Formulations for targeted release of agents under low pH conditions and methods of use thereof
AssigneeYale University
InventorsW. Mark Saltzman, Junwei Zhang, Jiangbing Zhou, Zhaozhong Jiang
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Abstract
Poly(amine-co-ester-co-ortho ester) polymers, methods of forming active agent-load nanoparticles therefrom, and methods of using the nanoparticles for drug delivery are disclosed. The nanoparticles can be coated with an agent that reduces surface charge, an agent that increases cell-specific targeting, or a combination thereof. Typically, the loaded nanoparticles are less toxic, more efficient at drug delivery, or a combination thereof compared to a control or other transfection reagents.
Claims17
A polymeric formulation comprising a poly(amine-co-ester-co-ortho ester) or poly(amine-co-amide-co-ortho ester) having the following formula:
- wherein each occurrence of m is an integer between 1 and 30, inclusive,
- each occurrence of n, p, and q is independently an integer between 1 and 20, inclusive,
- each occurrence of t, u, v, and w is independently an integer between 1 and 1000, inclusive, and
- J and Z are independently O or NR′, wherein R′ is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl,
- wherein the ortho ester has the following formula:
- wherein r and s are independently an integer between 1 and 20, inclusive,
- wherein R4, Riv, and Rv are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, arylthio, substituted arylthio, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, polyaryl, substituted polyaryl, C3-C20 cyclic, substituted C3-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid, poly(ethylene glycol), peptide, or polypeptide group, and
- wherein the ortho ester is covalently attached to the rest of the poly(amine-co-ester-co-ortho ester) or poly(amine-co-amide-co-ortho ester) at points d and/or e.
A method for making nanoparticles for delivering molecules to a compartment of a cell, wherein the molecules are released at the pH of the compartment, comprising
- (i) providing a poly(amine-co-ester-co-ortho ester) or poly(amine-co-amides-co-orthoester) having the following formula:
- wherein each occurrence of m is an integer between 1 and 30, inclusive,
- each occurrence of n, p, and q, is independently an integer between 1 and 20, inclusive, each occurrence of t, u, v, and w is independently an integer between 1 and 1000, inclusive, and
- J and Z are independently O or NR′,
- wherein R′ is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl,
- wherein the ortho ester has the following formula:
- wherein r and s are independently an integer between 1 and 20, inclusive,
- R4, Riv, and Rv are independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, aroxy, substituted aroxy, alkylthio, substituted alkylthio, arylthio, substituted arylthio, carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino, substituted amino, amido, substituted amido, polyaryl, substituted polyaryl, C3-C20 cyclic, substituted C3-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid, poly(ethylene glycol), peptide, or polypeptide group,
- wherein the ortho ester is covalently attached to the rest of the poly(amine-co-ester-co-ortho ester) or poly(amine-co-amide-co-ortho ester) at points d and/or e,
- (ii) precipitating the molecules by mixing the poly(amine-co-ester-co-ortho ester) or poly(amine-co-amide-co-ortho ester) with the molecules in a solution, and
- (iii) forming precipitate into nanoparticles.
Dependencies are inferred from the claim text.