Vascular Targeted Nanotherapeutic Management of Obesity
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Nanotherapeutics and Treatment of Obesity
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Vascular Targeted Nanotherapeutic Management of Obesity
- 1. Vascular Targeted Nanotherapeutic Management of Obesity PROHIBITIN BLOCKADE Ninian Peckitt FRCS FFD RCS FDS RCS FACCS Oral and Maxillofacial Surgeon / Facial Plastic Surgeon
- 2. Nanotherapy for Obesity - Proof of Concept • Independent studies have shown improved drug efficacy • using prohibitin (PHB)-targeted therapy in obese rodents and non- human primates • providing a proof of concept that targeted nanotherapy can be a feasible treatment for obesity
- 4. Molecular Liposuction Prohibitin • Protein Adapter Molecule • Blood vessels supporting Fat accumulation • Fat Atrophy Kolonin, Saha, Chan, Pasqualini, Arap Reversal of obesity by targeted ablation of adipose tissue Nature Medicine 2004 10: 625-632 role in normal cell cycle regulation replicative senescence cellular immortalisation tumour suppression Mitochondrial Marker (Prohibitin) ab2996
- 5. Molecular Liposuction Prohibitin Nature Medicine June 2004 Prohibitin – Protein Adapter Molecule • Mice doubled size eating a high-fat "cafeteria" diet. • Prohibitin antibody binding of receptor • Only weeks of treatment restored the normal weight of mice
- 6. Vascular Zip Codes • Pioneered by Arap and Pasqualini • Blood vessels are not simply a uniform and ubiquitous "pipeline" that services all parts of the body…. • ….but are different depending on the kind of organ or tissue they are supporting, • if unique molecules can be located that define each different kind of blood vessel, then drugs can be targeted to those "addresses" to treat associated diseases.
- 7. Molecular Liposuction Prohibitin Nature Medicine June 2004 Blood vessels that service white adipose tissue • White fat can rapidly expand (like a tumour) • Requires rapid production of blood vessels to deliver oxygen • Every single fat cell is encased by capillaries
- 8. Molecular Liposuction fat vascularity Prohibitin Nature Medicine June 2004 Blood vessels that service white adipose tissue • vast network of blood vessels is needed • many more blood vessels than needed to support other tissues • 1lb fat (2.2Kg) contains a mile 1500m of blood vessels,
- 9. Molecular Liposuction phage display library Prohibitin Nature Medicine June 2004 Blood vessels that service white adipose tissue • In vivo phage display library" screening technique (Genetically modified bacteriophages ) • billions of viral particles… each with different peptide on its outer coat. • Genetically modified phages injected into obese mice, • Look for binding onto protein receptors (adipose tissue blood vessels)
- 10. CKGGRAKDC-phage homing to white fat • CKGGRAKDC-phage homing to white fat. • Recovery of phage from 1 g of subcutaneous white fat • ob/ob mice intravenously injected (tail vein) • with 1010 transforming (TU) of the phage 6 h prior to tissue extraction.
- 12. CKGGRAKDC-phage fat homing of CKGGRAKDC motif
- 13. Localization of fitc-CKGGRAKDC peptide in isolated fat microvesels. CKGGRAKDC-phage fat homing of CKGGRAKDC motif
- 14. CKGGRAKDC-phage fat homing of CKGGRAKDC motif Peptide CKGGRAKDC-GG-D(KLAKLAK) Peritoneal Fat (Mice) 4 weeks of peptide injections TreatedControl
- 15. CKGGRAKDC-phage fat homing of CKGGRAKDC motif
- 16. Molecular Liposuction Prohibitin Binding Receptor Prohibitin Nature Medicine June 2004 Blood vessels that service white adipose tissue • Binding receptor identified as Prohibitin • known to regulate cell survival and growth. • Prohibitin expression inside the cells • e.g. mitochondria, nucleus • not normally found in blood vessels of several other tissues • not normally found in tumours derived from fat tissue
- 17. Molecular Liposuction phage display library Prohibitin Nature Medicine June 2004 Blood vessels that service white adipose tissue • Designer Drug • Creation of a synthetic ligand • A sequence of amino acids • Fit neatly into the Prohibitin receptor - like a lock and key • Ligand fused to it a corkscrew-shaped "drug" • Corkscrew drug induces self-destruction
- 18. Molecular Liposuction phage display library Prohibitin Nature Medicine June 2004 Blood vessels that service white adipose tissue • one month of treatment in severely obese mice • Restoration of the animal's normal body weight. • No mice were genetically altered / prone to obesity (they gained weight because they ate a high-fat diet)
- 19. Molecular Liposuction phage display library Prohibitin Nature Medicine June 2004 Blood vessels that service white adipose tissue • Creation of a synthetic ligand – Designer Drug (sequence of amino acids) • Drug Binds prohibitin receptor • Selectively destroy blood vessels
- 20. Vascular targeted nanotherapeutic approach for obesity treatment 2018 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260142/?fbclid=IwAR0VEcoHP5KOfCL8BsezsU3SkEojNtaXKyydGchgEg-P8QVlFkRpOGYAQfc
- 21. Ninian Peckitt FRCS FFD RCS FDS RCS FACCS