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. 2007 Jun 29;9(2):E241–E250. doi: 10.1208/aapsj0902027

Biodegradable intraprostatic doxorubicin implants

Ronnie Ortiz 1, Jessie L-S Au 1,3, Ze Lu 1, Yuebo Gan 1, M Guillaume Wientjes 1,3,✉
PMCID: PMC2751414  PMID: 17907765

Abstract

Systemic chemotherapy is not effective in the treatment of prostate-confined cancer. We developed biodegradable, doxorubicin-loaded cylinders for intraprostatic implantation and evaluated the feasibility of using regional intraprostatic drug therapy to treat prostate-confined cancer. Cylinders were prepared using poly(lactide-co-glycolide) (PLG) or PLG copolymers. The in vitro and in vivo drug release, intraprostatic pharmacokinetics, and histopathology in dogs implanted with the cylinders were studied. The doxorubicin-loaded cylinders made of PLG polymers of 7.9 to 54 kDa molecular weight (MW) had a diameter of ∼800 μm, drug loading of 10% to 30% (wt/wt), and even distribution of crystalline drug throughout the matrix. Burst release varied from 3% to 73%, and 7-day cumulative release from 4% to 90%. Decreasing polymer MW and increasing drug loading were associated with higher initial burst release and overall release rates. The in vivo drug release from cylinders (33-kDa PLG, 30% drug loading) in dog prostates was rapid (∼80% in 48 hours). Spatial drug distribution, visualized using confocal fluorescence microscopy, showed high concentrations confined to the lobule containing the implant (referred to as the implanted lobule), with steep concentration gradients over the septa separating the lobules. Concentrations in the implanted lobule were about 8 times higher than concentrations delivered by an intravenous injection. The implants caused necrotic cell death in the implanted lobule, without damage to prostatic nerve bundles or the urethra. These results indicate the feasibility of using biodegradable PLG cylinders as intraprostatic implants to selectively deliver high drug concentrations to prostate tissue.

Keywords: PLG, doxorubicin, prostate delivery, controlled release, biodegradable implants

