1. Young Innovators 2009
Prostate-Specific Membrane Antigen (PSMA)-Targeted Imaging, Diagnosis, and Therapy of Prostate Cancer using a PSMA inhibitor as a Homing Ligand
Sumith A. Kularatne
Philip S. Low
Purdue University
Part III

2. Design of PSMA-Targeted Chemotherapeutic Agents
IC50 = 1 nM (to LNCaP cell)
Low, P. S. & Kularatne, S. A. PCT/WO
IC50 = 0.8 nM (to LNCaP cells)

3. Relative Binding Affinity of DUPA-TubH for LNCaP Cells
+ 100 nM DUPA-99mTc
Relative affinity ~ 0.27
DUPA-TubH

4. LC-MS Analysis of Disulfide Carbonate Mediated Drug Release
DUPA-TubH
DTT = Dithiothreitol
t = 0 min
DTT
DUPA-Linker
t =60 min
DUPA-TubH

5. Potency of DUPA-TubH to LNCaP Cells in Culture
Competition with excess PMPA
DUPA-TubH
Kularatne, S. A., Wang, K., Santhapuram, H-K. R. & Low, P. S. Mol Pharm. 2009, 6,

6. Effects of DUPA-TubH I on Growth of LNCaP Tumors

7. Pathological Analysis of DUPA-TubH I Treated Mice
Saline Treated
DUPA-TubH I Treated
Treatment Group
% of tumor dead mass
Saline
< 10 %
xs PMPA +
DUPA-TubH I
> 95%
H & E (Hemotaxylin and Eosin) stain (400 x)
NL – no lesion identified
Treatment Group
Liver
Kidney
Spleen
Lung
Heart
Muscle
Intestine
Skin
Bone marrow
Saline NL
xs PMPA +
DUPA-TubH I
minor
Kularatne, S. A., Subramanian, B., van Alstine, W.& Low, P. S. (unpublished data)

8. Conclusions Developed PSMA-targeted imaging agents
Locate primary and metastatic disease
Detect CTCs in blood samples of prostate cancer patients
Monitor response to therapy
Detect disease recurrence following surgery
Select patients for subsequent DUPA-targeted chemotherapy
(B) Developed highly potent PSMA-targeted therapeutic
agents
(C) Developed Folate-targeted PET imaging and
immunotherapeutic agents

9. Acknowledgements Prof. Philip S. Low Prof. Philip L. Fuchs
Prof. Ei-chi Negishi
Prof. Hilkka I. Kenttämaa
Collaborators:
Dr. Z. Zhou (Purdue)
Dr. C. Post (Purdue)
Dr. W. Alstine (Purdue)
Dr. W. He (Purdue)
Dr. L. Hartmann (Mayo Clinic)
Dr. G. Klee (Mayo Clinic)
Dr. K. Wang (Endocyte Inc)
Dr. H-K. Santhapuram (Endocyte Inc)
Dr. R. Amato (The Methodist Hospital, TX)
Dr. Paul McQuade (Merck Research Laboratories, PA)
Special Thanks: Group members
Funding: Endocyte Inc, West Lafayette
Department of Chemistry, Purdue University

10. References Ghosh A, Heston, WDJ. Cell Biochem. 2004, 91, 528-539.
Mesters JR, Barinka C, Li W. EMBO J. 2006, 25,
Kozikowski AP, Zhang J, Nan FJ. Med. Chem. 2004, 47,
Jackson PF, Slusher BS. Curr. Med. Chem. 2001; 8,
Low, P. S. & Kularatne, S. A.. PCT/WO
Kularatne, S. A., Zhou, Z., Young, J., Post, C. B. & Low, P. S. Mol. Pharm. 2009, 6, 790–800
Kularatne, S. A., Wang, K., Santhapuram, H-K. R. & Low, P. S. Mol. Pharm. 6,
Slusher, B.S. et al J. Comp. Neurol. 315,
Ghosh, A. et al Cell. Biochem. 91,
Sodee, D.B. et al The Prostate 37,
Thomas, M. A. ;Kularatne, S. A., et. Al. Ann. N.Y. Acad. Sci. 2009, 1175: 32–3
Low, P. S., Wei, H. & Kularatne, S. A. PCT/WO
He, W., Kularatne, S. A., et. al. Int. J. Cancer, 2008, 123,
Kularatne, S. A., Chelvam V., Low P. S. et al. (Manuscript in submission
Kularatne, S. A., Subramanian, B., van Alstine, W.& Low, P. S. (unpublished data)
Young Innovators 2009

11. BIOS/Contact info
Born in Kandy, Sri Lanka, Sumith A. Kularatne graduated from the University of Peradeniya, Sri Lanka, with a B.S. (honors) in the Chemistry Honors program. He earned a master’s degree in organic chemistry from Wichita State University, Kansas, conducting research on synthesis of endo-[n.m.n.m] (n,m ≥ 3) metacyclophanes using Cu(I)-catalyzed cross-coupling/ Grignard system and elucidating of solvent effects in anion binding selectivity and stoichiometry of synthetic anion binding receptors using tri- & tetra-urea picket porphyrins as model systems (supramolecular chemistry). Sumith then earned a Ph.D. in organic/medicinal chemistry from Purdue University in October 2009, conducting research on receptor-mediated drug delivery using small molecular ligands for treatment of cancer and inflammatory diseases under the guidance of Ralph C. Corley Distinguished Professor Philip S. Low. Based on his current research work, he is an inventor on 5 pending patents and a co-author of 10 peer reviewed publications, 2 book chapters, and 12 proceedings/ paper presentations in meetings. He will be working with Prof. Peter G. Shultz at Scripps Research Institute, San Diego for his postdoctoral fellowship from November 2009.
Young Innovators 2009