Development of Tailor-Made Dendrimer Ternary Complexes for Drug/Gene Co-Delivery in Cancer

Abstract

Cancer gene therapy, mediated by non-viral systems, remains a major research focus. To contribute to this field, in this work we reported on the development of dendrimer drug/gene ternary complexes. This innovative approach explored the great capacity of both polyamidoamine (PAMAM)-paclitaxel (PTX) conjugate and polyethylenimine (PEI) polymers to complex a p53-encoding plasmid DNA (pDNA), highlighting the utility of considering two compacting agents. The pDNA complexation capacity has been investigated as function of the nitrogen to phosphate groups ratio (N/P), which revealed to be a tailoring parameter. The physicochemical properties of the conceived ternary complexes were revealed and were found to be promising for cellular transfection. Furthermore, the formulated co-delivery systems demonstrated to be biocompatible. The ternary systems were able of cellular internalization and payload intracellular release. Confocal microscopy studies showed the co-localization of stained pDNA with the nucleus of cancer cells, after transfection mediated by these carriers. From this achievement, p53 gene expression occurred with the production of protein. Moreover, the activation of caspase-3 indicated apoptosis of cancer cells. This work represents a great progress on the design of dendrimer drug/gene co-delivery systems towards a more efficient cancer therapy. In this way, it instigates further in vitro studies concerning the evaluation of their therapeutic potential, expectedly supported by the synergistic effect, in tumoral cells.

Development of WRAP5 Peptide Complexes for Targeted Drug/Gene Co-Delivery toward Glioblastoma Therapy

“…The N/P ratio is demonstrated to deeply influence the complexation behavior and, therefore, it was identified as a tailoring parameter [ 50 , 57 ]. As visualized in Figure 2 , WRAP5 and Tf-WRAP5 peptides could efficiently complex pDNA at N/P ratios higher than 0.1.…”

“…As observed, lower-sized complexes were obtained with an increase in the N/P ratio. The higher amine content strengthens the interaction between WRAP5 and pDNA, increasing pDNA condensation and, therefore, leading to smaller complexes [ 14 , 17 , 57 ]. This trend was observed for all peptide/pDNA complexes and the presence of both the Tf sequence and TMZ did not seem to affect it.…”

Recent Advances in Functional Polymer Materials for Energy, Water, and Biomedical Applications: A Review

“…Dendrimers are water-soluble, highly structured, designed polymer macromolecules. They are widely investigated as carriers for anti-tumor drugs [137]. PAMAM (polyamidoamine) dendrimers are being studied as efficient carriers (vectors) in gene therapy [138][139][140].…”

Peptides vs. Polymers: Searching for the Most Efficient Delivery System for Mitochondrial Gene Therapy

“…Due to their high loading capacity, biocompatibility, antigenicity, and lack of immune response, non-viral delivery systems based on cell-penetrating peptides (CPPs), micelles, polymers, and lipids have been commonly used in gene release studies [22][23][24][25]. Furthermore, ternary non-viral systems, for instance, constituted by polymers and/or peptides, have proven to be a valuable strategy to enhance payload encapsulation efficiency, thereby contributing to efficient gene delivery and expression [26][27][28].…”

“…Polymer-based systems are also widely explored as gene carriers, due to their favorable physicochemical properties, low toxicity, and tailorability [28,[37][38][39]. In this context, one of the most used polymers has been polyethylenimine (PEI), due to its ability to transport different types of nucleic acids, regardless of their type and size [40,41].…”