Stimuli-Regulated Smart Polymeric Systems for Gene Therapy

Abstract

The physiological condition of the human body is a composite of different environments, each with its own parameters that may differ under normal, as well as diseased conditions. These environmental conditions include factors, such as pH, temperature and enzymes that are specific to a type of cell, tissue or organ or a pathological state, such as inflammation, cancer or infection. These conditions can act as specific triggers or stimuli for the efficient release of therapeutics at their destination by overcoming many physiological and biological barriers. The efficacy of conventional treatment modalities can be enhanced, side effects decreased and patient compliance improved by using stimuli-responsive material that respond to these triggers at the target site. These stimuli or triggers can be physical, chemical or biological and can be internal or external in nature. Many smart/intelligent stimuli-responsive therapeutic gene carriers have been developed that can respond to either internal stimuli, which may be normally present, overexpressed or present in decreased levels, owing to a disease, or to stimuli that are applied externally, such as magnetic fields. This review focuses on the effects of various internal stimuli, such as temperature, pH, redox potential, enzymes, osmotic activity and other biomolecules that are present in the body, on modulating gene expression by using stimuli-regulated smart polymeric carriers.

Keywords: enzyme; gene carrier; internal stimuli; polyplexes; stimuli-responsive system; temperature; transfection.

Figure 1

Different intracellular stimuli (ROS, intracellular enzymes, redox condition and osmotic activity) mediated release of gene carriers and subsequent gene release inside cellular environment.

Figure 2

(a) The number of scientific papers published over the past decade on internal stimuli-based gene delivery (source: ISI Web of Knowledge: The Thompson Corporation; search terms: “internal stimuli/gene delivery”; date of search: February 2017). (b) The number of scientific papers published over the past decade on internal stimuli-based drug delivery systems (source: ISI Web of Knowledge: The Thompson Corporation; search terms: “internal stimuli/drug delivery”; date of search: February 2017).

Figure 3

(A) Schematic of the pH-sensitive charge/size dual-rebound gene delivery system. (B) Transfection efficiency of PEG((PLG/PEI)/DNA) [P((GP)D)] with various PEG mass ratios at different pH values (7.4 and 6.8) in CT26 cells for 2 h. (C) Mean fluorescence intensity of cellular uptake of polyethylenimine (PEI)/DNA (PD), poly(l-glutamate) (PLG)/(PEI/DNA) (G(PD)), (PLG/PEI)/DNA((GP)D) and PEG((PLG/PEI)/DNA)(P(GP)D) at different pH values (7.4 and 6.8). (D) CLSM images of CT26 cells incubated with D, PD, G(PD), (GP)D and P((GP)D) at different pH values (7.4 and 6.8); Cy5-DNA was tracked. Reproduced with permission from [46]. Copyright proceedings from the American Chemical Society, 2015.

Figure 3

(A) Schematic of the pH-sensitive charge/size dual-rebound gene delivery system. (B) Transfection efficiency of PEG((PLG/PEI)/DNA) [P((GP)D)] with various PEG mass ratios at different pH values (7.4 and 6.8) in CT26 cells for 2 h. (C) Mean fluorescence intensity of cellular uptake of polyethylenimine (PEI)/DNA (PD), poly(l-glutamate) (PLG)/(PEI/DNA) (G(PD)), (PLG/PEI)/DNA((GP)D) and PEG((PLG/PEI)/DNA)(P(GP)D) at different pH values (7.4 and 6.8). (D) CLSM images of CT26 cells incubated with D, PD, G(PD), (GP)D and P((GP)D) at different pH values (7.4 and 6.8); Cy5-DNA was tracked. Reproduced with permission from [46]. Copyright proceedings from the American Chemical Society, 2015.

Figure 4

Schematic illustration of multifunctional aminoglycosides-based hyperbranched polymers (HPs) with antibacterial activity, biocompatibility and gene transfection capability. Reproduced with permission from [80]. Copyright proceedings from Biomaterials, Elsevier, November 2016.

Figure 5

Schematic illustration showing PEG-coated polyplex micelles in MMP-2-expressing tumor tissue showing enhanced cellular uptake and endosomal escape for gene transfection. Reproduced with permission from [107]. Copyright proceedings from The Royal Society of Chemistry.

Figure 6

Schematic representation of the synthesis of PSOAT. Reproduced with permission from [115]. Copyright proceedings from Elsevier.

Figure 7

Effects of (A) chlorpromazine, (B) β-methyl cyclodextrin, (C) genistein and (D) wortmannin on transfection efficiency in A549 cells. Reproduced with permission from [116]. Copyright proceedings from the American Chemical Society.

Figure 8

Schematic representation of the synthesis of poly (mannitol-co-PEI) (PMT). Reproduced with permission from [122] Copyright proceedings from Elsevier).

Figure 9

Fluorescent microscopy images showing lysosome staining (red) and FITC-PEI/DNA polyplexes (green); (a) Polyplex with FITC (b) Colocalization spot using the Image J program; (c) overlay of lysosomes and polyplexes (yellow). Scale bar represents 5 μm. Reproduced with permission from [122]. Copyright proceedings from Elsevier).