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D. Bahadur Department of Metallurgical Engineering and Materials Science, Indian Institute of Technology, Bombay Indi

A warm treatment for cancer with drugs. D. Bahadur Department of Metallurgical Engineering and Materials Science, Indian Institute of Technology, Bombay India - 400076. Outline. Introduction to magnetic hyperthermia & sustained drug Delivery for cancer therapy

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D. Bahadur Department of Metallurgical Engineering and Materials Science, Indian Institute of Technology, Bombay Indi

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  1. A warm treatment for cancer with drugs D. Bahadur Department of Metallurgical Engineering and Materials Science, Indian Institute of Technology, Bombay India - 400076

  2. Outline • Introduction to magnetic hyperthermia & sustained drug Delivery for cancer therapy • Thermosensitive and pH sensitive nanostructures, hybrids & suspensions • Multifunctional nano particulates • Some animal experiments

  3. Magnetic Hyperthermia In-vitro assessment In vivo assessment Clinical trials???

  4. Mechanism of heating process for MNPs Hyperthermia 1. Hysteresis loss T2 2. Neel mechanism Rotation of the magnetization vector within the particles. T1 Tc Magnetization (emu/g) Applied field H(T) Intrinsic superparamagnetism (the particle magnetic moments aligns with external field) Extrinsic superparamagnetism (the particle itself aligns with field) Hysteresis loss at different temp. H 3. Brownian Mechanism Mechanical rotation of the magnetic particle

  5. Magnetic relaxation mechanisms H=0 H ≠ 0 H=0 Néel relaxation H = 0 Brownian relaxation

  6. Apply magnetic field to concentrate particles Inject NMPs, NMP will circulate through the blood stream Modulate field to release drug from particles Or to produce heat How would it work? Other options for targeting: 1 - Direct injection into tumor site 2 - Coating NMP with antibodies to target tumor Solid tumor

  7. Smart nanoparticulates for multifunctional bio applications • Biodegradable & biocmpatible polymeric suspension • Thermosensitive magnetic liposomes • Dendrimers • Thermosensitive NIPAM base LBL assembly and magnetic nanohydrogel • Biphasic suspension • Porous oxides • Layered double hydroxides

  8. Desired Properties of magnetic nanoparticulates • Size of magnetic particles : 5 –100 nm • Transition temperature: 42-60°C • Ferrofluid/ suspension preparation • High magnetization & losses • Higher heating ability (Specific Absorption Rate) • Delivery System • Sufficient biocompatibility • Selective heating and targeting

  9. Tc Tuning: In vivo switch • M1-xZnxFe2O4, γ-AlxFe2-xO3 (0≤x≤1), LSMO Magnetizatin (emu/gm) 2 73 325 Temperature (K) Bio-Medical Materials and Engg., 13, 387, 2003

  10. La1-xSrxMnO3 and its suspension J. Biomed. Mater. Res. 409, 2007

  11. Biodegradable and biocompatible suspension of nano sized magnetic particles • γ-Fe2O3 and its derivatives and manganites suspended in acropyl containing water • Properties different from conventional ferrofluid • High degree of biocompatibility is observed with HeLa cells • studies on mechanism of cell death : disruption of cytoskelton IEEE Trans. Mag, 41, 4069, 2005

  12. Effect of MHT on cell viability J. Appl. Phys., 97, 10Q 903, 2005.  

  13. Citrate-stabilized MNP: Conjugation & release of DOX Drug loading: DLS, Zeta and Fluorescence spectra Cytocompatibility: HeLa cells pH triggered drug release Hyperthermia treatment of cancer S. Nigam et al J. Magn. Magn. Mater. 323, 237  , 2011

  14. Multifunctional magnetic liposomes for cancer therapy Pradhan et al., J Contr Rel, 2010;142:108-12

  15. PBS FBS Calcein release study • Calcein release increases with addition of cholesterol and PEGylated lipid • Incorporation of 0.5 molar % DSPE-PEG2000-Folate does not interfere Pradhan et al., J Contr Rel, 142, 108, 2010

  16. Temperature sensitive doxorubicin release from folate targeted magnetic liposomes (MagFolDox) Release at 1 hr • About 50% release of doxorubicin in FBS at 43oC

  17. Folate targeting evaluation by FACS analysis in KB cells Control MagFolDox – MF MagFolDox – MF + 1mM FA MagFolDox + MF MagFolDox + MF + 1mM FA • Magnetic liposomes under magnetic field show higher folate receptor mediated internalization Pradhan et al. Journal of Controlled Release, 142, 108, 2010.

