In vivo tumor gene delivery using novel peptideticles: pH‐responsive and ligand targeted core–shell nanoassembly

Abstract

Modulating cancer causing genes with nucleic acid based-molecules as cutting-edge approaches need efficient delivery systems to succeed in clinic. Herein, we report design and fabrication of a novel tissue penetrating peptideticle with charge-structure switching in tumor microenvironment for an effective gene delivery. The comparative in vitro studies indicate that peptideticles identify and bind to tumor endothelial cells and efficiently penetrate into multicellular tumor spheroid. In addition, negatively charged peptideticle at pH 7.4, prevent unwanted interaction while its sharp charge-structure switching at pH 6.2-6.9 (e.g. in tumor tissue) facilitates malignant cells penetration. More importantly, upon systemic administration into tumor bearing mice, peptideticles effectively localized in tumor tissue and delivered luciferase gene with a 200-fold higher efficiency compared to their non-pH-responsive counterparts. In conclusion, this study presents a robust nanoassembly of safe materials for high efficient tumor gene delivery.

Cancer‐associated fibroblasts: Secretions, interactions, and therapy

“…42,43 CAFs release a high amount of lactic acid to the TME. Beside creating an acidified milieu for tumor progression, these high lactate levels account for macrophage polarization toward an M2 phenotype 32,42,44,45 through which they promote multiple tumorigenic functions including tumor growth, angiogenesis, epithelial-mesenchymal transition (EMT), and immune escape, invasion, stemness, and metastasis in cancer cells. 43,46,47 IL-6 released by CAFs is also responsible for influencing polarization of macrophages toward M2 phenotype.…”

Recent progress in biomedical applications of RGD‐based ligand: From precise cancer theranostics to biomaterial engineering: A systematic review

“…Targeted delivery methods have been invented to improve the effeteness of drug as well as eliminate its side effects by directing the drug to desired cell types or promoting a gene therapy (Alipour, Majidi, Molaabasi, Sheikhnejad, & Hosseinkhani, 2018;Cheraghi, Nazari, Alipour, Majidi, & Hosseinkhani, 2016). The differences between cellular compositions of the targeted and non-targeted cells are the key point for achieving this goal which can contribute to expressed surface receptors, the metabolism profiles, the site/location and the nature of the cells (Majumdar & Siahaan, 2012).…”

Tumor microenvironment: Interactions and therapy

“…These characteristics for cancer cells would make problematic their targeting by conventional chemotherapeutic drugs. Heterogeneity of cells within the tumor, variations in the tumor vasculature, insufficient penetration of drugs and their cytotoxicity to normal cells (Alipour et al, 2018) are among the other reasons for making these approaches even more complex.…”

“…CXCL12 released by CAFs is an inducer for recruitment of precursor ECs into the tumor stroma and for expanding this leaky vasculature (Ahirwar et al, 2018). Hypoxia in the TME is another cause for the formation of the fenestrated vasculature (Alipour et al, 2018). These penetrations within the tumor vasculature, although, may seem to be applicable for therapeutic purposes using Nano-drug delivery (Ho et al, 2018), highly variable fenestration within this vasculature is the main obstacle to the efficacy of such approaches (Alipour et al, 2018).…”

“…Hypoxia in the TME is another cause for the formation of the fenestrated vasculature (Alipour et al, 2018). These penetrations within the tumor vasculature, although, may seem to be applicable for therapeutic purposes using Nano-drug delivery (Ho et al, 2018), highly variable fenestration within this vasculature is the main obstacle to the efficacy of such approaches (Alipour et al, 2018). Vessel co-option is a process by which cancer cells invade the organ of origin along the pre-existing vasculature.…”