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Exploiting Nanomaterial-induced Autophagy For Cancer Therapy: More Than One Way To Skin A Cat

Exploiting Nanomaterial-induced Autophagy For Cancer Therapy: More Than One Way To Skin A Cat. Long-ping Wen School of Life Science University of Science & Technology of China. Autophagy (Self-Eating). Macroautophagy Microautophagy Chaperone-mediated Autophagy

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Exploiting Nanomaterial-induced Autophagy For Cancer Therapy: More Than One Way To Skin A Cat

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  1. Exploiting Nanomaterial-inducedAutophagy For Cancer Therapy:More Than One Way To Skin A Cat Long-ping Wen School of Life Science University of Science & Technology of China

  2. Autophagy (Self-Eating) • Macroautophagy • Microautophagy • Chaperone-mediated Autophagy Macroautophagy is most common and best studied 2

  3. Macroautophagy (Autophagy) Lysosome Encapsulation Isolation membrane Autophagosome Fusion Autolysosome Degradation A critical cellular degradation process

  4. Biological function of autophagy • Provision of energy to survive under starvation • Removal of unwanted cellular contents • Stress response Maintenance of cellular homeostasis 4

  5. Yoshinori Ohsumi The Nobel Prize in Physiology or Medicine 2016 was awarded to Yoshinori Ohsumifor his discoveries of mechanisms for autophagy

  6. Many small molecules have been shown to induce autophagy. Can nanomaterials do it? 6

  7. QD525 QD605 Nano Letters 6: 2826, 2006

  8. Yu L et al. Small24: 2784, 2009

  9. A great variety of nanomaterials have been shown to induce autophagy. Consensus Opinion: Elevation of autophagy level is a frequent (but NOT ALWAYS) response of cells upon exposure to nanomaterials 10

  10. Impact of autophagy on cell fate No Effect Pro-death Pro-survival

  11. Pro-death autophagy induced by nanomaterials

  12. Pro-survival autophagy induced by nanomaterial Nano P-VO2 Autophagy induction Zhou W et al. Nanotechnology24: 165102, 2013

  13. What’s good about nanomaterial-induced autophagy？ We can exploit it for therapeutic applications towards life-threatening human diseases such as cancer 14

  14. Several scenarios to exploit the pro-death property of nanomaterial-induced autophagy in cancer cells 15

  15. Direct killing of cancer cells Ni9Co1 Ni6Co4 Liu Y et al. Advanced Functional Materials23: 5930, 2013

  16. Chemosensitization Zhang Q et al. Autophagy 5: 1107, 2009

  17. How about the pro-survival autophagy? Knock it out! 19

  18. Autophagy inhibition enhances anti-cancer efficacy of silver nanoparticles Ag NPs (µg/mL) 0 5 10 15 20 control LC3-Ⅰ LC3-Ⅱ Wort GAPDH Ag NPs Ag NPs+Wort Lin J et al. Autophagy 10: 1-15, 2014 control Wortmannin Ag NPs Ag NPs+Wortmannin PI ANXA5-FITC

  19. Can we control nanomaterial-induced autophagy？ 21

  20. Optimizing Cancer Photothermal Therapy with Palladium-Copper Alloy Tetrapod Nanoparticles through Autophagy Inhibition and MSOT Imaging

  21. Major Obstacles for Photothermal Therapy • Limited light penetration • Incomplete cancer cell killing • Collateral damage to normal cells 24

  22. Major Obstacles for Photothermal Therapy • Limited light penetration • super photothermal conversion efficiency • Incomplete cancer cell killing • combine with chemotherapy (chemo-PTT) • Collateral damage to normal cells • imaging-guided PTT 25

  23. Two kinds of CuPd Tetrapod Nanoparticles TNPs-1 Cu Content:40% TNPs-2 Cu Content: 10%

  24. Size & Surface Charge

  25. UV-Vis-NIR Absorption & Temperature Elevation curve 1 W/cm2 808 nm laser, 10 ug/ml

  26. Autophagy Induction

  27. Normal Autophagic Flux and No Lysosomal Damage

  28. Inhibition of autophagy enhances cancer cell killing

  29. Inhibition of autophagy enhances cancer cell killing NIR- NIR+

  30. Further proof for autophagy dependence

  31. Further proof for autophagy dependence

  32. Multi-Spectral Optoacoustic Tomograpgy (MSOT)

  33. MSOT imaging in a tumor model

  34. Anti-cancer efficacy

  35. Anti-cancer efficacy

  36. Anti-cancer efficacy

  37. Model

  38. Summary • Induction of autophagy is a frequent cellular response upon exposure to nanomaterials • Nanomaterial-induced autophagy may increase, decrease, or have no effect on, cell death • Nanomaterial-induced autophagy maybe exploited for cancer therapy in different ways • Replacing traditional chemotherapeutics with chemical inhibitor of autophagy represents a novel chemo-PTT strategy for certain engineered nanomaterials with capability of inducing pro-survival autophagy 42

  39. Acknowledgement USTC, China • Yunjiao Zhang • Zeng Jie • Shuhong Yu • Yi Xie • Wei Zhou • Na Man SEU, China • Ning Gu ECNU, China • Qiang Zhang SCUT, China • Jun Wang • Li Ren AMU, China • Li Zhang

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