DOI: 10.3109/1061186X.2013.833207
Efficacy of docetaxel conjugates in PSMA expressing PCa 979
1
2. Israeli, RS, Powell CT, Corr JG, et al. Expression of the prostate-
specific membrane antigen. Cancer Res 1994;54:1807–11.
3. Ghosh A, Heston WDW. Tumor target prostate specific membrane
antigen (PSMA) and its regulation in prostate cancer. J Cell
Biochem 2004;91:528–39.
4. Ross JS, Sheehan CE, Fisher HA, et al. Correlation of primary
tumor prostate-specific membrane antigen expression with disease
recurrence in prostate cancer. Clin Cancer Res 2003;9:6357–62.
5. Ni X, Zhang Y, Ribas J, et al. Prostate-targeted radiosensitization
via aptamer-shRNA chimeras in human tumor xenografts. J Clin
Invest 2011;121:2383–90.
even though the P-DTX-mDUPA contains more targeting
moieties than P-DTX-EG -DUPA. These in vivo results show
1
2
1
that the spacer length between targeting moieties and HPMA
copolymer backbone affects the DUPA’s targeting effect, and
concomitantly the treatment efficacy of DTX conjugates
against C4-2 tumor-bearing nu/nu mice. However, it is also
possible that the enhanced treatment effect of P-DTX-
EG -DUPA result from other factors such as the change of
1
1
1
12
morphology and enhanced water solubility of conjugates.
Moreover, histology study showed that the DUPA-targeted
DTX conjugate exhibited no non-specific toxicity to the
treated mice. This formulation design provides a promising
targeted therapeutics for PSMA expressing prostate cancer
treatment. The DUPA-targeted DTX conjugates in this study
may prove the importance of spacer length in targeted drug
delivery, especially when the size of targeting moiety is small.
Further modifications, such as optimizing the targeting
moieties distribution and increasing the number of targeting
moieties per polymer chain, should further enhance the
DUPA targeting effect.
6. Dassie JP, Liu XY, Thomas GS, et al. Systemic administration of
optimized aptamer-siRNA chimeras promotes regression of PSMA-
expressing tumors. Nat Biotechnol 2009;27:839–46.
17. Bagalkot V, Farokhzad OC, Langer R, Jon S. An aptamer-
doxorubicin physical conjugate as a novel targeted drug-delivery
platform. Angew Chem Int Ed 2006;45:8149–52.
1
1
2
2
8. Els a¨ sser-Beile U, Reischl G, Wiehr S, et al. PET imaging of
prostate cancer xenografts with a highly specific antibody against
the prostate-specific membrane antigen. J Nucl Med 2009;50:
6
06–11.
9. Evans MJ, Smith-Jones PM, Wongvipat J, et al. Noninvasive
measurement of androgen receptor signaling with a positron-
emitting radiopharmaceutical that targets prostate-specific mem-
brane antigen. Proc Natl Acad Sci USA 2011;108:9578–82.
0. Henry MD, Wen S, Silva MD, et al. A prostate-specific membrane
antigen targeted monoclonal antibody chemotherapeutic conjugates
designed for the treatment of prostate cancer. Cancer Res 2004;64:
Acknowledgements
7
995–8001.
We thank members of Dr Kope cˇ ek’s laboratory for helpful
discussions and technical support and Dr Els a¨ sser-Beile for
providing the C4-2 tumor cell line and the 3 F/11 antibody.
We acknowledge Karthik Raman in Dr Balagurunathan’s
group and Vasudev Bhonde in Dr Looper’s group for help
with using the microwave instruments.
1. Moffatt S, Papasakelariou C, Wiehle S, Cristiano R. Successful
in vivo tumor targeting of prostate-specific membrane antigen with
a highly efficient J591/PEI/DNA molecular conjugate. Gene
Therapy 2006;13:761–72.
2
2
2
2. Aggarwal S, Singh P, Topaloglu O, et al. A dimeric peptide that
binds selectively to prostate-specific membrane antigen and inhibits
its enzymatic activity. Cancer Res 2006;66:9171–7.
3. Rege K, Patel SJ, Megeed Z, Yarmush ML. Amphipathic peptide-
based fusion peptides and immunoconjugates for the targeted
ablation of prostate cancer cells. Cancer Res 2007;67:6368–75.
4. Kularatne SA, Wang K, Santhapuram HKR, Low PS. Prostate-
specific membrane antigen targeted imaging and therapy of prostate
cancer using a PSMA inhibitor as a homing ligand. Mol
Pharmaceutics 2009;6:780–9.
