A prodrug-doped cellular Trojan Horse for the potential treatment of prostate cancer

Biomaterials

Volumn 91, Issue , 2016, Pages 140-150

  Levy, Oren ^a,b,c,d   Brennen, W Nathaniel ^e   Han, Edward ^a,b,c,d   Rosen, David Marc ^e   Musabeyezu, Juliet ^a,b,c,d   Safaee, Helia ^a,b,c,d   Ranganath, Sudhir ^a,b,c,d   Ngai, Jessica ^a,b,c,d   Heinelt, Martina ^a,b,c,d   Milton, Yuka ^a,b,c,d   Wang, Hao ^e   Bhagchandani, Sachin H ^a,b,c,d   Joshi, Nitin ^a,b,c,d   Bhowmick, Neil ^f   Denmeade, Samuel R ^e   Isaacs, John T ^e   Karp, Jeffrey M ^a,b,c,d  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c HARVARD STEM CELL INSTITUTE   (United States)

^d HARVARD MIT DIVISION OF HEALTH SCIENCES AND TECHNOLOGY   (United States)

^e JOHNS HOPKINS UNIVERSITY   (United States)

^f CEDARS SINAI MEDICAL CENTER   (United States)

Author keywords

Cell based drug delivery; Prostate cancer; Stem cells

Indexed keywords

ANTIGENS; CELL ENGINEERING; CELLS; CYTOLOGY; DISEASES; FLOWCHARTING; GENETIC ENGINEERING; STEM CELLS; UROLOGY;

CELL-BASED DRUG DELIVERIES; HUMAN MESENCHYMAL STEM CELLS; POLY(LACTIC-CO-GLYCOLIC ACID); PROOF OF PRINCIPLES; PROSTATE CANCERS; PROSTATE SPECIFIC ANTIGEN; SYSTEMIC DELIVERIES; THERAPEUTIC AGENTS;

CELL CULTURE;

G 114; POLYGLACTIN; PRODRUG; PROSTATE SPECIFIC ANTIGEN; THAPSIGARGIN; UNCLASSIFIED DRUG; ANTINEOPLASTIC AGENT; LACTIC ACID; POLYGLYCOLIC ACID; POLYLACTIC ACID-POLYGLYCOLIC ACID COPOLYMER;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CANCER GROWTH; CANCER INHIBITION; CONTROLLED STUDY; ENCAPSULATION; HUMAN; HUMAN CELL; MACROMOLECULE; MALE; MESENCHYMAL STEM CELL; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROSTATE CANCER; ANIMAL; CELL CULTURE; CHEMISTRY; CYTOLOGY; DRUG DELIVERY SYSTEM; DRUG EFFECTS; MESENCHYMAL STEM CELL TRANSPLANTATION; MESENCHYMAL STROMA CELL; METABOLISM; NUDE MOUSE; PATHOLOGY; PROCEDURES; PROSTATE; PROSTATIC NEOPLASMS; TUMOR CELL LINE;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL LINE, TUMOR; CELLS, CULTURED; DRUG DELIVERY SYSTEMS; HUMANS; LACTIC ACID; MALE; MESENCHYMAL STEM CELL TRANSPLANTATION; MESENCHYMAL STROMAL CELLS; MICE, NUDE; POLYGLYCOLIC ACID; PRODRUGS; PROSTATE; PROSTATE-SPECIFIC ANTIGEN; PROSTATIC NEOPLASMS;

EID: 84961833526     PISSN: 01429612     EISSN: 18785905     Source Type: Journal    
DOI: 10.1016/j.biomaterials.2016.03.023     Document Type: Article

References (84)

