**3.2 PAMAM dendrimer as drug delivery system**

Polymeric drug delivery can improve bioavailability and efficacy of therapeutics with intrinsically poor water solubility and high toxicity. Dendrimers, a class of highly branched polymers, are effective drug delivery vehicles due to their monodispersity and nanoscopic size. With each increase in dendrimer generation, the diameter increases linearly while the number of surface groups increases exponentially. These high density surface groups can be conjugated to drug molecules, targeting moieties and imaging agents, rendering dendrimers a versatile drug delivery platform. In addition, surface groups on dendrimers can be modified to modulate cytotoxicity and permeation across biological barriers.

During their synthesis, PAMAM dendrimers can be produced that are either anionic or cationic in nature, with "full generations" (ie. G1, G2) having amine terminal groups and "half generations" (ie, G0.5, G1.5) possessing carboxylic acid terminal groups. The size and charge of PAMAM dendrimers impact their cytotoxicity and transepithelial transport, with cationic dendrimers showing higher toxicity in vitro. Due to their intrinsically low cytotoxicity and appreciable transepithelial permeation characteristics across Caco-2 monolayers and everted rat intestinal sac models, anionic dendrimers show distinct advantages as vehicles for oral drug delivery, with higher generation dendrimers showing the greatest potential because of their large number of modifiable surface groups.

PAMAM has well-defined internal cavities and an open architecture, guest molecules can become directly encapsulated into the macromolecule interior through hydrophobic interactions. Drug-polymer conjugates are potential candidates for the selective delivery of anticancer agents to tumor tissue. The main advantages of conjugating drugs to polymeric carriers include an increase in water solubility of low soluble or insoluble drugs, and therefore, enhancement of drug bioavailability, protection of drug from deactivation and preservation of its activity during circulation, a reduction in antigenic activity of the drug leading to a less pronounced immunological body response, and the ability to provide passive or active targeting of the drug specifically to the site of its action.

Surface-modified dendrimers were predicted to enhance pilocarpine bioavailability [19]. The anticancer drugs adriamycin and methotrexate were encapsulated into PAMAM

inhibitors of endocytosis (i.e. cytochalasin B and deoxyglucose) or cellular metabolism (i.e. sodium azide) reduced the uptake that corresponded to lower transgene expression,

These dendrimers as nanocarriers possess the following advantages: (1) neutral surface of the dendrimer for low cytotoxicity; (2) existence of cationic charges inside the dendrimer (not on the outer surface) resulting in highly organized compact nanoparticles, which can potentially protect nucleic acids from degradation. Noteworthly, surface modified QPAMAM-NHAc dendrimer demonstrated enhanced cellular uptake of siRNA when compared with the internally cationic QPAMAM-OH dendrimer (degree of

George's study shows PEG-G5 and PEG-G6 dendrimers, with PEG conjugation molar ratio at 8% (PEG to surface amine per PAMAM), can facilitate dramatic intramuscular gene delivery in neonatal mice [17]. Park's group concluded that di-arginine conjugation to PAMAM dendrimers can improve polyplex stability, ntra-nuclear localization, and transfection efficiency but also induce charge density- and generation-dependent cytotoxicity. Therefore, a novel strategy for highly densed arginine conjugation maintaining low cytotoxicity will be needed for the development of efficient gene delivery carriers [18].

Polymeric drug delivery can improve bioavailability and efficacy of therapeutics with intrinsically poor water solubility and high toxicity. Dendrimers, a class of highly branched polymers, are effective drug delivery vehicles due to their monodispersity and nanoscopic size. With each increase in dendrimer generation, the diameter increases linearly while the number of surface groups increases exponentially. These high density surface groups can be conjugated to drug molecules, targeting moieties and imaging agents, rendering dendrimers a versatile drug delivery platform. In addition, surface groups on dendrimers can be

During their synthesis, PAMAM dendrimers can be produced that are either anionic or cationic in nature, with "full generations" (ie. G1, G2) having amine terminal groups and "half generations" (ie, G0.5, G1.5) possessing carboxylic acid terminal groups. The size and charge of PAMAM dendrimers impact their cytotoxicity and transepithelial transport, with cationic dendrimers showing higher toxicity in vitro. Due to their intrinsically low cytotoxicity and appreciable transepithelial permeation characteristics across Caco-2 monolayers and everted rat intestinal sac models, anionic dendrimers show distinct advantages as vehicles for oral drug delivery, with higher generation dendrimers showing

PAMAM has well-defined internal cavities and an open architecture, guest molecules can become directly encapsulated into the macromolecule interior through hydrophobic interactions. Drug-polymer conjugates are potential candidates for the selective delivery of anticancer agents to tumor tissue. The main advantages of conjugating drugs to polymeric carriers include an increase in water solubility of low soluble or insoluble drugs, and therefore, enhancement of drug bioavailability, protection of drug from deactivation and preservation of its activity during circulation, a reduction in antigenic activity of the drug leading to a less pronounced immunological body response, and the ability to provide

Surface-modified dendrimers were predicted to enhance pilocarpine bioavailability [19]. The anticancer drugs adriamycin and methotrexate were encapsulated into PAMAM

modified to modulate cytotoxicity and permeation across biological barriers.

the greatest potential because of their large number of modifiable surface groups.

passive or active targeting of the drug specifically to the site of its action.

regardless of cell type.

quaternization 97%).

**3.2 PAMAM dendrimer as drug delivery system** 

dendrimers (i.e. G=3 and 4) which had been modified with PEG monomethyl ether chains (i.e. 550 and 2000 Da respectively) attached to their surfaces. A similar construct involving PEG chains and PAMAM dendrimers was used to deliver the anticancer drug 5 fluorouracil. Encapsulation of 5-fluorouracil into G=4 increase in the cytotoxicity and permeation of dendrimers.

Dendrimers have ideal properties which are useful in targeted drug-delivery system. One of the most effective cell-specific targeting agents delivered by dendrimers is folic acid PAMAM dendrimers modified with carboxymethyl PEG5000 surface chains revealed reasonable drug loading, a reduced release rate and reduced haemolytic toxicity compared with the non-PEGylated dendrimer. A third-generation dendritic unimolecular micelle with indomethacin entrapped as model drug gives slow and sustained in vitro release, as compared to cellulose membrane control [20]. Controlled release of the Flurbiprofen could be achieved by formation of complex with amine terminated generation 4 (G4) PAMAM Dendrimers [21]. The results found that PEG-dendrimers conjugated with encapsulated drug and sustained release of methotrexate as compare to unencapsulated drug.
