlled release.…”

“…[91] Several groups are trying to develop supramolecular gels for anticancer drug encapsulationa nd controlled release. [92][93][94]63]…”

Nucleoside‐Based Self‐Assembling Drugs for Localized Drug Delivery

“…[3] These reversible interactions make LMWGs attractive agents for ar ange of applications including drugd elivery,t issue engineering,c atalysis, green chemistry,c hemical sensors ande lectronics, as they can be designed to gelate under very specific and/orm ild conditions. [9][10][11][12][13] With LMWG drug delivery systems, the ability of gels to remain localized in vivo allows greater site-specific delivery and can vastly increase drug efficacy while minimizing adverse systemic toxicity. [9][10][11][12][13] With LMWG drug delivery systems, the ability of gels to remain localized in vivo allows greater site-specific delivery and can vastly increase drug efficacy while minimizing adverse systemic toxicity.…”

“…[4][5][6] LMWGs therefore offer immense potential for novel, highly specific drug delivery systems via:1 )drug encapsulation with diffusion and/or degradation release, [7] 2) covalent binding of drug molecule(s) released by bond cleavage upon interaction with target stimulus, [8] or 3) prodrug gelatorc ompounds that form active systems when self-assembled (therapeutic molecular gels). [9][10][11][12][13] With LMWG drug delivery systems, the ability of gels to remain localized in vivo allows greater site-specific delivery and can vastly increase drug efficacy while minimizing adverse systemic toxicity. We proposed to synthesize al ibrary of poten-tial gelatord erivatives of gemcitabine 1 and lamivudine 2 as shown in Figure1.W eh ypothesized that aL MWG derived from chemotherapeutic gemcitabine 1 would allow the development of an intratumor therapy, potentially enhancing in vivo drug activity.S imultaneously,t his approach could hinder the first-pass metabolism of gemcitabine by cytidine deaminase (CDA) and deoxycytidine deaminase (dCDA).…”