Declaration of interest
This work is a part of PhD thesis of Zheng-hong Peng at
University of Utah. This work was supported in part by NIH
through grant RO1 CA132831.
2
2
5. Kularatne SA, Venkatesh C, Santhapuram HKR, et al. Synthesis
and biological analysis of prostate-specific membrane antigen-
targeted anticancer prodrugs. J Med Chem 2010;53:7767–77.
6. Sanna V, Pintus G, Bandiera P, et al. Development of polymeric
microbubbles targeted to prostate-specific membrane antigen as
prototype of novel untrasound contrast agents. Mol Pharmaceutics
References
1
.
Siegel R, Naishadham D, Jemal A. Cancer statistics. CA Cancer J
Clin 2013;63:11–30.
2
.
Olson WC, Heston WDW, Rajasekaran AK. Clinical trials of cancer
therapies targeting prostate-specific membrane antigen. Rev Recent
Clin Trials 2007;2:182–90.
2
011;8:748–57.
2
7. Banerjee SR, Pullambhatla M, Byun Y, et al. Sequential SPECT
and optical imaging of experimental models of prostate cancer with
a dual modality inhibitor of the prostate-specific membrane
antigen. Angew Chem Int Ed 2011;50:9167–70.
3
4
.
.
Siegel R, Desantis C, Virgo K, et al. Cancer treatment and
survivorship statistics. CA Cancer J Clin 2012;62:220–41.
Tannock IF, Wit R, Berry WR, et al. Docetaxel plus prednisone or
mitoxantrone plus prednisone for advanced prostate cancer. N Engl
J Med 2004;351:1502–12.
28. Humblet V, Misra P, Bhushan KR, et al. Multivalent scaffolds for
affinity maturation of small molecule cell surface binders and their
application to prostate tumor targeting. J Med Chem 2009;52:
544–50.
5
.
Davis ME, Chen Z, Shin DM. Nanoparticle therapeutics: an
emerging treatment modality for cancer. Nat Rev Drug Disc 2008;
7
:771–82.
29. Maresca KP, Hillier SM, Femia FJ, et al. A series of halogenated
heterodimeric inhibitors of prostate specific membrane antigen
(PSMA) as radiolabeled probes for targeting prostate cancer. J Med
Chem 2009;52:347–57.
30. Liu T, Nedrow-Byers JR, Hopkins MR, Berkman CE. Spacer length
effects on in vitro imaging and surface accessibility of fluorescent
inhibitor of prostate specific membrane antigen. Bioorg Med Chem
2011;21:7013–16.
6.
7.
8.
Duncan R. Polymer conjugates as anticancer nanomedicines. Nat
Rev Cancer 2006;6:688–701.
Kope cˇ ek J. Polymer–drug conjugates: origins, progress to date and
future directions. Adv Drug Delivery Rev 2013;65:49–59.
Kope cˇ ek J, Kope cˇ kov a´ P. Design of polymer-drug conjugates. In:
Kratz F, Senter P, Steinhagen H, eds. Drug delivery in oncology,
Vol. 2, Chapter 17. Weinheim, Germany: Wiley-VCH;
2
012:485–512.
31. Zhou J, Neale JH, Pomper MG, Kozikowski AP. NAAG peptidase
inhibitors and their potential for diagnosis and therapy. Nat Rev
Drug Disc 2005;4:1015–25.
9
.
Yu MK, Park J, Jon S. Targeting strategies for multifunctional
nanoparticles in cancer imaging and therapy. Theranostics 2012;2:
3
–44.
32. Jayaprakash S, Wang X, Heston WD, Kozikowski AP. Design and
synthesis of a PSMA inhibitor-doxorubicin conjugate for targeted
prostate cancer therapy. ChemMedChem 2006;1:299–302.
33. Zhang AX, Murelli RP, Barinka C, et al. A remote arene-binding
site on prostate specific membrane antigen revealed by antibody-
recruiting small molecules. J Am Chem Soc 2010;132:12711–16.
1
1
0. Zhou Y, Kope cˇ ek J. Biological rationale for the design of polymeric
anticancer nanomedicines. J Drug Target 2013;21:1–26.
1. Schulke N, Varlamova OA, Donovan GP, et al. The homodimer of
prostate-specific membrane antigen is a functional target for cancer
therapy. Proc Natl Acad Sci USA 2003;100:12590–5.