Cationic materials and formulations for drug delivery
Cationic polymers are provided for delivering anionic active agents, preferably in the form or nanoparticles and other nanostructures. The polymer can be a polycation homopolymer or a copolymer containing a polycation block. The polycations and polycation containing polymers can contain dicarboxylic acid ester units and units of (a-amino acid)-α, ω-alkylene diester units. The nanoparticles can contain high loadings of anionic active agents, with sustained release of the active agents. Methods of making the polycations and polycation containing polymers are provided. Methods of making the nanoparticles and formulating them for administration to an individual in need thereof are also provided.
1. A population of non-aggregated particles comprising:
(a) one or more cationic polymer cores comprising a block copolymer comprising a polycation block and a biodegradable polymer block; and
(b) a layer of anionic active agents encapsulating the one or more cationic polymer cores, wherein the particle has a zeta potential between −10 mV and −30 mV.
2. The particle population of claim 1 , wherein the one or more cationic polymer cores has a diameter between 10 nm and 200 nm.
3. The particle population of claim 1 , wherein the particle is a multi-core shell nanoparticle and the nanoparticle comprises more than one cationic particle core.
4. The particle population of claim 1 , wherein the particle has a diameter of between 10 nm and 1,000 nm.
5. The particle population of claim 1 , wherein the particle comprises a protective layer and the anionic active agents are dispersed between the protective layer and the one or more cationic particle cores.
6. The particle population of claim 5 , wherein the protective layer is selected from the group consisting of lipid monolayers, lipid bilayers, biodegradable polymer layers, polymer-lipid conjugate layers, and combinations thereof.
7. The particle population of claim 1 , wherein the cationic particle core comprises a second polymer comprising the biodegradable polymer but without the polycation block.
8. The particle population of claim 1 , wherein the biodegradable polymer is selected from the group consisting of poly(lactic acid), poly(glycolic acid), and poly (lactic-co-glycolic acid).
9. The particle population of claim 1 , wherein the polycation block comprises a polymer comprising dicarboxylic acid ester units and units of (α-amino acid)-α,ω-alkylene diester units.
10. The particle population of claim 9 , wherein the polycation block comprises units having the structure
wherein R 1 is selected from the group consisting of linear and branched alkyl and substituted alkyl, alkenyl, or alkylene oxide groups containing from 2 to 20 carbon atoms;
wherein R 2 is selected from the group consisting of aliphatic amines, cycloaliphatic amines, heterocyclic amines, and aromatic amines containing from 1 to 12 carbon atoms; and
wherein n is an integer between 1 and 1,000.
11. The particle population of claim 10 , wherein one or both R 2 is the side chain of a cationic amino acid selected from the group consisting of lysine, arginine, histidine, homolysine, ornithine, diaminobutyric acid, diaminopimelic acid, diaminopropionic acid, homoarginine, trimethyllysine, trimethylomithine, 4-aminopiperidine-4-carboxylic acid, 4-amino -1-carbamimidoylpiperidine-4-carboxylic acid and 4-guanidinophenylalanine.
12. A polymer comprising cationic units having the structure
wherein R 1 is selected from the group consisting of linear and branched alkyl and substituted alkyl, alkenyl, or alkylene oxide groups containing from 2 to 20 carbon atoms;
wherein R 2 is selected from the group consisting of aliphatic amines, cycloaliphatic amines, heterocyclic amines, and aromatic amines containing from 1 to 12 carbon atoms;
wherein R 2 is not the side chain of arginine; and
wherein n is an integer between 1 and 1,000.
13. The polymer of claim 12 , wherein the aromatic amines do not comprise an imidazole or R 2 is not the side chain of lysine.
14. The polymer of claim 12 , wherein the polymer is a block copolymer comprising
(a) a polycation block comprising the cationic units, and
(b) one or more additional blocks selected from the group consisting of hydrophobic polymer blocks, hydrophilic polymer blocks, amphiphilic polymer blocks, and additional cationic polymer blocks.
15. The polymer of claim 12 , wherein the cationic units comprise units having the structure
wherein R 1 is selected from the group consisting of linear and branched alkyl and substituted alkyl, alkenyl, or alkylene oxide groups containing from 2 to 100 carbon atoms;
wherein R 2 is selected from the group consisting of aliphatic amines, cycloaliphatic amines, heterocyclic amines, and aromatic amines containing from 1 to 100 carbon atoms; and
wherein n is an integer between 1 and 1000.
16. The polymer of claim 15 , wherein R 2 is the side chain of a cationic amino acid selected from the group consisting of lysine, arginine, histidine, homolysine, ornithine, diaminobutyric acid, diaminopimelic acid, diaminopropionic acid, homoarginine, trimethylysine, trimethylornithine, 4-aminopiperidine-4-carboxylic acid, 4-amino-1-carbamimidoylpiperidine-4-carboxylic acid and 4-guanidinophenylalanine.
17. The polymer of claim 12 , wherein the polymer has a molecular weight of between 0.5 kDa to 1000 kDa.
18. The polymer of claim 12 , wherein the polymer has a molecular weight of between 2 kDa and 10 kDa or 40 kDa and 60 kDa.
19. A pharmaceutical formulation comprising the particle population of claim 1 and a pharmaceutically acceptable excipient.
20. A method of making the polymer of claim 12 comprising a polycondensation reaction of a bis-(α-amino acid) diester with a di-acid or the activated ester thereof.
21. The method of claim 20 , wherein the di-acid is selected from the group consisting of succinic acid, adipic acid, and sebacic acid.
22. The method of claim 21 , wherein the polycondensation reaction is with an activated ester of the di-acid and the activated ester comprises a di-p-nitrophenyl ester of the di-acid.
23. A method of making the particle population of claim 1 comprising dissolving the block copolymer in a first solvent and adding a second solvent of a different hydrophobicity, then removing solvent under conditions wherein the polymer orients to form particles.
24. The particle population of claim 1 , wherein one or more of the cationic polymer cores comprise an inorganic particle and the cationic polymer block is on the surface of the inorganic particle.
25. The particle population of claim 24 , wherein the inorganic particle comprises a particle selected from the group consisting of gold particles, iron oxide particles, and silica particles.