Engineering Nanoparticles for Targeted Delivery of Nucleic Acid Therapeutics in Tumor

Abstract

In the past 10 years, with the increase of investment in clinical nano-gene therapy, there are many trials that have been discontinued due to poor efficacy and serious side effects. Therefore, it is particularly important to design a suitable gene delivery system. In this paper, we introduce the application of liposomes, polymers, and inorganics in gene delivery; also, different modifications with some stimuli-responsive systems can effectively improve the efficiency of gene delivery and reduce cytotoxicity and other side effects. Besides, the co-delivery of chemotherapy drugs with a drug tolerance-related gene or oncogene provides a better theoretical basis for clinical cancer gene therapy.

Keywords: cellular uptake; co-delivery; gene delivery; inorganics stimuli response; liposome; nanoparticles; nuclear entry; polymers; tumor therapy.

Figure 1

Schematic Illustrations of the siRNA-Based Therapeutics of CALAA-01 and siG12D-LODER (A) CALAA-01 is a polymer-based nanoparticle containing a targeting ligand on its surface (the human protein transferrin) and a small interfering RNA (siRNA) that targets the M2 subunit of ribonucleotide reductase (RRM2). Reproduced with permission from Zuckerman and Davis. Copyright © 2015 Springer Nature. (B) siG12D-LODER is a polymeric matrix of poly(lactic-co-glycolic) acid (PLGA) in a shape of a small cylindrical rod of 0.8 mm in diameter and 5.5 ± 1 mm in length. Reproduced with permission from Titze-de-Almeida et al. Copyright © 2017 Springer Nature.

Figure 2

Schematic of Endocytosis and Exocytosis Patterns of Nanoparticles Nanoparticles enter the cell via four types of pathways: clathrin-/caveolar-mediated endocytosis, phagocytosis, macropinocytosis, and pinocytosis. Nanoparticles exit the cell via three types of pathways: lysosome secretion, vesicle-related secretion, and non-vesicle-related secretion. MVBs, multivesicular bodies. Reproduced with permission from Oh and Park. Copyright © 2014 Dove Press Ltd.

Figure 3

The Application of PEI for Co-delivery of siRNA and DOX and the Schematic Synthesis of Folate-PEI-CDs/siRNA Nanoparticles (A) Confocal laser scanning microscope (CLSM) images of B16F10 cells incubated with PEI/siRNA/DOX for 24 hr. Scale bars, 20 μm. Reproduced with permission from Xu et al. Copyright © 2017 Elsevier. (B) Schematic diagram of synthesis route of folate-PEI-CDs/siRNA nanoassemblies. Reproduced with permission from He et al. Copyright © 2017 Elsevier.

Figure 4

The Schematic Process of SS-PAA/DNA In Vitro and the Formation of Poly(PEG-co-(BMDO-co-DMAEMA)) with EtBr (A) The concept of DNA condensation and subsequent intracellular release. (a) Formation of SS-PAAs/DNA polyplexes that are stable in the extracellular environment, (b) intracellular reduction of the disulfide linkages in the polymer of the polyplex, and (c) dissociation of DNA from the degraded polymer are shown. Reproduced with permission from Lin et al. Copyright © 2007 American Chemical Society. (B) Synthesis route for the formation of the poly(PEG-co-(BMDO-co-DMAEMA)) and poly(PEG-co-(BMDO-co-DMAEMA))·EtBr. Reproduced with permission Zhang et al. Copyright © 2012 American Chemical Society.

Figure 5

Schematic Illustration of the Modification of AuNP Beacon and the Mechanism of Cell Uptake Reproduced with permission from Li et al. Copyright © 2018 John Wiley & Sons, Inc.

Figure 6

The Schematic Process of AuNP-p(T)DNA and PLC-ZD55-IL-24 (A) Schematic showing the use of AuNP-p(T)DNA in enhancing the translation of different mRNA templates. Genes of interest were inserted separately into pcDNA6 plasmid vector containing BGH polyadenylation (P(A)) signal and transcribed to produce the respective mRNA templates with a poly(A) tail. AuNP-p(T)DNA was added to mRNA templates to allow hybridization between the poly(T) oligonucleotide on AuNP and the poly(A) tail on the mRNA, which facilitated the increased production of the respective proteins. Reproduced with permission from Chan et al. Copyright © 2018 American Chemical Society. (B) Synthetic route used to prepare PLC-ZD55-IL-24. Reproduced with permission from Chen et al. Copyright © 2016 American Chemical Society.