Potential use of folate-polyethylene glycol (PEG)-appended dendrimer (G3) conjugate with α-cyclodextrin as DNA carriers to tumor cells

Abstract

We previously reported that polyamidoamine STARBURST dendrimer (generation 3, G3) (dendrimer) conjugate with a-cyclodextrin (a-CyD) having an average degree of substitution of 2.4 of a-CyD (a-CDE) provided remarkable aspects as novel carriers for DNA and small-interfering RNA. To develop novel a-CDE derivatives with tumor cell specificity, we prepared folate-appended a-CDEs (Fol-a-CDEs) and folate-polyethylene glycol (PEG)-appended a-CDEs (Fol-PaCs) with the various degrees of substitution of folate (DSF), and evaluated in vitro and in vivo gene transfer activity, cytotoxicity, cellular association and physicochemical properties. In vitro gene transfer activity of Fol-a-CDEs (G3, DSF 2, 5 or 7) was lower than that of a-CDE (G3) in KB cells, folate receptor (FR)-overexpressing cancer cells. Of the three Fol-PaCs (G3, DSF 2, 5 or 7), Fol-PaC (G3, DSF 5) had the highest gene transfer activity in KB cells. The activity of Fol-PaC (G3, DSF 5) was significantly higher than that of a-CDE (G3) in KB cells, but not in A549 cells, FR-negative cells. Negligible cytotoxicity of the plasmid DNA (pDNA) complex with Fol-PaC (G3, DSF 5) was observed in KB cells or A549 cells up to a charge ratio of 100/1 (carrier/pDNA). The cellular association of the pDNA complex with Fol-PaC (G3, DSF 5) could be mediated by FR on KB cells, resulting in its efficient cellular uptake. Fol-PaC (G3, DSF 5) had a higher binding affinity with folate-binding protein than a-CDE (G3), although the physicochemical properties of pDNA complex with Fol-PaC (G3, DSF 5) were almost comparable to that with a-CDE (G3), although the onset charge ratio and the compaction ability of Fol-PaC (G3, DSF 5) were slightly different. Fol-PaC (G3, DSF 5) tended to show a higher gene transfer activity than a-CDE (G3) 12 h after intratumoral administration in mice. These results suggest that Fol-PaC (G3, DSF 5), not Fol-a-CDEs, could be potentially used as a FR-overexpressing cancer cell-selective DNA carrier.

Folic Acid-Decorated Polyamidoamine Dendrimer Mediates Selective Uptake and High Expression of Genes in Head and Neck Cancer Cells

“…Therefore, it can be targeted for developing active tumor-targeting therapies [9][10][11]. Although FR-targeted drug and gene delivery systems have been developed on the basis of dendrimers [12][13][14][15][16][17] and many other types of nanoparticle carriers [18][19][20][21][22][23], few nonviral vectors have been developed for HNSCC [24,25]. Given the scarcity of nonviral vectors for gene therapy of HNSCC and limited clinical outcomes, it is highly desirable to develop and evaluate vectors under the context of HNSCC.…”

Folate-conjugated nanoparticles as a potent therapeutic approach in targeted cancer therapy

“…The high anti-tumor gene delivery potential of FA-conjugated fifth generation (G5) PAMAM dendrimers into KB cancer cells has been demonstrated by other investigators [136]. Consistently, Arima and colleagues have reported that FA-PEG-appended polyamidoamine dendrimer (G3) conjugate with α-cyclodextrin exhibits high efficiency for gene delivery into FR-overexpressing (KB), but not FR-negative (A549), cells, both in vitro and in vivo [137]. The high gene transfection potential of dendrimers was also demonstrated using a pH-sensitive FA-PEG-chitosan-PAMAM-plasmid DNA (containing a high mobility group box 1, HMGB1) complexes both in vitro (in KB cells) and in vivo (S180 xenograft nude mice) [138].…”

Nanoparticulate Contrast Agents for CT, SPECT and PET Imaging

“…• controllable size, 128,129 • high density and a well-defined number of surface functional groups providing multifunctional modification for multiple purposes, [130][131][132] • reproducible pharmacokinetics due to monodispersity, [133][134][135] • enhanced biological, chemical, or physical activities of the compounds bound on the surface of the dendrimer due to the ''synergistic effect'' or ''multivalency effect'', 136,137 • excellent cellular uptake ability, [138][139][140] • ability to administer in different routes such as oral, injectable, transdermal, ocular, nasal, colon, rectal, and pulmonary. 134,141 Generally used dendrimers, polyamidoamine dendrimers, consist of ammonia core ( PAMAMs) and poly(propylene imine) dendrimers consist of butylenediamine core ( PPI) are commercially available.…”