Synthesis and evaluation of pegylated dendrimeric nanocarrier for pulmonary delivery of low molecular weight heparin.
OBJECTIVE
This study tests the hypothesis that pegylated dendrimeric micelles prolong the half-life of low molecular weight heparin (LMWH) and increase the drug's pulmonary absorption, thereby efficacious in preventing deep vein thrombosis (DVT) in a rodent model.


METHODS
Pegylated PAMAM dendrimer was synthesized by conjugating G3 PAMAM dendrimer with methyl ester of polyethylene glycol 2000 (PEG-2000). Fourier transform infrared (FTIR), nuclear magnetic resonance (NMR) spectra and thin layer chromatography (TLC) were used to evaluate the identity and purity of pegylated dendrimer. The particle size distributions of the formulations were measured by using a Nicomp Zeta meter, and drug entrapment efficiency was studied by azure A assay. The efficacy of pegylated dendrimers in enhancing pulmonary absorption, prolonging drug half-life, and preventing DVT was studied in a rodent model.


RESULTS
FTIR, NMR and TLC data confirmed that PAMAM dendrimer was conjugated to PEG-2000. The entrapment efficiency of LMWH in PEG-dendrimer micelles was about 40%. Upon encapsulation of LMWH, the particle size of PEG-dendrimer micelles increased from 11.7 to 17.1 nm. LMWH entrapped in PEG-dendrimer produced a significant increase in pulmonary absorption and the relative bioavailability of the formulation was 60.6% compared to subcutaneous LMWH. The half-life of the PEG-dendrimer-based formulation was 11.9 h, which is 2.4-fold greater than the half-life of LMWH in a saline control formulation. When the formulation was administered at 48-h intervals, the efficacy of LMWH encapsulated in pegylated dendrimers in reducing thrombus weight in a rodent model was very similar to that of subcutaneous LMWH administered at 24-h intervals.


CONCLUSIONS
Pegylated PAMAM dendrimer could potentially be used as a carrier for pulmonary delivery of LMWH for the long-term management of DVT.
Bai
Shuhua
S
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter Drive, Amarillo, Texas, 79106, USA.
Ahsan
Fakhrul
F
D000042:Absorption; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D001682:Biological Availability; D050091:Dendrimers / Q000138:chemical synthesis* / Q000737:chemistry; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D008168:Lung / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011092:Polyethylene Glycols / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D017550:Spectroscopy, Fourier Transform Infrared; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000188:drug therapy
D000925:Anticoagulants; D050091:Dendrimers; D004337:Drug Carriers; D006495:Heparin, Low-Molecular-Weight; D011092:Polyethylene Glycols