Injectable dendrimer hydrogel nanoparticles
The invention discloses injectable hydrogels which are in the form of crosslinked nano beads or particle in the size range 5 nm to 10 μm, comprising PAMAM dendrimer with asymmetrical peripheral end groups such that one of the terminal groups is involved in formation of hydrogel and the other in involved in the conjugation of drugs or imaging agents and their methods of preparation. The said gel is formed by reaction of the PAMAM dendrimer with asymmetrical end groups with other polymer wherein the other polymer is selected from the group of linear, branched, hyperbranched or star shaped polymers with functionalized terminal groups. The PAMAM dendrimer with asymmetrical terminal groups consists of a Generation 2 and above PAMAM dendrimer with symmetrical end groups modified using the amino acids or their modified forms. The gel disclosed in the present invention is formed as small crosslinked particles in the size range 25 nm to 10 μm and is suitable for injectable delivery of hydrogel to any of the body orifices, tissues by intramuscular or subcutaneous route and ocular delivery for the purpose of therapeutic treatment and imaging.
1. An injectable hydrogel nanoparticle comprising:
a plurality of poly(amidoamine) (PAMAM) dendrimers with an end group covalently bound to an amino acid linker selected from the group consisting of serine, aspartic acid, cysteine, glutamic acid, threonine, and tyrosine,
wherein the amino acid linker is covalently bound by a first functional group to a crosslinkable polymer and is covalently bound by a second, different functional group to a drug or imaging agent;
wherein the hydrogel nanoparticle is formed by crosslinking of the crosslinkable polymer.
2. The injectable hydrogel nanoparticle of claim 1 wherein the amino acid is in a protected form selected from the group consisting of tert-butylcarbonyl-serine-hydroxysuccinimide (Boc-Ser-NHS), tert-butylcarbonyl-aspartic acid (Boc-Asp-OH), tertbutylcarbonyl-glutamic acid (Boc-Glu-OH), fluorenylmethoxycarbonyl-serine (Fmoc-Ser), fluorenylmethoxycarbonyl-aspartic acid (Fmoc-Asp-OH), fluorenylmethoxycarbonyl-glutamic acid (Fmoc-Glu-OH), tert-butylcarbonylcysteine-hydroxysuccinimide (Boc-Cys-NHS), serine-methylester (H-ser-OMe), cysteine-methylester (H-Cys-OMe), aspartic acid-methylester (H-Asp-OMe), glutamic acid-methyl ester (H-Glu-OMe), tert-butylcarbonyl-threoninehydroxysuccinimide (Boc-Thr-NHS), threonine-methylester (H-Thr-OMe), fluorenylmethoxycarbonyl-threonine (Fmoc-Thr), tert-butylcarbonyl-tyrosinehydroxysuccinimide (Boc-Tyr-NHS), tert-butylcarbonyl-tyrosine (Boc-Tyr-OH), tyrosine-methylester (H-Tyr-OMe), cysteine-dithiopyridine (Cys-S-STP), and tertbutylcarbonyl-cysteine-dithiopyridine (Boc-Cys-S-STP) when it is covalently bound prior to attachment of the crosslinkable polymer and the drug or imaging agent.
3. The injectable hydrogel nanoparticle of claim 1 , wherein the crosslinkable polymer is selected from the group consisting of a linear polymer, a branched polymer, and a star shaped polymer.
4. The injectable hydrogel nanoparticle of claim 1 , wherein the diameter of the nanoparticle is between 5 nm and 10 μm.
5. The injectable hydrogel nanoparticle of claim 1 , formulated for intravenous, topical, intravitreal, intramuscular, or subcutaneous administration.
6. The injectable hydrogel nanoparticle of claim 1 , wherein the PAMAM dendrimer is a G4 PAMAM dendrimer.
7. The injectable hydrogel nanoparticle of claim 1 , wherein the drug is selected from the group consisting of macrolide antibiotics, tetracyclines, fluoroquinolones, cephalosporins, non-steroidal anti-inflammatory and analgesic drugs, and corticosteroids.
8. The injectable hydrogel nanoparticle of claim 3 , wherein the crosslinkable polymer is a functionalized polyethylene glycol (PEG) polymer.
9. The injectable hydrogel nanoparticle of claim 8 , wherein the functionalized PEG polymer is between 5 kDa and 80 kDa in size.
10. The injectable hydrogel nanoparticle of claim 8 , wherein the functionalized PEG polymer is between 20 and 40 kDa in size.
11. The injectable hydrogel nanoparticle of claim 7 , wherein the drug is selected from the group consisting of erythromycin, azithromycin, rapamycin, clarithromycin, minocycline, doxycycline, ciprofloxacin, enrofloxacin, ofloxacin, gatifloxacin, levofloxacin, norfloxacin, cefuroxime, cefaclor, cephalexin, cephadroxil, cepfodoxime proxetil, N-acetyl cysteine, ibuprofen, aspirin, acetaminophen, diclofenac sodium, fluocinolone acetonide, and methylprednisolone.