Folic acid dendrimers

HPLC has been helpful for identifying major structural defects of PAMAM dendrimers of different generations with different terminal groups and a folic acid-dendrimer conjugate. Findings from this study indicate that HPLC is an effective technique not only for characterization and separation of functionalized PAMAM dendrimers and conjugates, but also for investigation of the interaction between dendrimers and biomolecules. ... 

Entries on new materials, including re-cyclate plastics, fullerenes, hard-surfaced polymers, dendrimers, transflective materials, rapid prototyping materials, silicone nitride, supercritical fluids, bulk molding compounds, conversion coatings, folic acid, replacements for chloro-fluorocarbons ... 

Wiener and co-workers used folic acid-conjugated Gd(DTPA)-PAMAM dendrimers for visualizing the high-affinity folate receptor, overexpressed in many tumors.201 The contrast agent accumulated in the cells, resulting in a remarkable contrast enhancement on 7)-weighted images. 

Slowly add with mixing, the activated folic acid from step 3 to the amine-dendrimer solution to give a final molar ratio of folate-to-dendrimer of 5.5 1. 

Figure 13.13 Multifunctional anticancer poly(amido amine) (PAMAM) dendrimers. Clockwise from top diol, taxol, fluorescein isothiocyanate, folic acid, and acetyl groups.

Scheme 6. Folate-targeted dendrimeric contrast agent (a 2nd generation species is presented) on a 4th generation dendrimer, 3 to 5 peripheral amine groups are randomly substituted by folic acid, the rest being conjugated to Gd-DTPA chelates...

Dendrimers used for DNA delivery most commonly have positive net surface charges. The most well studied molecules for gene delivery are those based on an ethylene diamine or ammonia core with polyamidoamine (PAMAM) dendrites or those based on bufylenediamine cores and polypropylenimine (PPI) dendrites. Solubility of PAMAM dendrimers can be enhanced by partial acetylation of the reactive amino groups and they can be conjugated with various targeting entities such as folic acid to target receptors on specific cancer cells (42). 

Figure 5.29. PAMAM dendrimer multifunctional conjugates for cancer treatment. The FA group is a folic acid cancer cell target, and FITC is fluorescein isothiocyanate, used as an imaging agent. Also shown (bottom) is the molecular structure for the anticancer drug, taxol, denoting the -OH group that covalently attaches to the dendrimer. Reproduced with permission from Majoros, I. J. Myc, A. Thomas, T Mehta, C. Baker, J. R. Biomacromolecules, 2006, 7, 572. Copyright 2006 American Chemical Society.

Figure 41 Comparison of PAMAM dendrimers as passive or covalent drug carriers with a folate receptor ligand. FA, folic acid MTX, methotrexate PBS, phosphate-buffered saline. Reproduced with permission from Patti, A. K. Kukowska-Latallo, J. F. Baker, J. R. Adv. Drug Deliv. Rev. 2005, 57, 2203. Copyright 2005 Advanced drug delivery reviews.

Figure 42 Multifunctional PAMAM dendrimer as drug-delivery agent composed of folic acid, methotrexate, FITC, and acetyl- and Tris-capped NH2...

Figure 43 Folate targeted PAMAM dendrimers. Dose-dependent binding of G5-FI-FA-MTX in KB cells. The cells were maintained in FA-free medium and incubated with different concentrations of the indicated dendrimers for 1 h. The cells were then rinsed and resuspended in PBS buffer, and the fluorescence was measured in a flow cytometer (a). In panel b, the mean cell fluorescence, after being normalized for the fluorescence of standard solutions of the dendrimers, is presented. FA, folic acid MTX, methotrexate. FI, fluorescein isothiocyanate. Reproduced with permission from Thomas, T. P. Majoros, I. J. Kotlyar, A. etal. J. Med. Chem. 2005, 48, 3729 310 Copyright 2005 American Chemical Society.

Boronated PAMAM dendrimers can be targeted to tumor using epidermal growth factors [67,68], vascular endothelial growth factor [69], and folic acid, a vitamin that is transported into cells through folate receptor-mediated endocytosis [70]. 

FIGURE 7.14. Mice tumors treated without and with folic acid targeting. (Baker Jr, J. R. Dendrimer-Based Nanoparticles for Cancer therapy. Nanotechnology for Hematology. 2009, 1, 708-719). 

Malik et al. (1999) conjugated cisplatin, a potent anticancer drug, to PAMAM dendrimers and observed increased solubility, decreased systemic toxicity, and EPR effect to target tumors when administered intravenously. Targeting methotrexate to epithelial cancers using PAMAM-folic acid system also showed increased antitumor activity (Kukowska-Latallo et al. 2005) compared to free drug after intravenous administration. 

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