1. Briganti A., Suardi N., Gallina A., Abdollah F., Novara G., Ficarra V., Montorsi F. Predicting the risk of bone metastasis in prostate cancer. Cancer Treat. Rev. 2014, 40:3-11.
2. Cooper C.R., Chay C.H., Pienta K.J. The role of alpha(v)beta(3) in prostate cancer progression. Neoplasia 2002, 4:191-194.
3. Jin J.-K., Dayyani F., Gallick G.E. Steps in prostate cancer progression that lead to bone metastasis. Int. J. Cancer 2011, 128:2545-2561.
4. Agarwal N., Di Lorenzo G., Sonpavde G., Bellmunt J. New agents for prostate cancer. New agents for prostate cancer 2014, 25(9):1700-1709.
5. Dayyani F., Gallick G.E., Logothetis C.J., Corn P.G. Novel therapies for metastatic castrate-resistant prostate cancer. J. Natl. Cancer Inst. 2011, 103:1665-1675.
6. Lin, J., Sinibaldi, V.J., Carducci, M.A., Denmeade, S., Song, D., Deweese, T., Eisenberger, M.A. PhAse I trial with a combination of docetaxel and 153Sm-Lexidronam in patients with castration-resistant metastatic prostate Cancer. Urol. Oncol. 29, 670-675.
7. Oudard S. Progress in emerging therapies for advanced prostate cancer. Cancer Treat. Rev. 2013, 39:275-289.
8. Roth J.C., Curiel D.T., Pereboeva L. Cell vehicle targeting strategies. Gene Ther. 2008, 15:716-729.
9. Peer D., Karp J.M., Hong S., Farokhzad O.C., Margalit R., Langer R. Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2007, 2:751-760.
10. Ernsting M.J., Murakami M., Roy A., Li S.-D. Factors controlling the pharmacokinetics, biodistribution and intratumoral penetration of nanoparticles. J. Control. Release 2013, 172:782-794.
11. Dawidczyk C.M., Kim C., Park J.H., Russell L.M., Lee K.H., Pomper M.G., Searson P.C. State-of-the-art in design rules for drug delivery platforms: lessons learned from FDA-approved nanomedicines. J. Control. Release 2014, 187:133-144.
12. Wong C., Stylianopoulos T., Cui J., Martin J., Chauhan V.P., Jiang W., Popovic Z., Jain R.K., Bawendi M.G., Fukumura D. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc. Natl. Acad. Sci. U. S. A. 2011, 108:2426-2431.
13. Chauhan V.P., Jain R.K. Strategies for advancing cancer nanomedicine. Nat. Mater. 2013, 12:958-962.
14. Brennen W.N., Denmeade S.R., Isaacs J.T. Mesenchymal stem cells as a vector for the inflammatory prostate microenvironment. Endocr. Relat. Cancer 2013, 20:R269-R290.
15. Brennen W.N., Chen S., Denmeade S.R., Isaacs J.T. Quantification of mesenchymal stem cells (MSCs) at sites of human prostate cancer. Oncotarget 2013, 4:106-117.
16. Kidd S., Spaeth E., Dembinski J.L., Dietrich M., Watson K., Klopp A., Battula V.L., Weil M., Andreeff M., Marini F.C. Direct evidence of mesenchymal stem cell tropism for tumor and wounding microenvironments using in vivo bioluminescent imaging. Stem Cells 2009, 27:2614-2623.
17. Ankrum J., Karp J.M. Mesenchymal stem cell therapy: two steps forward, one step back. Trends Mol. Med. 2010, 16:203-209.
18. Ankrum J.A., Ong J.F., Karp J.M. Mesenchymal stem cells: immune evasive, not immune privileged. Nat. Biotechnol. 2014, 32:252-260.
19. Vander Griend D.J., Antony L., Dalrymple S.L., Xu Y., Christensen S.B., Denmeade S.R., Isaacs J.T. Amino acid containing thapsigargin analogues deplete androgen receptor protein via synthesis inhibition and induce the death of prostate Cancer cells. Mol. Cancer Ther. 2009, 8:1340-1349.
20. Denmeade S.R., Jakobsen C.M., Janssen S., Khan S.R., Garrett E.S., Lilja H., Christensen S.B., Isaacs J.T. Prostate-specific antigen-activated thapsigargin prodrug as targeted therapy for prostate cancer. J. Natl. Cancer Inst. 2003, 95:990-1000.
