title: Polyacetal-stilbene conjugates - The first examples of polymer therapeutics for the inhibition of HIF-1 in the treatment of solid tumours.
abstract: We report here the first examples of Polymer Therapeutics synthesised with the intention of inhibiting Hypoxia Inducible Factor-1 (HIF-1), a transcription factor heavily involved in numerous cell processes under a low oxygen environment. Four compounds were selected for use in these systems; Diethylstilbestrol (DES), Bisphenol A (BIS), Dienestrol (DIENES) and Hexestrol (HEX), which were chosen from a large family of similar molecules known as Stilbenes. These are non-steroidal molecules with structural similarities to oestrogen, and of which DES and BIS have previously been reported for HIF-1 inhibition. These molecules were incorporated into a poly(ethylene glycol) (PEG) based polyacetal system using a reaction of short PEG chains with di(ethylene glycol) divinyl ether units and an acid catalyst and without the need for biodegradable linkers. With an improved polyacetal synthesis strategy we obtained high yields of water soluble polymer conjugates with desirable drug loadings and tailored molecular weights (Mw 23,000-35,000g/mol) with relatively narrow polydispersities (pdi 1.3-1.5). These polymers were found to be hydrolytically cleaved under acid conditions (such as those found in endosomes, lysosomes or the extracellular fluid of some tumours) yielding the free drug. Additionally, they were found to be stable over prolonged periods of time at pH 7.4 mimicking blood plasma. Of the four polymers synthesised, the conjugates of DES and BIS displayed the best activity for HIF-1α inhibition in HeLa 9xHRE-Luc tumour cells. More importantly, these conjugates were found to exhibit little to no cell toxicity, contrary to the free drugs, and consequently, they significantly enhanced drug therapeutic index (TI 3.5 vs. 7.2 for free DES vs. DES-polyacetal 2a, and TI 1.1 vs. >20 for free BIS vs. BIS-polyacetal 1b).
authors.affiliation: Polymer Therapeutics Lab., Centro de Investigación Príncipe Felipe, C/Eduardo Primo Yúfera 3, Valencia 46012, Spain.
authors.forename: Richard M
authors.initials: RM
authors.lastname: England
authors.forename: Esther
authors.initials: E
authors.lastname: Masiá
authors.forename: Vanessa
authors.initials: V
authors.lastname: Giménez
authors.forename: Rut
authors.initials: R
authors.lastname: Lucas
authors.forename: María J
authors.initials: MJ
authors.lastname: Vicent
mesh_terms: D000080:Acetals / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D018929:Cell Culture Techniques; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D004355:Drug Stability; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics; D008156:Luciferases / Q000235:genetics; D015394:Molecular Structure; D008970:Molecular Weight; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000080:Acetals; D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011108:Polymers; D013267:Stilbenes; C016067:polyacetal; D011092:Polyethylene Glycols; D008156:Luciferases