A Hybrid Nanovector of Suicide Gene Engineered Lentivirus Coated with Bioreducible Polyaminoglycosides for Enhancing Therapeutic Efficacy against Glioma

Abstract

An emerging hybrid nanovector integrating the merits of both viral and nonviral vectors has attracted much attention as the next generation of promising gene vectors to overcome the primary challenge of cancer gene therapy. Due to its inherent advantages, lentivirus (Lv) has been increasingly applied and investigated in medical fields. Herein, a new hybrid nanovector (SS‐HPT/Lv) composed of the Lv core and reduction‐responsive hyperbranched polyaminoglycoside (SS‐HPT) shell is designed via electrostatic interaction. In comparison with polybrene (commercial enhanced transfection reagent), SS‐HPT endows the hybrid nanovector with better biosafety. Furthermore, both the appropriate nanoparticle sizes and positive surface potentials contribute to the endocytosis and rescue of SS‐HPT/Lv from endocytic vesicles. Regarding therapeutic application, lentiviral vector acquires permanent transgene expression with the capability of integrating to the host chromosome, and SS‐HPT/Lv exhibits an improved transduction efficacy. The cytosine deaminase/5‐fluorocytosine suicide gene therapy system mediated by SS‐HPT/Lv performs an enhanced antitumor efficiency and extends the survival time of glioma‐bearing rats. Such a hybrid nanovector strategy would open a new avenue to the development of gene vectors for treating malignant cancers.

Materials promoting viral gene delivery

“…275 Recently, they reported, LVpolyaminoglycoside complexes, which efficiently induce cell apoptosis to glioma cells by facilitating cellular uptake via endocytosis pathways. 276 Polysaccharides are highly suitable biopolymers for viral gene delivery, mainly as hydrogels that adapt to the tissue environment. Release of VPs is achieved by degradation into non-toxic components.…”

Advances and potential pitfalls of oncolytic viruses expressing immunomodulatory transgene therapy for malignant gliomas

“…In 2014, we also demonstrated that in animal models of human GSCs, an oncolytic HSV-1 that encodes an endostatin-angiostatin fusion gene could greatly enhance antitumor efficacy compared to HSV-1 without the fusion gene by generating antitumor angiogenic activity 21 . Later, our research team found that viruses that express the suicide gene cytosine deaminase (CD) could significantly enhance antitumor efficacy and prolong the life expectancy of tumor-bearing animals by the subsequent conversion of nontoxic prodrugs into toxic prodrugs 22,23 . Our research team independently developed a novel oHSV-1 containing the CD therapeutic gene.…”

Degradable branched polycationic systems for nucleic acid delivery

“…(b) Representative T2WI images of intracranial tumors monitored by MRI on Day 5–24 after C6 cell implantation with different treatments. (Reprinted with permission from Fan et al (). Copyright 2019 Wiley‐VCH)…”

“…HDDE was acquired through the reaction of 2-hydroxyethyldisulfide and epichlorohydrin under alkaline conditions. According to Steinhilber's method, a series of redox-responsive ARP were prepared through amino-epoxy ring-opening reaction by using HDDE (Fan et al, 2019;Huang, Ding, Qi, Yu, & Xu, 2016). Such branched polycationic systems from HDDE demonstrated good redox-responsive degradability.…”

“…The disulfide linkages imparted SS-HP with reducibility, resulting in better genedelivery performance and antitumor effects than the counterparts without disulfide linkages. Moreover, a novel hybrid nanovector (SS-HPT/Lv; Figure 5a) was fabricated by using negatively charged lentivirus (Lv) and positively charged SS-HPT (Fan et al, 2019). The reduction-responsive properties of SS-HPT can benefit the biodegradability of the delivery system.…”