21. Jakobsen C.M., Denmeade S.R., Isaacs J.T., Gady A., Olsen C.E., Christensen S.B. Design, synthesis, and pharmacological evaluation of thapsigargin analogues for targeting apoptosis to prostatic cancer cells. J. Med. Chem. 2001, 44:4696-4703.
22. Denmeade S.R., Isaacs J.T. Engineering enzymatically activated "molecular grenades" for cancer. Oncotarget 2012, 3:666-667.
23. Brawley O.W. Prostate Cancer epidemiology in the United States. World J. Urol. 2012, 30:195-200.
24. Denmeade S.R., Sokoll L.J., Chan D.W., Khan S.R., Isaacs J.T. Concentration of enzymatically active prostate-specific antigen (PSA) in the extracellular fluid of primary human prostate cancers and human prostate cancer xenograft models. Prostate 2001, 48:1-6.
25. Williams S.A., Singh P., Isaacs J.T., Denmeade S.R. Does PSA play a role as a promoting agent during the initiation and/or progression of prostate cancer?. Prostate 2007, 67:312-329.
26. Williams S.A., Jelinek C.A., Litvinov I., Cotter R.J., Isaacs J.T., Denmeade S.R. Enzymatically active prostate-specific antigen promotes growth of human prostate cancers. Prostate 2011, 71:1595-1607.
27. Denmeade S.R., Lou W., Lovgren J., Malm J., Lilja H., Isaacs J.T. Specific and efficient peptide substrates for assaying the proteolytic activity of prostate-specific antigen. Cancer Res. 1997, 57:4924-4930.
28. Denmeade S.R., Isaacs J.T. The SERCA pump as a therapeutic target: making a "smart bomb" for prostate cancer. Cancer Biol. Ther. 2005, 4:14-22.
29. Tombal B., Weeraratna A.T., Denmeade S.R., Isaacs J.T. Thapsigargin induces a calmodulin/calcineurin-dependent apoptotic cascade responsible for the death of prostatic cancer cells. Prostate 2000, 43:303-317.
30. Brøgger Christensen S., Andersen A., Kromann H., Treiman M., Tombal B., Denmeade S., Isaacs J.T. Thapsigargin analogues for targeting programmed death of androgen-independent prostate cancer cells. Bioorg. Med. Chem. 1999, 7:1273-1280.
31. Lin X.S., Denmeade S.R., Cisek L., Isaacs J.T. Mechanism and role of growth arrest in programmed (apoptotic) death of prostatic cancer cells induced by thapsigargin. Prostate 1997, 33:201-207.
32. Christensen S.B., Skytte D.M., Denmeade S.R., Dionne C., Møller J.V., Nissen P., Isaacs J.T. A Trojan Horse in drug development: targeting of thapsigargins towards prostate cancer cells. Anticancer. Agents Med. Chem. 2009, 9:276-294.
33. Jain R.A. The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices. Biomaterials 2000, 21:2475-2490.
34. Jain R.A., Rhodes C.T., Railkar A.M., Malick A.W., Shah N.H. Comparison of various injectable protein-loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices: in-situ-formed implant versus in-situ-formed microspheres versus isolated microspheres. Pharm. Dev. Technol. 2000, 5:201-207.
35. Jain R.K., Stylianopoulos T. Delivering nanomedicine to solid tumors. Nat. Rev. Clin. Oncol. 2010, 7:653-664.
36. Sarkar D., Ankrum J.a, Teo G.S.L., Carman C.V., Karp J.M. Cellular and extracellular programming of cell fate through engineered intracrine-, paracrine-, and endocrine-like mechanisms. Biomaterials 2011, 32:3053-3061.
37. Ankrum J.A., Dastidar R.G., Ong J.F., Levy O., Karp J.M. Performance-enhanced mesenchymal stem cells via intracellular delivery of steroids. Sci. Rep. 2014, 4:4645.
