1.11 Polymer based nanocarriers .1 Polymer nanoparticle
1.11.3 Dendrimer
Table 1.3: Polymeric micelle formulation of anticancer drugs currently in clinical trials.
Trade
Name Drug Polymer
Used Indication Phase Company
SP1049C Doxorubicin Poloxamer
Metastatic Adenocarcinom
a of the Upper Gastrointestinal
Tract
Phase III
Supratek Pharma Ltd.
Canada
NK911 Doxorubicin PEG –b–
poly(aspartic acid)
Metastatic or Recurrent Solid
Tumors
Phase II
Nippon Kayaku Co. Ltd., Japan Genexol-
PM Paclitaxel
Methoxy poly(ethylene glycol)-b-poly (lactide)
Lung and Brest Cancer
Phase II
Samyang Co., South Korea NK105 Paclitaxel
Modified PEG –b– poly(aspartic acid)
Stomach Cancer Phase II
NanoCarri er Co.
Ltd., Japan
variety of carrier molecules, both hydrophobic and hydrophilic, and are useful delivery agents for genes and drugs. Recently, dendrimers have emerged as new alternatives and efficient tools for delivery of anticancer therapeutics (Wolinsky and Grinstaff, 2008).
There are mainly two strategies to synthesize dendrimers, (i) divergent method, in which the branching units are grown outwards from a central core (Tomalia et al., 1985) and (ii) convergent method, in which the dendrimer is synthesized from the periphery and terminate at the core (Hawker and Fréchet, 1990). The branching units are described by generation, starting with the central core molecule as generation 0 (G0) and increasing with each successive addition of branching points (i.e. G1, G2 etc.) and adopt a more globular shape with increasing generation. Dendrimers are often characterized by their terminal generation, such that a G5 dendrimer refers to a polymer with four generations of branch points emanating from a central branched core. In general, dendrimers possess empty internal cavities and can encapsulate hydrophobic drug molecules. In addition, they have a much higher surface functional group density when compared with conventional macromolecules, giving rise to their applications for enhancing the solubility of many drugs. Furthermore, the large numbers of surface functional groups on dendrimer's outer shell can be modified or conjugated with a variety of interesting guest molecules. So, broadly there are three methods for using dendrimers in drug delivery: (a) the drug is covalently attached to the periphery of the dendrimer to form dendrimer prodrugs, (b) the drug is coordinated to the outer functional groups via ionic interactions, or (c) the dendrimer acts as a unimolecular micelle by encapsulating a pharmaceutical through the formation of a dendrimer-drug (i.e., host–guest) supramolecular assembly. Over the last few years many dendritic molecules have been developed for effective anticancer therapy and the majority of studies have been performed with polyamidoamine (PAMAM) dendrimer. Various anticancer drugs have been
solubilized by conjugation to the dendrimer surface or simple non covalent interaction with dendrtic core for efficient delivery of these therapeutic molecules to tumor cells. Ooya et al.
(2004) have reported the hydrotopic solubilization of paclitaxel in aqueous solution by poly (glycerol) dendrimer formulations whereas Neerman et al. (2004) used melamine based dendrimers to solubilize methotrexate and 6-mercaptopurine, two FDA approved anticancer drugs. Their study also showed that the solubilization in dendrimer reduces drug toxicity in C3H mice models. In another study, Morgan et al. (2006) have used fourth generation Poly (glycerol succinic acid) (G4-PGLSA) dendrimers with carboxylate peripheral groups to encapsulate 10-hydroxycamptothecin (10-HCPT) and 7-butyl-10-aminocamptothecin (BACPT) for delivery to cancer cells. The encapsulation in dendrimer increased overall water solubility of the hydrophobic drug molecules and also showed significant anticancer activity as evaluated with HT-29 colon carcinoma, MCF-7 breast carcinoma, non–small cell lung carcinoma (NCI-H460), and glioblastoma (SF-268) cell lines. In a recent study Lee et al. (2006) prepared an asymmetric doxorubicin functionalized bow-tie dendrimer by PEGylation of one side of a 2,2-bis (hydroxyl methyl) propionic acid dendrimer (G3) and attachment of the drug via an acyl hydrazone linkage (pH sensitive linkage) to the other side (G4) resulting in overall doxorubicin content of 8-10% and following intravenous administration to BALB/c mice with C-26 colon carcinoma tumors showed approximately 9 fold higher tumor uptake compared to free doxorubicin. A single injection of doxorubicin- conjugated dendrimer caused complete tumor regression and 100% survival of mice over two months, while no cures were observed by free drug treatment. It is well established that the conjugation of special targeting moieties (sugar, folic acid, peptide, antibody etc.) to dendrimers can lead to preferential distribution of the cargo in the targeted tissue or cells (Yang et al., 2009). Researchers have shown that folic acid conjugated dendrimers
demonastrated a dramatic enhancement of binding avidity with target tumor cells that overexpress folic acid receptors (Quintana et al., 2002). In several studies folic acid conjugated PAMAM dendrimers were synthesized and further conjugated to anticancer drug methotrexate or paclitaxel. These drug conjugated dendrimers were shown to deliver the drug preferentially in KB cells (overexpressing folic acid receptors) in a targeted manner (Kono et al., 1999; Majoros et al., 2006). Shukla et al. (2005) conjugated a double cyclized RGD (RGD-4C) peptide to partially acetylated G5-PAMAM dendrimer and used for the targeting of tumor neovasculature via uniquely expressed integrins in human umbilical vein endothelial cells (HUVEC). Several research groups have explored monoclonal antibody conjugation to dendrimers for specific targeting of tumor cells that overexpress certain antigens. Anti-prostate specific membrane antigen (PSMA), J591, conjugated G5-PAMAM dendrimer was found to specifically bind to PMSA-positive LNCaP.FGC cells but not to PMSA-negative PC-3 cells (Patri et al., 2004; Thomas et al., 2004). A similar type of study showed that dendrimer conjugated to human growth factor receptor-2 (HER-2) monoclonal antibody (often overexpressed in breast and ovarian cancer) targets HER-2 expressing tumors in animals (Shukla et al. 2006). Wu et al. (2006) achieved targeted delivery of methotrexate to epidermal growth factor receptor–positive brain tumors by means of cetuximab (IMC-C225) dendrimer bioconjugates.
Figure 1.13: Structures of different dendrimers used for delivery of therapeutic molecules (Lee et al., 2005). The G value indicates the generation numbers of each dendrimer.