PAMAM dendrimers as efficient drug and gene delivery nanosystems for cancer therapy

Abstract

Drug delivery systems for cancer chemotherapy are employed to improve the effectiveness and decrease the side-effects of highly toxic drugs. Most chemotherapy agents have indiscriminate cytotoxicity that affects normal, as well as cancer cells. To overcome these problems, new more efficient nanosystems for drug delivery are increasingly being investigated. Polyamidoamine (PAMAM) dendrimers are an example of a versatile and reproducible type of nanocarrier that can be loaded with drugs, and modified by attaching target-specific ligands that recognize receptors that are over-expressed on cancer cells. PAMAM dendrimers with a high density of cationic charges display electrostatic interactions with nucleic acids (DNA, siRNA, miRNA, etc.), creating dendriplexes that can preserve the nucleic acids from degradation. Dendrimers are prepared by conducting several successive "generations" of synthetic reactions so their size can be easily controlled and they have good uniformity. Dendrimers are particularly well-suited to co-delivery applications (simultaneous delivery of drugs and/or genes). In the current review, we discuss dendrimer-based targeted delivery of drugs/genes and co-delivery systems mainly for cancer therapy.

Keywords: Co-delivery; Gene delivery; Nanovehicles; PAMAM dendrimers; Targeted drug delivery.

Fig. 1

Schematic representation of PAMAM-NH₂ dendrimer G0 to G4. PAMAM-NH₂ dendrimer starts from an ethylene diamine core; the branches or arms were attached by exhaustive Michael addition to methyl acrylate followed by exhaustive aminolysis of the resulting methyl ester using ethylene diamine. Reprinted with permission from Ref. [11].

Fig. 2

Representiation of G-0.5 PAMAM ended to (a) carboxylate group and (b) with carboxylate group surface.

Fig. 3

Shematic representation of PAMAM-drug conjugation in which direct and clevage linker conjugations have been shown.

Fig. 4

Conjugation of the anti-HER-2 antibody, trastuzomab (TZ) to PAMAM dendrimer loaded with docetaxel and FITC (fluorescent label). (a) Cell uptake by receptor-mediated endocytosis; (b) Endosomal escape of PAMAM was accomplised and endosome containing cargo-burst open; (c) The anti-cancer drug is released into the cytosol, and reaches the nucleus and induces apopotosis [83].

Fig. 5

Targeted DNA delivery system based on PAMAM dendrimer. (a) Dendriplex formed by electrostatic interaction between PAMAM and DNA, and the anti-EGFR antibody h-R3 attached via electrostatic interaction; (b) receptor-ligand mediated endocytosis; (c) endosomal escape leads to lysosomal breakage; (d) DNA was released and transported into the nucleus [78].

Fig. 6

Molecular dynamics simulation of G1 PAMAM complexation with siRNA. After (a) 0 ns (nanoseconds); (b) 4 ns; (c) 8 ns; (d) 12 ns; (e) 16 ns; and (f) 20 ns. The endosomal pH in this simulation was almost 5, and this simulation was performed to determine the relationship between endosomal escape and the proton sponge effect. At low pH siRNA was more compact than at pH = 7. Reprinted with permission from Ref. [107].

Fig. 7

Targeted PAMAM dendrimer for co-delivery of a drug and siRNA. (a) Doxorubicin and siRNA against major vault protein (MVP), plus hyaluronic acid (as a targeting agent) were conjugated to PAMAM dendrimer. (b) Hyaluronic acid interacted with its receptor CD44. (c) Complex was taken up by receptor-mediated endcytosis. (d) Strong buffering capacity allows proton and chloride influx. (e) Resulting in endosomal membrane rupture. (f) Release of cargo (DOX and siRNA) into the cytosol, inducing apoptosis and MVP gene silencing respectively.