38. Ankrum J.A., Miranda O.R., Ng K.S., Sarkar D., Xu C., Karp J.M. Engineering cells with intracellular agent-loaded microparticles to control cell phenotype. Nat. Protoc. 2014, 9:233-245.
39. Cohen S., Yoshioka T., Lucarelli M., Hwang L.H., Langer R. Controlled delivery systems for proteins based on poly(lactic/glycolic acid) microspheres. Pharm. Res. 1991, 8:713-720.
40. Thomas T.T., Kohane D.S., Wang A., Langer R. Microparticulate formulations for the controlled release of interleukin-2. J. Pharm. Sci. 2004, 93:1100-1109.
41. Brandy Y., Ononiwu I., Adedeji D., Williams V., Mouamba C., Kanaan Y., Copeland R.L., Wright D.A., Butcher R.J., Denmeade S.R., et al. Synthesis and cytotoxic activities of some 2-arylnaphtho[2,3-D]oxazole-4,9-Dione derivatives on androgen-dependent (LNCaP) and androgen-independent (PC3) human prostate cancer cell lines. Invest. New Drugs 2012, 30:1709-1714.
42. Cailleau R., Young R., Olivé M., Reeves W.J. Breast tumor cell lines from pleural effusions. J. Natl. Cancer Inst. 1974, 53:661-674.
43. Dalrymple S.L., Becker R.E., Isaacs J.T. The quinoline-3-carboxamide anti-angiogenic agent, tasquinimod, enhances the anti-prostate cancer efficacy of androgen ablation and taxotere without effecting serum PSA directly in human xenografts. Prostate 2007, 67:790-797.
44. Leibowitz-Amit R., Templeton A.J., Alibhai S.M., Knox J.J., Sridhar S.S., Tannock I.F., Joshua A.M. Efficacy and toxicity of abiraterone and docetaxel in octogenarians with metastatic castration-resistant prostate cancer. J. Geriatr. Oncol. 2015, 6:23-28.
45. Kellokumpu-Lehtinen P.L., Hjalm-Eriksson M., Thellenberg-Karlsson C., Astrom L., Franzen L., Marttila T., Seke M., Taalikka M., Ginman C. Toxicity in patients receiving adjuvant docetaxel+hormonal treatment after radical radiotherapy for intermediate or high-risk prostate cancer: a preplanned safety report of the SPCG-13 trial. Prostate Cancer Prost. Dis. 2012, 15:303-307.
46. Pridgen E.M., Langer R., Farokhzad O.C. Biodegradable, polymeric nanoparticle delivery systems for cancer therapy. Nanomed. (Lond). 2007, 2:669-680.
47. Fassas A., Buffels R., Kaloyannidis P., Anagnostopoulos A. Safety of high-dose liposomal daunorubicin (daunoxome) for refractory or relapsed acute myeloblastic leukaemia. Br. J. Haematol. 2003, 122:161-163.
48. 2. Ann. Oncol. 2000, 11:1029-1033.
49. Maeda H. The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting. Adv. Enzyme Regul. 2001, 41:189-207.
50. Alexis F., Pridgen E., Molnar L.K., Farokhzad O.C. Factors affecting the clearance and biodistribution of polymeric nanoparticles. Mol. Pharm. 2008, 5:505-515.
51. Owens D.E., Peppas N.a Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int. J. Pharm. 2006, 307:93-102.
52. Gjorgieva D., Zaidman N., Bosnakovski D. Mesenchymal stem cells for anti-cancer drug delivery. Recent Pat. Anticancer. Drug Discov. 2013, 8:310-318.
53. Roger M., Clavreul A., Venier-Julienne M.C., Passirani C., Sindji L., Schiller P., Montero-Menei C., Menei P. Mesenchymal stem cells as cellular vehicles for delivery of nanoparticles to brain tumors. Biomaterials 2010, 31:8393-8401.
54. Dwyer R.M., Kerin M.J. Mesenchymal stem cells and cancer: tumor-specific delivery vehicles or therapeutic targets?. Hum. Gene Ther. 2010, 21:1506-1512.
55. Gao Z., Zhang L., Hu J., Sun Y. Mesenchymal stem cells: a potential targeted-delivery vehicle for anti-cancer drug, loaded nanoparticles. Nanomed. Nanotechnol. Biol. Med. 2013, 9:174-184.
