US 2019/0290685 A1 · 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-methylropionamidine)] dinitrate salt (P1 Al) 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.

Claims20

Dependent claims

A pharmaceutical composition comprising a compound of formula I and a silica mesoporous nanoparticle;

wherein X is halo, —OC(O)R9, nitrate, H2O or sulfate;
R1 and R2 are amino groups or together with the platinum atom to which they are attached, R1 and R2 form the ring —NH2—(CH2)v—NH2— wherein v is 1, 2, or 3;
R3 is —N(R6)—, wherein R6 is hydrogen or C1-C6alkyl;
each R4 is independently an amino, a nitro, —NHC(O)(R10), —C(O)NHR10, or halo;
R10 is hydrogen, C1-6 alkyl, phenyl, naphthyl, C3-6 cycloalkyl, norbornyl, or adamantyl;
q is 0, 1, or 2;
R5 is a direct bond, —NH— or C1-C6alkylene;
or R5 and X together with the atoms to which they are attached form a 6- or 7-membered ring, wherein said 6- or 7-membered ring contains a linking group —C(O)O— or —OC(O)—;
R7 is hydrogen, methyl, or —C(O)O—R8;
wherein
R8 is hydrogen, C1-6 alkyl, phenyl, naphthyl, C1-6 cycloalkyl, norbornyl, or adamantyl, a natural or unnatural amino acid or a peptide;
R9 is hydrogen, C1-6 alkyl, phenyl, naphthyl, C3-6 cycloalkyl, norbornyl, or adamantyl;
Y is C1-C6alkyl;
and
Z is one or more counterions sufficient to balance the charge of the compound.

12 more elements

Dependencies are inferred from the claim text.

Compositions and associated methods of mesoporous nanoparticles comprising platinum-acridine molecules

Life of this patent

Compositions and associated methods of mesoporous nanoparticles comprising platinum-acridine molecules

Life of this patent

Abstract

Claims20