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Genetic Modulation of Baculoviral DNA
First, baculoviruses were genetically modified to express a human gene (Vegf) [see Fig.1]
Fig.1 Schematic illustration of genetically-modification of baculoviruses
Efficacy of viral transfection and entry into human cells was demonstrated in vitro using human vascular cells. Expression of Vegf protein was determined using immunocytochemistry (Fig.2).
Fig.2 Human vascular cell transfected with baculovirus expressing Vegf gen
Encapsulation and Adherence of Nanoparticles to Stent
Baculoviruses were then encapsulated in PGLA nanospheres (here). In vitro techniques were used to demonstrate that the nanoparticles housing the genetically modified baculovirus were:
ii) viral transfection was preserved, and
iii) Vegf protein expression was maintained after encapsulation.
After viability of encapsulation methodology, nanoparticles were then adhered to a bare metal stent. [Fig.3]
Fig.3 Micrograph showing nanoparticle adhesion to stent surface
Proof-of-Concept Animal Model
To show proof-of-concept in vivo, stents coated with nanoparticles housing genetically-modified baculovirus were placed into balloon-damaged canine femoral arteries (Fig.4). The baculo/Vegf-stent induced a significant reduction of neointima formation and vessel stenosis, when compared to controls (Paul et al., 2013). Thus, the baculo/Vegf-stent significantly enhanced endothelial recovery (re-endothelialization) at the injured site.
Fig.4 Balloon catheter placed in a canine femoral artery
These findings demonstrate the potential of this newly developed baculovirus-based biotherapeutic stent to ameliorate damaged vascular biology and diminish re-narrowing (ISR) of a blood vessel stent by inhibiting neointima formation.
⊕ Paul A, Hasan A, Rodes L, Sangaralingam M and Prakash S (2014) Bioengineered baculoviruses as new class of therapeutics using micro and nanotechnologies: principles, prospects and challenges. Adv Drug Rev 71, 115-30 (Pubmed)
⊕ Paul A, Elias CB, Shum-Tim D, and Prakash S. (2013) Bioactive baculovirus nanohybrids for stent based rapid vascular re-endothelialization. Sci Reports 3, 2366 (pdf)
⊕ Paul A, Shum-Tim D, Prakash S. (2013) Angiogenic nanodelivery systems for myocardial therapy. Methods Mol Biol. 1036, 137-49 (Pubmed)
⊕ Binsalamah ZM, Paul A, Prakash S, Shum-Tim D.(2012) Nanomedicine in cardiovascular therapy: recent advancements. Expert Rev Cardiovasc Ther. 10(6), 805-15 (Pubmed)
⊕ Paul A, Shao W, Shum-Tim D, Prakash S. (21012) The attenuation of restenosis following arterial gene transfer using carbon nanotube coated stent incorporating TAT/DNA(Ang1+Vegf) nanoparticles. Biomaterials. 33(30):7655-64 (Pubmed)
⊕ Paul A, Shao W, Abbasi S, Shum-Tim D, Prakash S. (2012) PAMAM dendrimer-baculovirus nanocomplex for microencapsulated adipose stem cell-gene therapy: in vitro and in vivo functional assessment. Mol Pharm. 9(9), 2479-88 (Pubmed)
⊕ Jardin BA, Elias CB, Prakash S. (2012) Expression of a secreted protein in mammalian cells using baculovirus particles. Methods Mol Biol. 801, 41-63 (Pubmed)
⊕ Binsalamah ZM, Paul A, Khan AA, Prakash S, Shum-Tim D. 2011) Intramyocardial sustained delivery of placental growth factor using nanoparticles as a vehicle for delivery in the rat infarct model. Int J Nanomedicine. 6, 2667-78 (pdf)
⊕ Paul A, Binsalamah ZM, Khan AA, Abbasia S, Elias CB, Shum-Tim D, Prakash S. (2011) A nanobiohybrid complex of recombinant baculovirus and Tat/DNA nanoparticles for delivery of Ang-1 transgene in myocardial infarction therapy. Biomaterials. 32(32), 8304-18 (Pubmed)
⊕ Prakash S, Malhotra M, Shao W, Tomaro-Duchesneau C, Abbasi S. (2011) Polymeric nanohybrids and functionalized carbon nanotubes as drug delivery carriers for cancer therapy. Adv Drug Deliv Rev. 6, 1340-51 (Pubmed)
⊕ Khan AA, Paul A, Abbasi S, Prakash S. (2011) Mitotic and antiapoptotic effects of nanoparticles coencapsulating human VEGF and human angiopoietin-1 on vascular endothelial cells. Int J Nanomedicine. 6, 1069-81 (pdf)
⊕ Malhotra M, Lane C, Tomaro-Duchesneau C, Saha S, Prakash S. (2011) A novel method for synthesizing PEGylated chitosan nanoparticles: strategy, preparation, and in vitro analysis. Int J Nanomedicine. 6, 485-94 (pdf)
⊕ Paul A, Elhayek E, Shum-Tim D, Prakash S. (2010) Recent Advancements in Pharmacological Stent Therapy Using Polymeric Materials: Opportunities and Challenges. Curr Drug Deliv. 2010 May 24 (Pubmed)
MangoGen Pharma Inc. is a biotherapeutic company with a mission to develop novel approaches to deliver specific gene therapy for the treatment of wound healing. Our proof-of-concept has shown that our approach can accelerate the re-endothelialization around a stent site, reducing the risk of re-stenosis. The potential outcomes of this approach are improved patient outcome, and significant socioeconomic savings.
The MangoGen team is dedicated to developing and producing this novel stent.
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