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Avidin fusion protein-expressing lentiviral vector for targeted drug delivery
Hanna P Lesch1, Jere T Pikkarainen, Minna U Kaikkonen
1Department of Biotechnology and Molecular Medicine, A.I. Virtanen Institute, FIN-70210 Kuopio, Finland.
Abstract:
One of the main objectives of cancer therapy is to enhance the effectiveness of the drug by concentrating it at the target site and to minimize the undesired side effects to nontarget cells. We have previously constructed a fusion protein, Lodavin, consisting of avidin and the endocytotic part of the low-density lipoprotein receptor, and demonstrated its applicability to transient drug targeting in vivo. In this study we produced a lentiviral vector expressing this fusion protein and evaluated its safety and efficacy. The results showed that lentivirus-mediated gene transfer led to long-term avidin fusion protein expression on glioma cells and that the receptor was able to bind biotinylated compounds. Repeated administration was proven feasible and the optimal time frame(s) for administration of biotinylated therapeutic and/or imaging compounds was elucidated. Intravenous or intracranial injection of the virus into BDIX rats led to the production of antibodies against transgene (avidin), but repeated administration of the vector was unable to boost this effect. Neutralizing antibodies against the lentivirus were also detected. Furthermore, we showed that the anti-avidin antibodies did not significantly affect the ligand-binding capacity of the avidin fusion protein. The therapeutic efficacy of avidin fusion protein in tumor treatment was tested in vitro with biotinylated and nonbiotinylated nanoparticles loaded with paclitaxel. In vivo applicability of lentivirus was studied in the BDIX rat glioma model, in which high receptor expression was detected in the tumor area. The lentivirus-mediated delivery of the avidin fusion protein thus represents a potential approach for the repeated targeting of cytotoxic compounds to cancer cells.
Insights
This study developed a lentiviral vector for sustained delivery of the Lodavin fusion protein, enabling targeted cancer therapy with biotinylated drugs and minimizing side effects.
Area of Science:
- Biotechnology
- Oncology
- Gene Therapy
Background:
- Cancer therapy aims to improve drug efficacy at the target site while reducing side effects.
- Lodavin, a fusion protein of avidin and a low-density lipoprotein receptor fragment, was previously shown for transient drug targeting.
- Lentiviral vectors offer a platform for sustained gene expression.
Purpose of the Study:
- To produce a lentiviral vector expressing the Lodavin fusion protein.
- To evaluate the safety and efficacy of lentivirus-mediated Lodavin delivery for cancer therapy.
- To determine the feasibility of repeated administration and optimal timing for therapeutic compound delivery.
Main Methods:
- Production of a lentiviral vector encoding the avidin-low-density lipoprotein receptor fusion protein (Lodavin).
- Evaluation of Lodavin expression and binding capacity in glioma cells after lentiviral gene transfer in BDIX rats.
- Assessment of antibody production against the transgene and lentivirus.
- In vitro testing of therapeutic efficacy using paclitaxel-loaded nanoparticles.
- In vivo studies in a rat glioma model.
Main Results:
- Lentivirus-mediated gene transfer resulted in long-term Lodavin expression on glioma cells, with maintained binding of biotinylated compounds.
- Repeated administration of the lentiviral vector was feasible, and optimal timeframes for therapeutic compound delivery were identified.
- Antibodies against avidin and neutralizing antibodies against the lentivirus were detected, but anti-avidin antibodies did not significantly impair ligand binding.
- In vitro studies demonstrated therapeutic potential with paclitaxel-loaded nanoparticles.
- High Lodavin receptor expression was observed in the tumor area in vivo.
Conclusions:
- Lentivirus-mediated delivery of the avidin fusion protein enables sustained expression and targeted delivery of therapeutic agents to cancer cells.
- This approach holds potential for repeated targeting of cytotoxic compounds, improving cancer treatment strategies.
- The safety and efficacy profile supports further investigation of this gene therapy vector for glioma treatment.
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