56. Xu C., Mu L., Roes I., Miranda-Nieves D., Nahrendorf M., Ankrum J.a, Zhao W., Karp J.M. Nanoparticle-based monitoring of cell therapy. Nanotechnology 2011, 22:494001.
57. Xu C., Miranda-Nieves D., Ankrum J.a., Matthiesen M.E., Phillips J.a., Roes I., Wojtkiewicz G.R., Juneja V., Kultima J.R., Zhao W., et al. Tracking mesenchymal stem cells with iron oxide nanoparticle loaded poly(lactide-co-glycolide) microparticles. Nano Lett. 2012, 12:4131-4139.
58. Shah R.B., Mehra R., Chinnaiyan A.M., Shen R., Ghosh D., Zhou M., Macvicar G.R., Varambally S., Harwood J., Bismar T.A., et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res. 2004, 64:9209-9216.
59. Nadal R., Schweizer M., Kryvenko O.N., Epstein J.I., Eisenberger M.A. Small cell carcinoma of the prostate. Nat. Rev. Urol. 2014, 11:213-219.
60. Aparicio A.M., Harzstark A.L., Corn P.G., Wen S., Araujo J.C., Tu S.-M., Pagliaro L.C., Kim J., Millikan R.E., Ryan C., et al. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin. Cancer Res. 2013, 19:3621-3630.
61. Aygun C. Small cell carcinoma of the prostate: a case report and review of the literature. Md. Med. J. 1997, 46:353-356.
62. Nicolete R., dos Santos D.F., Faccioli L.H. The uptake of PLGA micro or nanoparticles by macrophages provokes distinct in vitro inflammatory response. Int. Immunopharmacol. 2011, 11:1557-1563.
63. Menge T., Gerber M., Wataha K., Reid W., Guha S., Cox C.S., Dash P., Reitz M.S., Khakoo A.Y., Pati S. Human mesenchymal stem cells inhibit endothelial proliferation and angiogenesis via cell-cell contact through modulation of the VE-cadherin/β-catenin signaling pathway. Stem Cells Dev. 2012, 22. 120626080437008.
64. Otsu K., Das S., Houser S.D., Quadri S.K., Bhattacharya S., Bhattacharya J. Concentration-dependent inhibition of angiogenesis by mesenchymal stem cells. Blood 2009, 113:4197-4205.
65. Mariotti M., Colognato R., Rimoldi M., Rizzetto M., Sisto F., Cocce V., Bonomi A., Parati E., Alessandri G., Bagnati R., et al. Mesenchymal stromal cells uptake and release paclitaxel without reducing its anticancer activity. Anticancer. Agents Med. Chem. 2015, 15:400-405.
66. Pascucci L., Coccè V., Bonomi A., Ami D., Ceccarelli P., Ciusani E., Viganò L., Locatelli A., Sisto F., Doglia S.M., et al. Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: a new approach for drug delivery. J. Control. Release 2014, 192:262-270.
67. Pacioni S., D'Alessandris Q.G., Giannetti S., Morgante L., De Pascalis I., Coccè V., Bonomi A., Pascucci L., Alessandri G., Pessina A., et al. Mesenchymal stromal cells loaded with paclitaxel induce cytotoxic damage in glioblastoma brain xenografts. Stem Cell Res. Ther. 2015, 6:194.
68. Pessina A., Leonetti C., Artuso S., Benetti A., Dessy E., Pascucci L., Passeri D., Orlandi A., Berenzi A., Bonomi A., et al. Drug-releasing mesenchymal cells strongly suppress B16 lung metastasis in a syngeneic murine model. J. Exp. Clin. Cancer Res. 2015, 34:82.
69. Pessina A., Coccè V., Pascucci L., Bonomi A., Cavicchini L., Sisto F., Ferrari M., Ciusani E., Crovace A., Falchetti M.L., et al. Mesenchymal stromal cells primed with paclitaxel attract and kill leukaemia cells, inhibit angiogenesis and improve survival of leukaemia-bearing mice. Br. J. Haematol. 2013, 160:766-778.
70. Klopp A.H., Spaeth E.L., Dembinski J.L., Woodward W.a., Munshi A., Meyn R.E., Cox J.D., Andreeff M., Marini F.C. Tumor irradiation increases the recruitment of circulating mesenchymal stem cells into the tumor microenvironment. Cancer Res. 2007, 67:11687-11695.
