No abstract

Dendrimers have come a long way in the last 25 years since their inception. Originally created as a wonder molecule of chemistry, dendrimer is now in the fourth class of polymers. Dr. Donald Tomalia first published his seminal work on Poly(amidoamine) (PAMAM) dendrimers in 1985. Application of dendrimers as a drug delivery system started in late 1990s. Dendrimers for drug delivery are employed using two approaches: (i) formulation and (ii) nanoconstruct. In the formulation approach, drugs are physically entrapped in a dendrimer using non-covalent interactions, whereas drugs are covalently coupled on dendrimers in the nanoconstruct approach. We have demonstrated the utility of PAMAM dendrimers for enhancing solubility, stability and oral bioavailability of various drugs. Drug entrapment and drug release from dendrimers can be controlled by modifying dendrimer surfaces and generations. PAMAM dendrimers are also shown to increase transdermal permeation and specific drug targeting. Dendrimer platforms can be engineered to attach targeting ligands and imaging molecules to create a nanodevice. Dendrimer nanotechnology, due to its multifunctional ability, has the potential to create next generation nanodevices.

We report unexpected anti-inflammatory properties for naked, unmodified poly(amidoamine) (PAMAM) dendrimers bearing simple surface functionality (e.g., -NH(2), -OH, etc.). This property was discovered serendipitously while studying the drug delivery features of PAMAM dendrimer-indomethacin complexes. Activity was quantitated by using three independently recognized in vivo anti-inflammatory assay methods, namely, (1) the carrageenan-induced paw edema model (acute activity), (2) the cotton pellet test, and (3) the adjuvant-induced arthritis assay in rats (chronic activities). Those dendrimers bearing amine or hydroxyl surface groups exhibited significant anti-inflammatory activity in the carrageenan-induced paw edema model. For example, [core: 1,2-diaminoethane]; (G = 4.0); {dendri-poly(amidoamine)-(NH(2))(64)} (i.e., G4-NH(2)) exhibited a mean percent inhibition of 35.50 +/- 1.6% 3 h after administration and [core: 1,2-diaminoethane] (G = 4.0); {dendri-poly(amidoamine)-(OH)(64)} (i.e., G4-OH) gave a mean percent inhibition of 31.22 +/- 1.58% 3 h after administration. On the other hand, [core: 1,2-diaminoethane] (G = 4.5); {dendri-poly(amidoamine)-(CO(2)H)(128)} (i.e., G4.5-CO(2)H) exhibited mild anti-inflammatory activity with a mean percent inhibition of 14.00 +/- 2.5% 3 h after administration. Unexpectedly, G4-NH(2) showed significantly higher activity compared to naked indomethacin (i.e., 50 +/- 3.1% vs 22 +/- 1.2%) using the cotton pellet granuloma model. Similarly, in the adjuvant-induced arthritis model, G4-NH(2) compared to naked indomethacin gave a mean percent inhibition of 30 +/- 1.9% versus 11 +/- 0.9% 14 days after administration.

This work includes investigation on solubility enhancement of indomethacin (IND) in the presence of poly(amidoamine) (PAMAM) dendrimers and passive targeting of the PAMAM/IND complex so formed to the inflamed regions in an animal model. The complex formation was confirmed by infrared and (1)H nuclear magnetic resonance spectroscopy methods. Solubility of IND in aqueous G4-PAMAM followed Higuchi's A(N) curve depending on pH of the solubilizing medium. The solubility was decreased upon addition of dendrimer to the IND saturated solution at various pH, indicating aggregation behavior of the PAMAM/IND complex and conforming to the Higuchi's A(N) solubility profile. The in vitro release of IND from the PAMAM/IND complex through a cellophane membrane, from a Franz diffusion cell, showed 79 +/- 3.2% drug release in 24 h. The drug release was further retarded in the presence of human serum albumin (HSA) suggesting the significance of complex HSA binding in altering in vivo behavior of the complex. Intravenous administration of the PAMAM/IND complex formulation in rats showed a two-compartment pharmacokinetic profile. Enhanced effective IND concentrations in the inflamed regions were obtained for the prolonged time period with the PAMAM/IND complex compared to the free drug in arthritic rats indicating preferred accumulation of IND to the inflamed region. The targeting efficiency of PAMAM/IND complex was 2.29 times higher compared to free drug. In contrast to the previous investigations, two interesting findings reported here are: (a) solubility behavior of IND in G4-PAMAM dendrimer deviates from linearity with increasing concentrations of dendrimer at acidic to neutral pH values and (b) inspite of lymphatic drainage, retention of PAMAM/IND complexes occurs at the inflammatory site.

The purpose of the investigation was to evaluate the potential of polyamidoamine (PAMAM) dendrimer as nanoscale drug delivery units for controlled release of water insoluble and acidic anti-inflammatory drug. Flurbiprofen (FB) was selected as a model acidic anti-inflammatory drug. The aqueous solutions of 4.0 generation (G) PAMAM dendrimer in different concentrations were prepared and used further for solubilizing FB. Formation of dendrimer complex was characterized by Fourier transform infrared spectroscopy. The effect of pH on the solubility of FB in dendrimer was evaluated. Dendrimer formulations were further evaluated for in vitro release study and hemolytic toxicity. Pharmacokinetic and biodistribution were studied in male albino rats. Efficacy of dendrimer formulation was tested by carrageenan induced paw edema model. It was observed that the loaded drug displayed initial rapid release (more than 40% till 3rd hour) followed by rather slow release. Pharmacodynamic study revealed 75% inhibition at 4th hour that was maintained above 50% till 8th hour. The mean residence time (MRT) and terminal half-life (THF) of the dendritic formulation increased by 2-fold and 3-fold, respectively, compared with free drug. Hence, with dendritic system the drug is retained for longer duration in the biosystem with 5-fold greater distribution. It may be concluded that the drug-loaded dendrimers not only enhanced the solubility but also controlled the delivery of the bioactive with localized action at the site of inflammation.