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By - Amit Misra

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  1. 1. SOME HEALTHY CYNICISM REGARDING NANOMETER-SIZED DRUG AND ANTIGEN DELIVERY SYSTEMS Amit Misra Pharmaceutics Division, Central Drug Research Institute, CSIR, Lucknow Vaccine Delivery: Vinod Labhasetwar , Rajeev Raghuvanshi (NII). Pulmonary Delivery: Rolee Sharma, Pavan Muttil, Awadh Yadav, Rahul Verma Amit Singh (CDRI); Jayanthi Suryakumar , Vineeth Raghavan, Rakesh Sinha, Vijay Modak, (Lupin), Swati Subodh (TCGA). GLUT targeting: K Bhargava, Sraddhanjali Mohapatra, Mukesh Kanojiya, V Sasikiran, Heikham Kajal Devi, Saman Habib (CDRI) Male Contraception: Ritu Malik, Gopal Gupta (CDRI) Shailesh Tondwal, Kripa Shankar, KS Venkatesh (IIT-K)
  2. 2. Moliere, The Bourgeois Gentleman; Act Two, Scene Four (Adapted by Timothy Mooney)* … MONSIEUR JOURDAIN : ... Before you go, I must confide to you a secret. I am in love with a lady of great rank and quality, and wish to ask your help in writing her a note which I intend to drop most casually at her feet . … PHILOSOPHY MASTER : Oh, certainly. A verse you'd like to jot? J : No, no, no verse for me. PM : So you want prose? J : No, neither . PM : Well, I think we must suppose/ It's one or its the other. J : Why? PM : I guess/ That those are all the options to express. … PM : To make the point most terse./ What isn't verse is prose, and what's not prose is verse. …. J: And this, the way I speak. What name would be applied to the -- PM: The way you speak? J: Yes. PM: Prose. J:Well, what do you know about that! These forty years now, I've been speaking in prose without knowing it! How grateful am I to you for teaching me that! ----------------- Amit: Well, what do you know about that! These twenty years now, I’ve been making colloidal drug delivery systems without knowing that I’ve been doing nanomedicine! How grateful am I to you for having invited me to speak today! *
  3. 3. PLGA (50:50, 48 KDa) Particles incorporating tetanus toxoid (TT) AlPO 4 -Al(OH) 3 inorganic microparticles with surface-adsorbed TT CASE 1: VACCINE DELIVERY
  4. 4. <ul><li>Groups: </li></ul><ul><li>2 Lf TT (7.5 μ g) adsorbed on alum; X2, 3wk (conventional) </li></ul><ul><li>1 Lf TT in NP + 1Lf on alum , single injection (combination) </li></ul><ul><li>2 Lf TT in NP, single injection (single dose NP) </li></ul><ul><li>2 Lf TT on alum, single injection (singled dose MP) </li></ul><ul><li>Blank NP + 2Lf TT, single injection (NP adsorbed) </li></ul>A: TT on Alum (Conventional)
  5. 5. C: NP Single Dose B: Combination D: MP Single Dose
  6. 6. <ul><li>Inhalable microparticles containing anti-tuberculosis drugs </li></ul><ul><li>Giving drugs by mouth: convenience versus non-target tissue bioavailability and toxicity </li></ul><ul><li>Pulmonary delivery, targeting alveolar macrophages: inhalation apparatus </li></ul><ul><li>Preparation of dry powder inhalation: industrially scalable– spray drying shelf stability– 2 yrs at least 2 drugs (resistance)– isoniazid and rifampicin / rifabutin targeting to macrophages sustained release biodistribution serum and tissue PK/PD inhalation safety/toxicity </li></ul><ul><li>M tuberculosis induces ‘alternative activation’ of host macrophage: can microparticle phagocytosis rescue infected macrophages to classical activation ? </li></ul><ul><li>Free radicals, Th1 versus Th2 cytokines, apoptosis versus necrosis </li></ul><ul><li>Genome-wide expression profiling by microarray, validation by real-time PCR </li></ul><ul><li>Inter-individual differences in responses to microparticles: polymorphism at the HLA and VDR loci? </li></ul>
  7. 8. Early Efficacy Latency/Recrudescence Oxidative Radicals Nitric Oxide
  8. 9. Apoptosis
  9. 10. DRB1*1501 allele in healthy volunteers VDR Polymorphisms in Apa1 , Bsm1 and Fok1 fragments
  10. 11. Donor 4 Donor 1 Donor 1 Human diversity, not particle reproducibility, influences outcome of treatment B
  11. 12. CASE 3: Receptor-mediated targeting of nanoparticles containing anti malarial agents to RBC via mammalian + parasite Glucose Transporters Uninfected RBC Infected RBC Mammalian GLUT-1 PfHT-1 Nanoparticles displaying free glucose moiety should be targeted to infected rather than uninfected RBC through mammalian GLUT as well as plasmodial hexose transporter RBC separated in FACS (A, blue region) show dose-dependent fluorescence (B) when whole blood is incubated with FITC-labelled NP. NP uptake by RBC in whole blood is inhibited by GLUT-blocker phloretin (C), and is competed out by natural GLUT ligand, glucose (D). A B C D Nanoparticles bearing free glucose on surface
  12. 14. CASE 3: Setting a Pulse to Catch a Pulse : Non-invasive Episodic Intervention in the Hypothalamo-Pituitary-Testicular Axis for Male Contraception Hours
  13. 16. A C D E F TUNEL labeling, Hoechst counterstain of anterior pituitary sections on Day 71. (A, B): Untreated control, (C,D): Sham-treated, (E,F): pulsatile transdermal testosterone
  14. 17. Kruskal Wallis ANOVA on ranks (P < 0.05) followed by post –hoc Tukey test(P<0.05). *Significant difference ( P <0.01) from untreated control, # Significant difference ( P <0.01) from sham control. Behaviour and Fertility No. of days Control Sham Treated Mating frequency/ animal Deliveries/ mating Mating frequency/ animal Deliveries/ matings Mating frequency/ animal Deliveries/ matings 0-30 (n=6) 0.78 0.84 0.75 0.33 0.3* # 0.25* 30-71 (n=6) 0.61 0.66 0.3 0.88 0.2* 0.5 # 71-81 (n=4) 0.15 1 0.45 1 0.1 0* # 81-136 (n=2) 0.69 0.6 1.65 0.25 0.97 # 0.142*
  15. 18. Cynicism, Skepticism and Hope Cynical about enhanced permeability, efficacy and toxicity (nano-size fits all) policy, funding agency, civil society and media priorities Skeptical about size-specific effects, amenability to scale-up, adaptation to shopfloor Hopeful about “… being the right size” (Haldane, 1926)