Poly-Gamma-Glutamic Acid (γ-PGA)-Based Encapsulation of Adenovirus to Evade Neutralizing Antibodies

Ibrahim Khalil,Mariastella Scandola,Iza Radecka,Barbara Mendrek,Angel Armesilla,Maria Focarete,Sathishkumar Kurusamy,Marek Kowalczuk,Abhishek Gupta,Martin Khechara,Tamara Khalaf

doi:10.3390/molecules23102565

Abstract

In recent years, there has been an increasing interest in oncolytic adenoviral vectors as an alternative anticancer therapy. The induction of an immune response can be considered as a major limitation of this kind of application. Significant research efforts have been focused on the development of biodegradable polymer poly-gamma-glutamic acid (γ-PGA)-based nanoparticles used as a vector for effective and safe anticancer therapy, owing to their controlled and sustained-release properties, low toxicity, as well as biocompatibility with tissue and cells. This study aimed to introduce a specific destructive and antibody blind polymer-coated viral vector into cancer cells using γ-PGA and chitosan (CH). Adenovirus was successfully encapsulated into the biopolymer particles with an encapsulation efficiency of 92% and particle size of 485 nm using the ionic gelation method. Therapeutic agents or nanoparticles (NPs) that carry therapeutics can be directed specifically to cancerous cells by decorating their surfaces using targeting ligands. Moreover, in vitro neutralizing antibody response against viral capsid proteins can be somewhat reduced by encapsulating adenovirus into γ-PGA-CH NPs, as only 3.1% of the encapsulated adenovirus was detected by anti-adenovirus antibodies in the presented work compared to naked adenoviruses. The results obtained and the unique characteristics of the polymer established in this research could provide a reference for the coating and controlled release of viral vectors used in anticancer therapy.

Highlights

Cancer is still the second leading cause of death in developing and developed countries [1,2].Despite the increasing rate of survival in the last 40 years, the severe side effects of radiation and chemotherapy cancer treatment have been acknowledged to be of major importance, and could cause a number of problems, including systemic toxicity, mild cognitive impairments, and mouthMolecules 2018, 23, 2565; doi:10.3390/molecules23102565 www.mdpi.com/journal/moleculesMolecules 2018, 23, 2565 ulcerations [3]
In another study by Liu and coworkers (2018), a supramolecular hydrogel was used for drug-resistant cancer therapy [14]
The results indicate that γ-PGA is mostly in salt form

Summary

Introduction

Cancer is still the second leading cause of death in developing and developed countries [1,2].Despite the increasing rate of survival in the last 40 years, the severe side effects of radiation and chemotherapy cancer treatment have been acknowledged to be of major importance, and could cause a number of problems, including systemic toxicity, mild cognitive impairments, and mouthMolecules 2018, 23, 2565; doi:10.3390/molecules23102565 www.mdpi.com/journal/moleculesMolecules 2018, 23, 2565 ulcerations [3]. New types of treatment have been established These new approaches include gene therapy [3,5], nanoparticulate vectors [6,7,8], modified bacteria [9,10], and the utility of the immune system [11,12]. Viruses that have the ability to replicate inside cancer cells and subsequently causing death to these infected cells have shown great promise; these are called oncolytic viruses [15,16,17,18]. There has been an increasing interest in oncolytic adenoviral vector anticancer therapy due to these viruses’ ability to efficiently infect a variety of both dividing and nondividing cells, and because of their high-affinity binding site for attaching to the coxsackie virus and adenovirus (Ad) receptor (CAR) of susceptible cells.

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