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1. (WO2018081553) COMPOSITIONS AND ASSOCIATED METHODS OF MESOPOROUS NANOPARTICLES COMPRISING PLATINUM-ACRIDINE MOLECULES

Pub. No.:    WO/2018/081553    International Application No.:    PCT/US2017/058749
Publication Date: Fri May 04 01:59:59 CEST 2018 International Filing Date: Sat Oct 28 01:59:59 CEST 2017
IPC: A61K 31/473
C07D 487/06
Applicants: WAKE FOREST UNIVERSITY
Inventors: BIERBACH, Ulrich
ZHENG, Ye
SINGH, Ravi
Title: COMPOSITIONS AND ASSOCIATED METHODS OF MESOPOROUS NANOPARTICLES COMPRISING PLATINUM-ACRIDINE MOLECULES
Abstract:
Large-pore mesoporous silica nanoparticles (MSN) were prepared and functionalized to serve as a robust and biocompatible delivery platform for platinum-acridine (PA) anticancer agents. The material showed a high loading capacity for the dicationic, hydrophilic hybrid agent [PtCl(en)(N-[acridin-9-ylaminoethyl]-N-methylpropionamidine)] dinitrate salt (P1 A1) and virtually complete retention of payload at neutral pH in a high-chloride buffer. In acidic media mimicking the pH inside the cells' lysosomes, rapid, burst-like release of P1 A1 from the nanoparticles is observed. Coating of the materials in phospholipid bilayers resulted in nanoparticles with greatly improved colloidal stability. The lipid and carboxylate- modified nanoparticles containing 40 wt.% drug caused S phase arrest and inhibited cell proliferation in pancreatic cancer cells at submicromolar concentrations similar to carrier-free P1A1. One feature of the nanoparticle-delivered P1A1 was that the payload did not escape from the acidified lysosomal vesicles into the cytoplasm, but was shuttled to the nuclear membrane and released into the nucleus.