Transepithelial transport of PEGylated anionic poly(amidoamine) dendrimers: implications for oral drug delivery.

The purpose of this work was to assess the impact of PEGylation on transepithelial transport of anionic poly(amidoamine) dendrimers. Cytotoxicity, uptake and transport across Caco-2 cells of PEGylated G3.5 and G4.

Targetable HPMA copolymer-aminohexylgeldanamycin conjugates for prostate cancer therapy.

Purpose: This study focuses on the synthesis and characterization of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-cyclo-RGD (Arg-Gly-Asp) conjugates for delivery of geldanamycin to prostate tumors.

Materials And Methods: HPMA copolymers containing aminohexylgeldanamycin (AH-GDM) with and without the targeting peptide RGDfK were synthesized and characterized. Drug release from copolymers was evaluated using cathepsin B.

Tumor-targeted HPMA copolymer-(RGDfK)-(CHX-A''-DTPA) conjugates show increased kidney accumulation.

N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-RGDfK conjugates targeting the alpha(v)beta(3) integrin have shown increased accumulation in solid tumors and promise for selective delivery of radiotherapeutics to sites of angiogenesis- or tumor-expressed alpha(v)beta(3) integrin. An unresolved issue in targeting radiotherapeutics to solid tumors is toxicity to non-target organs. To reduce toxicity of radiolabeled conjugates, we have synthesized HPMA copolymer-RGDfK conjugates with varying molecular weight and charge content to help identify a polymeric structure that maximizes tumor accumulation while rapidly clearing from non-targeted organs.

Potential oral delivery of 7-ethyl-10-hydroxy-camptothecin (SN-38) using poly(amidoamine) dendrimers.

Purpose: To investigate potential application of poly(amidoamine) (PAMAM) dendrimers for improving the delivery of SN-38.

Methods: Complexes of SN-38 with generation 4 amine terminated PAMAM dendrimers were synthesized with varying amounts of drug. Stability of the complexes as well as influence of complexation on permeability across and cellular uptake by Caco-2 cells was evaluated.

Endocytosis inhibitors prevent poly(amidoamine) dendrimer internalization and permeability across Caco-2 cells.

Previous studies from our group demonstrated visual evidence that endocytosis mechanism(s) contribute to the internalization and intracellular trafficking of cationic and anionic poly(amidoamine) (PAMAM) dendrimers across Caco-2 cells. These dendrimers colocalized with established endocytosis markers, which suggested PAMAM dendrimers may be internalized by a clathrin-dependent endocytosis mechanism and are rapidly trafficked to endosomal and lysosomal compartments. In the present study, generation 4 PAMAM-NH2 (G4NH2) dendrimer was labeled with tritium to measure the rate of uptake and permeability in Caco-2 cells.

Surface acetylation of polyamidoamine (PAMAM) dendrimers decreases cytotoxicity while maintaining membrane permeability.

Improving the oral bioavailability of therapeutic compounds remains a challenging area of research. Polyamidoamine (PAMAM) dendrimers are promising candidates for oral drug delivery due to their well-defined compact structure, versatility of surface functionalities, low polydispersity, and ability to enhance transepithelial transport. However, potential cytotoxicity has hampered the development of PAMAM dendrimers for in vivo applications.

Endocytosis and interaction of poly (amidoamine) dendrimers with Caco-2 cells.

Purpose: To investigate the internalization and subcellular trafficking of fluorescently labeled poly (amidoamine) (PAMAM) dendrimers in intestinal cell monolayers.

Materials And Methods: PAMAM dendrimers with positive or negative surface charge were conjugated to fluorescein isothiocyanate (FITC) and visualized for colocalization with endocytosis markers using confocal microscopy. Effect of concentration, generation and charge on the morphology of microvilli was observed using transmission electron microscopy.

Transport of poly(amidoamine) dendrimers across Caco-2 cell monolayers: Influence of size, charge and fluorescent labeling.

Purpose: To investigate the transport of poly(amidoamine) (PAMAM) dendrimers with positive, neutral and negatively charged surface groups across Caco-2 cell monolayers.

Methods: Cationic PAMAM-NH2 (G2 and G4), neutral PAMAM-OH (G2), and anionic PAMAM-COOH (G1.5-G3.

Interaction of cis-(6-benzhydrylpiperidin-3-yl)benzylamine analogues with monoamine transporters: structure-activity relationship study of structurally constrained 3,6-disubstituted piperidine analogues of (2,2-diphenylethyl)-[1-(4-fluorobenzyl)piperidin-4-ylmethyl]amine.

To explore structure-activity relationships (SAR) of a novel conformationally constrained lead cis-3,6-disubstituted piperidine derivative derived from (2,2-diphenylethyl)-[1-(4-fluorobenzyl)piperidine-4-ylmethyl]amine (I), a series of compounds was synthesized by derivatizing the exocyclic N-atom at the 3-position of the lead. This study led to the formation of substituted phenyl and heterocyclic derivatives. All novel compounds were tested for their affinity at the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in competing for the binding of [3H]WIN 35 428, [3H]citalopram, and [3H]nisoxetine, respectively.