Transepithelial transport and toxicity of PAMAM dendrimers: Implications for oral drug delivery

Abstract

This article summarizes efforts to evaluate poly(amido amine) (PAMAM) dendrimers as carriers for oral drug delivery. Specifically, the effect of PAMAM generation, surface charge and surface modification on toxicity, cellular uptake and transepithelial transport is discussed. Studies on Caco-2 monolayers, as models of intestinal epithelial barrier, show that by engineering surface chemistry of PAMAM dendrimers, it is possible to minimize toxicity while maximizing transepithelial transport. It has been demonstrated that PAMAM dendrimers are transported by a combination of paracellular and transcellular routes. Depending on surface chemistry, PAMAM dendrimers can open the tight junctions of epithelial barriers. This tight junction opening is in part mediated by internalization of the dendrimers. Transcellular transport of PAMAM dendrimers is mediated by a variety of endocytic mechanisms. Attachment or complexation of cytotoxic agents to PAMAM dendrimers enhances the transport of such drugs across epithelial barriers. A remaining challenge is the design and development of linker chemistries that are stable in the gastrointestinal tract (GIT) and the blood stream, but amenable to cleavage at the target site of action. Recent efforts have focused on the use of PAMAM dendrimers as penetration enhancers. Detailed in vivo oral bioavailability of PAMAM dendrimer – drug conjugates, as a function of physicochemical properties will further need to be assessed.

Poly(amido amine) dendrimers in oral delivery

“…This pattern leads alternatively to amine-terminated full generation or carboxyl-terminated half-generation dendrimers after each addition step in the synthesis. 20 As the generation number increases, the number of functional groups doubles, while the diameter of dendrimer increases by about 1 nm. 20,21 PAMAM dendrimers because of their highly tunable and controlled synthesis have the unique advantage of having very low polydispersities.…”

“…20 As the generation number increases, the number of functional groups doubles, while the diameter of dendrimer increases by about 1 nm. 20,21 PAMAM dendrimers because of their highly tunable and controlled synthesis have the unique advantage of having very low polydispersities. A complete generation of PAMAM dendrimers has primary amine groups on the surface (pKa D 6.85) and tertiary amine groups within the core (pKa D 3.86).…”

“…24 Due to their charge-based ability to interact with biological membranes, PAMAM dendrimers were shown to permeate across epithelial barriers of the gut, therefore, making them potential polymeric carriers for the delivery of drugs and macromolecules across the GI barrier. 20 PAMAM dendrimers were also utilized as non-viral gene delivery vectors due to their nanoscale size and their ability to condense DNA thereby protecting DNA from in vivo environment. 22,25 PAMAM dendrimers were also shown to be useful in other fields of nanomedicine such as electrochemical bio(sensing), 26 and photodynamic therapy.…”

“…29 Based on other in vitro cytotoxicity studies, the rank order of cytotoxicity of PAMAM dendrimers is hydroxyl-terminated<carboxyl-terminated<amine-terminated systems. 20,31 Cytotoxicity evaluation performed on Caco-2 cells using the lactate dehydrogenase (LDH) assay showed that carboxyl-terminated dendrimers of generations 3.5 and 4.5 were shown to be toxic only at a higher donor concentration of 10.0 mM compared to amine-terminated dendrimers of generations 3.0 and 4.0 which are toxic to 1.0 mM. 29,30 The influence of cationic PAMAM G4-NH 2 on Madin-Darby canine kidney (MDCK) cell monolayer integrity was performed by determining the permeability of mannitol across MDCK cells.…”

Advanced nanocarriers for an antitumor peptide

“…They are characterized as safe and non-immunogenic and they are used in drug delivery, delivery of antisense nucleotides and gene therapy, both in vitro and in vivo due to the reproducibility of their pharmacokinetic behavior (Eichman et al, 2001;Asthana et al, 2005;Svenson and Tomalia, 2005). According to the literature, dendrimers have been shown to cross cell barriers and membranes by the mechanism of endocytosis (Jevprasesphant et al, 2004;Sadekar and Ghandehari, 2012).…”