71. Yu X., Lu C., Liu H., Rao S., Cai J., Liu S., Kriegel A.J., Greene A.S., Liang M., Ding X. Hypoxic preconditioning with cobalt of bone marrow mesenchymal stem cells improves cell migration and enhances therapy for treatment of ischemic acute kidney injury. PLoS One 2013, 8:e62703.
72. Das R., Jahr H., van Osch G.J.V.M., Farrell E. The role of hypoxia in bone marrow-derived mesenchymal stem cells: considerations for regenerative medicine approaches. Tissue Eng. Part B. Rev. 2010, 16:159-168.
73. Ellem S.J., Taylor R.a., Furic L., Larsson O., Frydenberg M., Pook D., Pedersen J., Cawsey B., Trotta A., Need E., et al. A pro-tumourigenic loop at the human prostate tumour interface orchestrated by oestrogen, CXCL12 and mast cell recruitment. J. Pathol. 2014, 234:86-98.
74. Mirzamohammadi S., Aali E., Najafi R., Kamarul T., Mehrabani M., Aminzadeh A., Sharifi A.L.I.M. Effect of 17β-Estradiol on mediators involved in mesenchymal stromal cell trafficking in cell therapy of diabetes. Cytotherapy 2015, 17:46-57.
75. Levy O., Mortensen L.J., Boquet G., Tong Z., Perrault C., Benhamou B., Zhang J., Stratton T., Han E., Safaee H., et al. A small-molecule screen for enhanced homing of systemically infused cells. Cell Rep. 2015, 10:1261-1268.
76. Levy O., Zhao W., Mortensen L.J., Leblanc S., Tsang K., Fu M., Phillips J.A., Sagar V., Anandakumaran P., Ngai J., et al. mRNA-engineered mesenchymal stem cells for targeted delivery of Interleukin-10 to sites of inflammation. Blood 2013, 122:e23-e32.
77. Abrami L., Fivaz M., Van Der Goot F.G. Adventures of a pore-forming toxin at the target cell surface. Trends Microbiol. 2000, 8:168-172.
78. Degiacomi M.T., Iacovache I., Pernot L., Chami M., Kudryashev M., Stahlberg H., van der Goot F.G., Dal Peraro M. Molecular assembly of the aerolysin pore reveals a swirling membrane-insertion mechanism. Nat. Chem. Biol. 2013, 9:623-629.
79. Williams S.a., Merchant R.F., Garrett-Mayer E., Isaacs J.T., Buckley T.J., Denmeade S.R. A prostate-specific antigen-activated channel-forming toxin as therapy for prostatic disease. J. Natl. Cancer Inst. 2007, 99:376-385.
80. Abrami L., Fivaz M., Decroly E., Seidah N.G., Jean F., Thomas G., Leppla S.H., Buckley J.T., van der Goot F.G. The pore-forming toxin proaerolysin is activated by furin. J. Biol. Chem. 1998, 273:32656-32661.
81. Denmeade S.R., Egerdie B., Steinhoff G., Merchant R., Abi-Habib R., Pommerville P. Phase 1 and 2 studies demonstrate the safety and efficacy of intraprostatic injection of PRX302 for the targeted treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia. Eur. Urol. 2011, 59:747-754.
82. Elhilali M.M., Pommerville P., Yocum R.C., Merchant R., Roehrborn C.G., Denmeade S.R. Prospective, randomized, double-blind, vehicle controlled, multicenter phase IIb clinical trial of the pore forming protein PRX302 for targeted treatment of symptomatic benign prostatic hyperplasia. J. Urol. 2013, 189:1421-1426.
83. Brennen W.N., Kisteman L.N., Isaacs J.T. Rapid selection of mesenchymal stem and progenitor cells in primary prostate stromal cultures. Prostate 2016, 76:552-564.
84. Janssen S., Rosen D.M., Ricklis R.M., Dionne C.A., Lilja H., Christensen S.B., Isaacs J.T., Denmeade S.R. Pharmacokinetics, biodistribution, and antitumor efficacy of a human glandular kallikrein 2 (hK2)-activated thapsigargin prodrug. Prostate 2006, 66:358-368.