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Rishi R. Adhikary , Rinti Banerjee

Rishi R. Adhikary , Rinti Banerjee. DEVELOPMENT OF NOVEL THERANOSTIC AGENTS FOR INTRA-NASAL DELIVERY OF TEMOZOLOMIDE IN GLIOBLASTOMA TREATMENT. Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay Mumbai, India. KEY COMPONENTS. THERANOSTICS. GLIOBLASTOMA.

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Rishi R. Adhikary , Rinti Banerjee

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  1. Rishi R. Adhikary, Rinti Banerjee DEVELOPMENT OF NOVEL THERANOSTIC AGENTS FOR INTRA-NASAL DELIVERY OF TEMOZOLOMIDE IN GLIOBLASTOMA TREATMENT Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay Mumbai, India

  2. KEY COMPONENTS THERANOSTICS GLIOBLASTOMA Source: http://en.wikipedia.org/wiki/Glioblastoma_multiforme ULTRASOUND RESPONSIVE AGENTS TEMOZOLOMIDE NOSE-TO-BRAIN DRUG DELIVERY Source: Gray's anatomy : the anatomical basis of clinical practice

  3. NANOTECHNOLOGY- NANOMEDICINE “There is Plenty of Room at the Bottom” Richard P. Feynman to the American Physical Society in Pasadena on December 1959 Source: http://en.wikipedia.org/wiki/Richard_Feynman

  4. TRIGGER RESPONSIVE NANOCARRIERS Ultrasound Use of the prodrug TEMOZOLOMIDE Alkaline pH of Glioblastoma pH • Inexpensive, portable, clinically trusted • Simultaneous trigger responsive therapy and diagnostic imaging- THERANOSTICS • In the CNS: • Opening of the BBB • Hyperthermia Basic pH Source: Burger A, Abraham DJ. Burger's Medicinal Chemistry and Drug Discovery: Chemotherapeutic agents: Wiley; 2003.

  5. SCHEMATIC OF THE NANOCARRIER

  6. ULTRASOUND CONTRAST AGENTS:MICROBUBBLES Figure: Gross appearance of the microbubble suspension showing two distinct layers. (1) Upper Layers containing the larger bubbles (Scale 10µm) (2)Lower layers containing the microbubbles (Scale 100 nm)

  7. TEMOZOLOMIDE-LOADEDSOLID LIPID NANOPARTICLES Choline CH2 rocking vibrations Phosphate CH2 stretching mode C=O stretching mode C-H asymmetric stretch CH3 stretching mode

  8. FINAL STIMULUS RESPONSIVE PARTICLES Figure: The formation of the proposed Microbubble- SLN constructs as seen in (a) and (b) Cryo TEM images and (c) and (d) Cryo FEG SEM images (Scale bars equal to 1µm in (a); 2µm in the (b); 100 nm in (c) and (d))

  9. INTRANASAL DELIVERY:MUCOADHESIVENESS Figure: Contact angle measurements for determination of mucoadhesiveness. The values given indicate the mean contact angle and error bars indicate the standard deviation (* p value <0.0001 compared to glass). Also, significant difference shown (p value < 0.0001) between SLN and Coated microbubbles+SLN (Error Bar representing Standard Deviation)

  10. DRUG CROSSING THE ARTIFICIAL BLOOD BRAIN BARRIER (PAMPA) * * Percentage of drug crossing the BBB Figure: Temozolomide crossing the artificial BBB in 1 hour v/s in 18hrs for various formulations (* indicates significant difference, p-value <0.05) (error bars represent standard deviation)

  11. THERAPY: SUSTAINED RELEASE * * Figure: Sustained release of temozolomide from each of the solid lipid nanoparticles over time in Simulated Nasal Fluid and artificial CSF (* indicates p-value < 0.001) (error bars represent standard deviation) Figure: Drug release of temozolomide from each of the solid lipid nanoparticles over time in Simulated Nasal Fluid and artificial CSF at 1 hour (* indicates p-value < 0.001) (error bars represent standard deviation)

  12. DISRUPTION OF NANOCARRIERS Figure : The Cryo FEG SEM images of SLN-loaded microbubbles prior to application of ultrasound (a) and after ultrasound application (b-f). Ultrasound was applied using a sonoporator probe of 1MHz frequency, 100 % duty cycle for 15 second at various intensities (in watt/cm2) viz. (b) 0.2 W/cm2 (c) 0.5 W/cm2 (d) 1 W/cm2 (e) 2 W/cm2 (f) 3 W/cm2

  13. THERAPY: TRIGGERED RELEASE IN CSF * * Figure : Temozolomide release from the drug delivery systems in the presence or absence of ultrasound and microbubbles for two different SLNs (* indicates significant difference, p-value <0.01) (error bars represent standard deviation)

  14. DIAGNOSTIC IMAGING:CLINICAL ULTRASOUND Agar Phantom Agarose Phantom Degassed Water SLN Microbubbles Coated Microbubbles Final Particles

  15. CONCLUSIONS & TRANSLATIONAL ASPECTS • THERANOSTIC AGENT: -Stimulus Responsive Drug Delivery (THERApy)-DiagNOSTIC imaging: contrast agent • Suitable for Intranasal Administration • Targeted treatment- Triggered therapy • Novel alternative for toxic and invasive treatments

  16. Thank you!!! Acknowledgements: • Prof. Rinti Banerjee • Dr. RimaMukherjee • Nanomedicine Lab • Indian Institute of Technology Bombay • Sophisticated Analytical Instrument Facility (SAIF) • Industrial Research and Consultancy Centre (IRCC)

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