Nanoparticles in cancer medicine a physician s perspective

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1 Nanoparticles in cancer medicine a physician s perspective Sunil Krishnan, MD John E. and Dorothy J. Harris Professor Director, Center for Radiation Oncology Research MD Anderson Cancer Center Disclosure Information Sunil Krishnan I have the following financial relationships to disclose: Grant or research support from: NIH, DoD, CPRIT, Alliance for Nanohealth, Shell, Hitachi, FUSF, Dunn Foundation, MDACC Royalties Taylor and Francis (book sales) I WILL NOT include discussion of investigational or offlabel use of a product in my presentation. Physical dose enhancement Hainfeld et al. Phys Med Biol 2004; 49: N

2 The underlying physics Ejection of orbital electron & emission of x-ray fluorescence photon (or characteristic x-ray) K L Courtesy: Nivedh Manohar, PhD 4 M Physical dose enhancement Cho et al. Phys Med Biol 2009 Physical dose enhancement Cho et al. Phys Med Biol

3 Physical dose enhancement Cho et al. Phys Med Biol 2009, 54(16): Physical dose enhancement Cho, Krishnan Med Phys 2010 Physical dose enhancement 3

4 Internalization 50nm 14nm 74nm 50nm 74nm 14nm Chithrani DB, et al. Rad Res (6): Enhancing physical dose enhancement hn hn on the order of 10 m e- e- e- nanoparticles Passive targeting nanoparticles + peptides Active targeting Conjugated gold nanorod 4

5 % ID Normalized Tumor Volume C225-GNR PEG-GNR Gold nanorod Control 30 min 4 hrs 24 hrs Krishnan lab, unpublished data Tumor regrowth delay Control PEG-GNR C-GNR Cetuximab Rad Cetuximab + Rad PEG-GNR + Rad C-GNR + Rad Days after treatment Biodistribution PEG-GNR C225-GNR Brain Heart Lung Liver Spleen Kidney Tumor Blood Cho SH. Phys Med Biol 2005; 50: N

6 Clonogenic survival Surviving Fraction Average Number of Foci per cell 30 min 24 hrs Control Surviving Fraction Control PEG-GNR PEG-GNR C225-GNR C225-GNR Dose (Gy) Dose (Gy) DEF 10% DEF 15% DNA damage DNA damage No Radiation Radiation (4 Gy) GNR + Rad (4 Gy) 50 C225-GNR + Rad (4 Gy) Time after irradiation (hrs) R4 R4 + GNR R4 + cgnr C C C γ H2AX H2AX PARP 6

7 C225-GNR + Radiation PEG-GNR + Radiation Radiation Normalized protein carbonyl content -NTP ratio Apoptotic markers E Caspase mediated apoptotic markers Rad (4 Gy) pgnr + Rad cgnr + Rad C C C hr post IR Procaspase 3 Procaspase 9 Procaspase 8 Actin Mitochondrial mediated apoptotic markers Rad (4 Gy) pgnr + Rad cgnr + Rad hr post IR C C C Bcl-2 Bax PUMA Actin G NTP NTP NTP H Ra pgnr d cgnr Contro 1 hr 24 l hr ppm (t1) Rad pgnrcgnr Total oxidative stress Protein carbonyl assay Rad 1.2 GNR 1.1 CGNR Control Immediate 1 hr 4 hrs Time after 4 Gy radiation Tissue effects Post irradiation time 4 hrs 4 days 7

8 Average microvessel density per field of view with 10X objective Tissue effects Radiation (10 Gy) GNR + Rad (10Gy) C225-GNR + Rad (10 Gy) * hrs 4 days Post irradiation period Intracellular distribution Time Intracellular distribution Wolfe T, et al. Nanomedicine 2015;11:

9 The underlying physics Ejection of orbital electron & emission of x-ray fluorescence photon (or characteristic x-ray) K L Courtesy: Nivedh Manohar, PhD 25 M Summary Bhattarai SR, et al. Nanoscale Apr 20;9(16): Summary Targeted payload delivery feasible with smaller nanoparticles bioconjugated to peptides/antibodies Tumor accumulation does not increase much, BUT distribution is altered at the cellular level Both the intracellular localization and the perivascular sequestration result in greater radiosensitization at a biological level, mediated primarily by: Increased DNA damage and downstream signaling Increased oxidative stress Increased vascular disruption 9

