Folate and Folate−PEG−PAMAM Dendrimers: Synthesis, Characterization, and Targeted Anticancer Drug Delivery Potential in Tumor Bearing Mice

Abstract

Ligand-mediated targeting of drugs especially in anticancer drug delivery is an effective approach. Dendrimers, due to unique surface topologies, can be a choice in this context. In the present study, PAMAM (polyamidoamine) dendrimers up to fourth generation were synthesized and characterized through infrared (IR), nuclear magnetic resonance (NMR), electrospray ionization (ESI) mass spectrometric, and transmission electron microscopic (TEM) techniques. Primary amines present on the dendritic surface were conjugated through folic acid and folic acid-PEG (poly(ethylene glycol))-NHS (N-hydroxysuccinimide) conjugates. Tumor in mice was induced through the use of KB cell culture. Prepared dendritic conjugates were evaluated for the anticancer drug delivery potential using 5-FU (5-fluorouracil) in tumor-bearing mice. Approximately 31% of 5-FU was loaded in folate-PEG-dendritic conjugates. Results indicated that folate-PEG-dendrimer conjugate was significantly safe and effective in tumor targeting compared to a non-PEGylated formulation. Tailoring of dendrimers via PEG-folic acid reduced hemolytic toxicity, which led to a sustained drug release pattern as well as highest accumulation in the tumor area.

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy

“…An early example of in vivo passive targeting Is the conjugation of a sodium carboxyl-terminated G-3.5 polyamidoamine (PAMAM) dendrimer with cisplatin for the treatment of B16F10 induced melanomas, achieving an enhanced antitumor efficacy compared with the free drug [372]. Also, there are preclinical promising in vitro and in vivo results with active targeting dendrimers [73,365], for example antibody-dendrimer conjugates showed better efficacy than free antibodies [380][381][382][383], peptide (RGD) dendrimer conjugates showed enhanced tumor targeting [384][385][386], and folic acid functionalized dendrimers generated better tumor accumulations than untargeted controls or free drug, producing a stronger reduction of the tumor size [73,[387][388][389][390]. The slow translation of these preclinical studies to clinical trials may be due to the current toxicity of dendrimers [391,392], with the aim of the current research in the development of new biocompatible and less toxic alternatives [367,[393][394][395][396][397][398][399].…”

Influence of dendrimers on red blood cells

“…amino) groups and multiple cationic charge [12,19]. Folic acid is often conjugated to dendrimers to increase the target specificity of these nanoparticles and facilitate dendrimers' location near the tumour, since in various cancer cell lines folic acid receptor are overexpressed [20,21]. In physiological conditions the erythrocyte outer surface is negatively charged due to the presence of glycolipids and some glycated membrane proteins [7].…”

Folate-modified Annonaceous acetogenins nanosuspensions and their improved antitumor efficacy

“…32 Due to higher reactivity, [33][34][35] the γ-activated carboxyl group of FA might have preferentially reacted with the amino group of NH 2 -β-CD and resulted in the γ-activated derivative under kinetic control. Characterization of the synthesized FA-β-CD is shown in Figure 1.…”