Abstract
A safe and efficacious cancer medicine is necessary due to the increasing population of cancer patients whose particular diseases cannot be cured by the currently available treatment. Adenoviral (Ad) vectors represent a promising therapeutic medicine for human cancer therapy. However, several improvements are needed in order for Ad vectors to be effective cancer therapeutics, which include, but are not limited to, improvement of cellular uptake, enhanced cancer cell killing activity, and the capability of vector visualization and tracking once injected into the patients. To this end, we attempted to develop an Ad as a multifunctional platform incorporating targeting, imaging, and therapeutic motifs. In this study, we explored the utility of this proposed platform by generating an Ad vector containing the poly-lysine (pK), the herpes simplex virus type 1 (HSV-1) thymidine kinase (TK), and the monomeric red fluorescent protein (mRFP1) as targeting, tumor cell killing, and imaging motifs, respectively. Our study herein demonstrates the generation of the triple mosaic Ad vector with pK, HSV-1 TK, and mRFP1 at the carboxyl termini of Ad minor capsid protein IX (pIX). In addition, the functionalities of pK, HSV-1 TK, and mRFP1 proteins on the Ad vector were retained as confirmed by corresponding functional assays, indicating the potential multifunctional application of this new Ad vector for cancer gene therapy. The validation of the triple mosaic Ad vectors also argues for the ability of pIX modification as a base for the development of multifunctional Ad vectors.
Highlights
Cancer remains the second leading cause of death worldwide, and accounted for approximately 7.9 million deaths (13% of all deaths) in 2007 according to the World Health Organization (WHO, ‘‘The top 10 causes of death’’)
The incorporation of three types of protein IX (pIX) fusion protein in the triple mosaic Ad vector was demonstrated by Western blot and enzyme-linked immunosorbent assays (ELISAs)
Electron microscopy was used to demonstrate that these three types of pIX fusion protein were exposed on the viral surface and could coexist in a single viral particle
Summary
Cancer remains the second leading cause of death worldwide, and accounted for approximately 7.9 million deaths (13% of all deaths) in 2007 according to the World Health Organization (WHO, ‘‘The top 10 causes of death’’). An in vivo imaging modality, which provides a means to study the distribution (e.g. accumulation, spread, retention, and etc.) of anti-cancer therapeutics, can address key issues that are fundamental to the design and test of novel anticancer therapies, especially for replicative virus-based therapeutics [4,5,6,7]. To combine these functionalities, and in an effort to create more potent and reliable anti-cancer therapeutics, we attempted to generate a multifunctional adenoviral (Ad) vector for the detection and treatment of cancer.
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