10 Percent of AuNps released 38.5 o C 41.5 o C Another approach Thermosensitive liposome PEG Hydrophobic region Aqueous core AuNp nm 100 TSLAuNps NTSLAuNps 80 Phospholipid bilayer Temperature ( o C ) Focused ultrasound 10

11 Normalized tumor volume Normalized tumor volume Radiosensitization Control TSLAuNp HT TSLAuNp + Rad Rad TSLAuNp + HT+ Rad Days Radiosensitization Control HT TSLAuNp TSLAuNp + HT NTSLAuNp + HT Rad AuNp+Rad TSLAuNp + Rad NTSLAuNp + Rad HT+ Rad NTSLAuNp + HT + Rad TSLAuNp + HT+ Rad Days after intravenous injection Deep penetration of tumors 11

12 Summary Triggered release from thermosensitive liposomes enhances deep penetration of nanoparticles Deep penetration improves radiosensitization independent of the effect of hyperthermic radiosensitization In principle, this could be a class solution for a variety of tumor types Photoacoustic imaging (A) (A 1 ) (A 2 ) (B) (A 3 ) (C) (A 4 ) Xray fluorescence imaging Manohar N, et al. Sci Rep Feb 25;6:

13 Hydrophobic region Phospholipid bilayer PEG Aqueous core AuNp Normalized tumor volume Normalized Tumor Volume XRT ~25nm conjugated nanorod 4.0 Control 3.8 PEG-GNR 3.6 C-GNR Cetuximab 3.4 Rad 3.2 Cetuximab + Rad 3.0 PEG-GNR + Rad 2.8 C-GNR + Rad Progressive intracellular 1.6 accumulation Inc d 1.0oxidative stress 0.8 Inc d DNA damage Days after treatment FUS XRT nm ~120nm Thermosensitive liposome with gold Control TSLAuNp HT TSLAuNp + Rad Rad TSLAuNp + HT+ Rad 0 Deep penetration Days of nanoparticles Summary Larger particles for vascular-targeted applications (thermoablation, hyperthermia, vascular imaging) Smaller particles for parenchymal applications (imaging, targeted payload delivery) Combinations of above Unresolved issues related to clinical translation 13

14 2 µ 500 nm The target population Patients receiving radiation therapy for cancer ~60% of all patients receive radiation therapy Often, standard doses of radiation therapy are unable to cure the tumor but higher doses cannot be given due to high risk of side effects from overdosing adjacent normal organs Can one give the same (standard) dose of radiation to the tumor but make it behave like a higher dose of radiation? We need new approaches Pipeline Breakdown According to Number of Drugs Marketed# 93 Registered# 1 Pre-registration# 5 Phase III# 47 Phase II# 103 Phase I# 62 Preclinical# 73 No Data# 5 Suspended# 7 Ceased# 150 A new radiosensitization strategy 14

15 What nanoparticles work best? Bland? Spheres Spicy? 20 nm Rods Triangles 20 nm What nanoparticles work best? Where do we stand today? Courtesy: Jan Gabriel Schuemann Sawakuchi Prasanna PG, et al. Rad Res 2015: 184(3):

16 Roadmap to the clinic Acknowledgements Krishnan lab Parmesh Diagaradjane Amit Deorukhkar Edward Agyare Dev Chatterjee Shanta Bhattarai Pankaj Singh Jihyoun Lee Aaron Brown Kevin Kotamarti Nga Diep Krystina Sang Jacobo Orenstein Cardona Norman Colon Hee Chul Park Brook Walter Texas Southern Univ Huan Xie UT Austin James Tunnell Raiyan Zaman Priya Puvanakrishnan Jaesook Park Georgia Tech Sang Cho Seong-Kyun Cheong Bernard Jones Imaging Physics John Hazle Jason Stafford Andrew Elliott Baylor Jeffrey Rosen Rachel Atkinson Amit Joshi Nanospectra Glenn Goodrich Don Payne Jon Schwartz James Wang Rice Naomi Halas Funding NIH - KL2, R21 x 2, R01 x 2, U01, T32 DoD, CPRIT, ANH pre-center grant, Shell UT Cntr Biomed Engg, Hitachi, FUSF, MDACC 16

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