Bharali et al 6. Non- or low-immunogenicity associated with most dendrimer surfaces modiﬁed with small functional groups or polyethylene glycol (PEG). 7. Surface groups that can be modiﬁed to optimize biodis- tribution; receptor mediated targeting, therapy dosage or controlled release of drug from the interior space. 8. Ability to arrange excretion mode from body, as a func- tion of nanoscale diameter. Dendrimer and anticancer drug delivery One of the major applications of dendrimers is as a delivery vehicle for various anticancer drugs. The structure and tunable surface functionality of dendrimers allows for the encapsulation/conjugation of multiple entities, either in the core or on the surface, rendering them ideal carriers for various anticancer drugs. There are numerous examples of dendrimer mediated targeted drug delivery. In 2002, Jesus and colleagues43 had explored the pos- sibility of a 2, 2-bis (hydroxymethyl) propanoic acid based dendritic scaffold as a delivery carrier for doxorubicin in vitro and in vivo. This dendritic nanoformulation, which contains doxorubicin covalently bound through a hydrazone linkage to a high molecular weight 3-arm polyethylene oxide; exhibits reduced cytotoxicity in vitro. However, in vivo biodistribu- tion experiments showed minimal accumulation of the DOX- dendrimer conjugate in vital organs, including the liver and heart, and increased half-life of doxorubicin compared to the free drug. Thus, it was hypothesized that proper choices of nanocarrier systems can increase the circulation half-life to effectively exploit the enhanced permeation retention (EPR) effect phenomenon and thus have tremendous potential to increase the efﬁcacy of the drug to a greater extent. In an attempt to improve the efﬁcacy of doxorubicin, Lai and colleagues44 utilize photochemical internalization (PCI) technology for site-speciﬁc delivery of membrane imperme- able macromolecules from endocytic vesicles into the cyto- sol. PCI technology has been demonstrated to successfully enhance the cytotoxicity of cancerous tissue by destroying the cytoplasmic membrane and facilitating the release of macromolecules entrapped in cytoplasmic vesicles. PAMAM dendrimers were conjugated to doxorubicin through the amide (PAMAM–amide–DOX) or the hydrazone (PAMAM– hyd–DOX) bonds. Two different PCI strategies referred to as ‘light after’, and ‘light before’, where exposure to light is either after or before treatment with doxorubicin respec- tively, were applied to evaluate the cytotoxic effects of these doxorubicin PAMAM conjugates against Ca9-22, gingival carcinoma, cells. It was observed that only the ‘light after’ PCI 4 treatment signiﬁcantly increased the nuclear accumulation of doxorubicin from the PAMAM-hyd-DOX conjugates and thus exhibited higher cytotoxicity probably due to the synergistic effects. Both PCI strategies failed to improve the cytotoxicity of PAMAM-amide-DOX conjugates. Many investigators have also explored the feasibility of cisplatin incorporation in dendrimers. One of the early exam- ples is PAMAM dendrimer generation 3.5 conjugated to cisplation through the sodium carboxylate surface giving a dendrimer–platinate (dendrimer–Pt; 20–25 wt% platinum), which resulted in a fairly water soluble nanoformulation with the ability to release cisplatin slowly in vitro.45 It was observed that this formulation showed superior activity over cisplatin when injected i.p. into mice bearing B16F10 tumor cells, whereas the dendrimer-Pt and cisplatin were equi-active i.p. against i.p. L1210. Also, when administered i.v. to treat a palpable s.c. B16F10 melanoma, the dendrimer-Pt displayed additional antitumor activity whereas cisplatin was inactive. Zhou and colleagues46 synthesized poly (amide-amine) based dendrimers with a cyclic core and four direction branches using the method referred to as ‘time-sequenced propagation technique’. Using this technique, they successfully synthesized dendrimers from generation 0.5 to generation 5.5. Further, dendrimers were then reacted with 1-bromoacetyl-5- ﬂuorouracil to form dendrimer–5FU conjugates. In vitro release kinetics in PBS revealed that the release of 5FU depends on the generation of the dendrimer used for the conjugation, and indicated that such a dendritic polymer could be a promising carrier for the controlled release of antitumor drugs. PEGylated dendrimers are one of the sub-classes of dendrimers that attract numerous scientists due to its pro- longed blood circulation time, lower level of toxicity and relatively lower accumulation in different organs. Also, in vivo experiments show a signiﬁcantly higher accumulation in the tumor tissues due to the EPR effect.47 PEG-dendrimers are generally synthesized by the conjugation of PEG or polyeth- ylene oxide (PEO) chains to a multifunctional dendritic chain. A 2006 study by Lee and colleagues48 showed the feasibility of polyester-based dendrimer–PEO–doxorubicin conjugate to substantially inhibit the progression of DOX-insensitive C-26 tumor subcutaneously implanted in BALB/c mice. This dendrimer–PEO–doxorubicin conjugate also showed the ability to eliminate the tumors at certain doses and was found to be more or less the same as compared to an equal amount of Doxil, which is currently available for liposome formulation of DOX. Additionally, Bhadra and colleagues,49 used PEGylated PAMAM dendrimers for the incorporation of 5FU. Thus, as International Journal of Nanomedicine 2009:4