  18. In vitro therapeutic efficacy study of thermo-chemotherapy *MH – Magnetic hyperthermia • Synergistic cytotoxic effect due to combined magnetic hyperthermia and chemotherapy has been observed • (as per Valeriote's method)

  19. ZnO assemblies as novel drug carrier Drug loading and drug release Schematic representation of DOX loading K. C. Barick, et al , J. Mater. Chem. 20 (2010) 6446

  20. Multifunctional macromolecules for cancer therapy POLYMER MATRIX DENDRIMER PEG MNP DRUG ANTIBODY Dendrimer functionalized Magnetic nanoparticle Magnetic nanoparticle encapsulated in polymer matrix

  21. Arginine based dendrimer stabilized magnetic nanoparticles • Direct formation of a dendritic • block on the surface of MNPs • The structure of the novel dendritic • system was tailored by using • methyl acrylate and biocompatible • arginine as branching units • Drug release profile of DOX in acetate • buffer (pH 5) against PBS (pH 7.3) • Drug release in the absence and • presence of an AC magnetic field S.Chandra et al New J. Chem., 2010, 34, 648–655

  22. OEG grafted amidoamine Dendrimer-DOX Conjugate • Mutual interaction between • dendrimer and drug based • on hydrogen bonds • Facilitates easy drug • release Drug loading efficiency was found to be 52% S. Chandra et al, J. Mater. Chem., 2011 (in press)

  23. Drug Release Behaviour • For the cancer cells that are not inhibited by the initial stage of the DOX release, the slow DOX release is necessary to prevent their further proliferation S. Chandra et al Mater. Chem., 2011 (in press)

  24. Viabilities of MCF-7 and HeLa cells incubated with MEM media containing DOX- loaded dendrimer 2

  25. Thermoresponsivehydrogel of Poly-NiPAM via LBL assembly Gahrwar et al.J. Nanosci. & nanoTech 9,5355, 2009 J. of Colloid &Interf. Sci. 324, 47, 2008 • Swelling and deswelling completely reversible ! • Thermoresponsivity preserved ! • Charge reversal at each deposition step

  26. Raising transition temperature for hyperthermia & drug delivery poly(NIPAAm) Chitosan Scheme showing shrinkage of hydrogel particles due to expulsion of water as well as there is a shift in LCST due to crosslinking of CS to PNIPAAm

  27. Drug delivery studies • Water-bath assisted drug • delivery studies were carried out • anti-cancer drug doxorubicin • For poly(NIPAAm) temperature • triggered release studies • confirmed its thermosensitivity • at low pH • There was nearly 80% jump • in release from 20oC to 37oC in • acidic medium • Chitosan being pH sensitive • allows the materials (NHG-1 which consists of 2 wt% CS )to enhance the release in acidic medium at fixed temperature Temperature & pH triggered release Chemical structure of doxorubicin • For magnetic hydrogel, there was nearly 90% enhancement in release • of drug at 44oC when compared with body temperature (37oC) release in 1h • of time

  28. Animal Experiments Biocompatibility studies …Histology • Histopathological parameters • like SGPT, SGOT, BUN and • Creatinine have been studied • SGPT and SGOT determine • lever functions • Significantly higher level may • indicate acute liver damage • and heart failure Histological studies • SGPT and SGOT are • expressed in unit per Liter Manish Jaiswal et al, 2011 • We observe there was an instant increase in both the parameters after 1h of i.v. administration of dose • Increment in SGPT was more significant, almost 100 % rise, especially for dose I, (compared to control • group) was reported which gradually declined over next 48 h and attained its normal value till 7 days • of study

  29. In vivo hyperthermia …(Contd.) • Tumor volume was measured after every 72h for • next 10-12 days depending upon the mouse • health conditions . • Tumor volume was calculated using the formula: • V= (ab2)*π/6 • Where, a and b are longer and shorter dimensions of tumor measured in both transverse and longitudinal directions of thigh area (using Vernier caliper) Figure: Plot showing the change in tumor volume of both Control and hyperthermia treated mice. Data expressed as Avg .± S.D., n =3 • The on going work is continued with • double dose and three times hyperthermia • treatment • Which will further be repeated with same • sample conjugated with anti-cancer drug • doxorubicin, a process known as • “Thermo-chemotherapy” wherein both heat • and drug help destroy cancer cells (d) (c) Figure: representative images of tumor size (a) Control and (b) hyperthermia treated after 10 days of observation

  30. Acknowledgements • Nanomission, DST, Govt. of India, DIT, Govt of India • S.D Sharma of BARC • To my collaborators: Christian Plank from Munich, Walter Richtering from Aachen, Eitenne Duguet from Bordeaux • Rinti Banerjee, Dulal Panda & Rohit Srivastava of Bioschool • To all my students

  31. Acknowledgement (contd.) Dr. Sudeshna Chandra (Analytical Chem) Dr.Madhulika Sharma ( Physics) S.Prabhkaran ( Electronics, Mater. Sci) T.Sriharsha ( Phys, Mater. Sci) Bharati Panigrahy( Physics) Manish Jaiswal ( Physics) Anand Prakash ( Phys., Mater. Sci) Sarika Singh ( Chemistry) Jagriti Gupta ( Chemistry) Saumya Nigam ( Biotechnology) Suneel ( Chemical Engg) Niroj Sahoo ( Maater. Sci) Prashant Sahoo ( Chem. Met.Engg) Manasjit Gogoi ( Biochemistry) Sudarshan Kini ( Biochemistry, nanotech) Akshaya Swain ( Phys, Mater. Sci) Leena Pradhan ( Bio science) Dushyant ( Physics) Madhu Saikh ( Met Engg) Asif khan ( Biomedical) Jyotikant ( Nanotechnology) Ishwar prasad Rao ( Physics) Neerav Barola Kunal Atanu Sanket Rishi

  32. Thank You ….

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