Folate coupled poly(ethyleneglycol) conjugates of anionic poly(amidoamine) dendrimer for inflammatory tissue specific drug delivery.

Folate receptor is overexpressed on the activated (but not quiescent) macrophages in both animal models and human patients with naturally occurring rheumatoid arthritis. The aim of this study was to prepare folate targeted poly(ethylene glycol) (PEG) conjugates of anionic dendrimer (G3.5 PAMAM) as targeted drug delivery systems to inflammation and to investigate its biodistribution pattern in arthritic rats. Folate-PEG-PAMAM conjugates, with different degrees of substitution were synthesized by a two-step reaction through a carbodiimide-mediated coupling reaction and loaded with indomethacin. Folate-PEG conjugation increased the drug loading efficiency by 10- to 20-fold and the in vitro release profile indicated controlled release of drug. The plasma pharmacokinetic parameters indicated an increased AUC, circulatory half-life and mean residence time for the folate-PEG conjugates. The tissue distribution studies revealed significantly lesser uptake by stomach for the folate-PEG conjugates, thereby limiting gastric-related side effect. The time-averaged relative drug exposure (r(e)) of the drug in paw for the folate-PEG conjugates ranged from 1.81 to 2.37. The overall drug targeting efficiency (T(e)) was highest for folate-PEG conjugate (3.44) when compared to native dendrimer (1.72). The folate-PEG-PAMAM conjugates are the ideal choice for targeted delivery of antiarthritic drugs to inflammation with reduced side-effects and higher targeting efficiency.

[1]  P. Low,et al.  Folate-targeted imaging of activated macrophages in rats with adjuvant-induced arthritis. , 2002, Arthritis and rheumatism.

[2]  Narendra Kumar Jain,et al.  Solubility Enhancement of Indomethacin with Poly(amidoamine) Dendrimers and Targeting to Inflammatory Regions of Arthritic Rats , 2004, Journal of drug targeting.

[3]  P. Srinath,et al.  Pharmacodynamic and pharmacokinetic evaluation of lipid microspheres of indomethacin. , 1998, Pharmaceutica Acta Helvetiae.

[4]  J. Baker,et al.  Efficient transfer of genetic material into mammalian cells using Starburst polyamidoamine dendrimers. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[5]  J. Fréchet,et al.  Designing dendrimers for drug delivery. , 1999, Pharmaceutical science & technology today.

[6]  S. Jain,et al.  A PEGylated dendritic nanoparticulate carrier of fluorouracil. , 2003, International journal of pharmaceutics.

[7]  R. Müller,et al.  Synthesis and biological evaluation of folate receptor-targeted boronated PAMAM dendrimers as potential agents for neutron capture therapy. , 2003, Bioconjugate chemistry.

[8]  P. Diwan,et al.  Biodisposition of PEG-coated lipid microspheres of indomethacin in arthritic rats. , 2005, International journal of pharmaceutics.

[9]  P. Low,et al.  Endocytosis of folate-protein conjugates: ultrastructural localization in KB cells. , 1993, Journal of cell science.

[10]  Oladapo Bakare,et al.  Studies on PEGylated and Drug-Loaded PAMAM Dendrimers , 2005 .

[11]  K. Kono,et al.  Water-soluble dendritic unimolecular micelles: their potential as drug delivery agents. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[12]  Youngseon Choi,et al.  Targeting Cancer Cells with DNA-Assembled Dendrimers: A Mix-and-Match Strategy for Cancer , 2005, Cell cycle.

[13]  M. Brechbiel,et al.  Biodistribution of a 153Gd-Folate Dendrimer, Generation = 4, in Mice With Folate-Receptor Positive and Negative Ovarian Tumor Xenografts , 2002, Investigative radiology.

[14]  Anil K Patri,et al.  Dendritic polymer macromolecular carriers for drug delivery. , 2002, Current opinion in chemical biology.

[15]  Thommey P. Thomas,et al.  PAMAM dendrimer-based multifunctional conjugate for cancer therapy: synthesis, characterization, and functionality. , 2006, Biomacromolecules.

[16]  P. Diwan,et al.  Long-circulating liposomes of indomethacin in arthritic rats--a biodisposition study. , 2000, Pharmaceutica acta Helvetiae.

[17]  B. Newbould,et al.  CHEMOTHERAPY OF ARTHRITIS INDUCED IN RATS BY MYCOBACTERIAL ADJUVANT. , 1963, British journal of pharmacology and chemotherapy.

[18]  K. Kono,et al.  Synthesis of polyamidoamine dendrimers having poly(ethylene glycol) grafts and their ability to encapsulate anticancer drugs. , 2000, Bioconjugate chemistry.

[19]  Antony D'Emanuele,et al.  Dendrimer-drug interactions. , 2005, Advanced drug delivery reviews.

[20]  Anil K Patri,et al.  Targeted drug delivery with dendrimers: comparison of the release kinetics of covalently conjugated drug and non-covalent drug inclusion complex. , 2005, Advanced drug delivery reviews.

[21]  P. Low,et al.  Folate-mediated tumor cell targeting of liposome-entrapped doxorubicin in vitro. , 1995, Biochimica et biophysica acta.

[22]  E. W. Meijer,et al.  Dendrimers: relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of 125I-labelled polyamidoamine dendrimers in vivo. , 2000, Journal of controlled release : official journal of the Controlled Release Society.