Demonstrating the importance of polymer-conjugate conformation in solution on its therapeutic output: Diethylstilbestrol (DES)-polyacetals as prostate cancer treatment.
The design of improved polymeric carriers to be used in the next generation of polymer therapeutics is an ongoing challenge. Biodegradable systems present potential advantages regarding safety benefit apart from the possibility to use higher molecular weight (Mw) carriers allowing PK optimization, by exploiting the enhanced permeability and retention (EPR)-mediated tumor targeting. Within this context, we previously designed pH-responsive polyacetalic systems, tert-polymers, where a drug with the adequate diol-functionality was incorporated within the polymer mainchain. The synthetic, non-steroidal estrogen, diethylstilboestrol (DES) clinically used for the treatment of advanced prostate cancer was chosen as drug. In order to improve the properties of this tert-polymer, novel polyacetalic systems as block-co-polymers, with more defined structure have been obtained. This second generation polyacetals allowed higher drug capacity than the tert-polymer, a biphasic DES release profile at acidic pH and due to its controlled amphiphilic character readily formed micelle-like structures in solution. These features result in an enhancement of conjugate therapeutic value in selected prostate cancer cell models. Exhaustive physico-chemical characterization focusing on nanoconjugate solution behavior and using advanced techniques, such as, pulsed-gradient spin-echo NMR (PGSE-NMR) and small-angle neutron scattering (SANS), has been carried out in order to demonstrate this hypothesis. Clear evidence of significantly different conformation in solution has been obtained for both polyacetals. These results demonstrate that an adequate control on molecular or supramolecular conformation in solution with polymer therapeutics is crucial in order to achieve the desired therapeutic output.
Polymer Therapeutics Lab., Centro de Investigación Príncipe Felipe, Av. Autopista del Saler 16, 46012 Valencia, Spain.
Vanessa
V
Giménez
Craig
C
James
Ana
A
Armiñán
Ralf
R
Schweins
Alison
A
Paul
María J
MJ
Vicent
D000080:Acetals / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004054:Diethylstilbestrol / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004355:Drug Stability; D004705:Endocytosis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D018613:Microscopy, Confocal; D008968:Molecular Conformation; D008970:Molecular Weight; D011108:Polymers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012995:Solubility; D012996:Solutions; D013237:Stereoisomerism
D000080:Acetals; D000970:Antineoplastic Agents; D004337:Drug Carriers; D011108:Polymers; D012996:Solutions; C016067:polyacetal; D004054:Diethylstilbestrol