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References

  • 1.Pienta KJ, Smith DC. Advances in prostate cancer chemotherapy: a new era begins. CA Cancer J Clin. 2005;55:300–318. doi: 10.3322/canjclin.55.5.300. [DOI] [PubMed] [Google Scholar]
  • 2.Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer statistics, 2003. CA Cancer J Clin. 2003;53:5–26. doi: 10.3322/canjclin.53.1.5. [DOI] [PubMed] [Google Scholar]
  • 3.Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2005;352:1977–1984. doi: 10.1056/NEJMoa043739. [DOI] [PubMed] [Google Scholar]
  • 4.Bracarda S, de Cobelli O, Greco C, et al. Cancer of the prostate. Crit Rev Oncol Hematol. 2005;56:379–396. doi: 10.1016/j.critrevonc.2005.03.010. [DOI] [PubMed] [Google Scholar]
  • 5.Lu-Yao GL, Yao SL. Population-based study of long-term survival in patients with clinically localized prostate cancer. Lancet. 1997;349:906–910. doi: 10.1016/S0140-6736(96)09380-4. [DOI] [PubMed] [Google Scholar]
  • 6.Chen CT, Gan Y, Au JL, Wientjes MG. Androgen-dependent and-independent human prostate xenograft tumors as models for drug activity evaluation. Cancer Res. 1998;58:2777–2783. [PubMed] [Google Scholar]
  • 7.Chen CT, Au JL, Wientjes MG. Pharmacodynamics of doxorubicin in human prostate tumors. Clin Cancer Res. 1998;4:277–282. [PubMed] [Google Scholar]
  • 8.Ikeda R, Chikazawa I, Kobayashi Y, et al. Prophylaxis of recurrence in superficial bladder carcinoma by intravesical chemotherapy—comparative study between instillation of combined double anticancer agents and single anticancer agent. Gan To Kagaku Ryoho. 1999;26:509–514. [PubMed] [Google Scholar]
  • 9.Aigner KR, Gailhofer S, Kopp S. Regional versus systemic chemotherapy for advanced pancreatic cancer: a randomized study. Hepatogastroenterology. 1998;45:1125–1129. [PubMed] [Google Scholar]
  • 10.Beger HG, Link KH, Gansauge F. Adjuvant regional chemotherapy in advanced pancreatic cancer: results of a prospective study. Hepatogastroenterology. 1998;45:638–643. [PubMed] [Google Scholar]
  • 11.Firusian N, Dempke W. An early phase II study of intratumoral P-32 chromic phosphate injection therapy for patients with refractory solid tumors and solitary metastases. Cancer. 1999;85:980–987. doi: 10.1002/(SICI)1097-0142(19990215)85:4<980::AID-CNCR28>3.0.CO;2-H. [DOI] [PubMed] [Google Scholar]
  • 12.McClay EF, Howell SB. A review: intraperitoneal cisplatin in the management of patients with ovarian cancer. Gynecol Oncol. 1990;36:1–6. doi: 10.1016/0090-8258(90)90099-7. [DOI] [PubMed] [Google Scholar]
  • 13.Recio FO, Piver MS, Hempling RE, Driscoll DL. Five-year survival after second-line cisplatin-based intraperitoneal chemotherapy for advanced ovarian cancer. Gynecol Oncol. 1998;68:267–273. doi: 10.1006/gyno.1998.4940. [DOI] [PubMed] [Google Scholar]
  • 14.Sandor V, Stark-Vanes V, Pearson D, et al. Phase II trial of chemotherapy alone for primary CNS and intraocular lymphoma. J Clin Oncol. 1998;16:3000–3006. doi: 10.1200/JCO.1998.16.9.3000. [DOI] [PubMed] [Google Scholar]
  • 15.Orfanos CE, Zouboulis CC, Almond-Roesler B, Geilen CC. Current use and future potential role of retinoids in dermatology. Drugs. 1997;53:358–388. doi: 10.2165/00003495-199753030-00003. [DOI] [PubMed] [Google Scholar]
  • 16.Schneebaum S, Arnold MW, Staubus A, Young DC, Dummond D, Martin EW. Intraperitoneal hyperthermic perfusion with mitomycin C for colorectal cancer with peritoneal metastases. Ann Surg Oncol. 1996;3:44–50. doi: 10.1007/BF02409050. [DOI] [PubMed] [Google Scholar]
  • 17.Ishikawa O, Ohigashi H, Imaoka S, et al. Regional chemotherapy to prevent hepatic metastasis after resection of pancreatic cancer. Hepatogastroenterology. 1997;44:1541–1546. [PubMed] [Google Scholar]
  • 18.Link KH, Gansauge F, Gorich J, Leder GH, Rilinger N, Beger HG. Palliative and adjuvant regional chemotherapy in pancreatic cancer. Eur J Surg Oncol. 1997;23:409–414. doi: 10.1016/S0748-7983(97)93720-3. [DOI] [PubMed] [Google Scholar]
  • 19.Inaba T. Quantitative measurements of prostatic blood flow and blood volume by positron emission tomography. J Urol. 1992;148:1457–1460. doi: 10.1016/s0022-5347(17)36939-2. [DOI] [PubMed] [Google Scholar]
  • 20.Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharm Res. 1993;10:1093–1095. doi: 10.1023/A:1018943613122. [DOI] [PubMed] [Google Scholar]
  • 21.Wientjes MG, Zheng JH, Hu L, Gan Y, Au JL. Intraprostatic chemotherapy: distribution and transport mechanisms. Clin Cancer Res. 2005;11:4204–4211. doi: 10.1158/1078-0432.CCR-04-1969. [DOI] [PubMed] [Google Scholar]
  • 22.Fung LK, Shin M, Tyler B, Brem H, Saltzman WM. Chemotherapeutic drugs released from polymers: distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea in the rat brain. Pharm Res. 1996;13:671–682. doi: 10.1023/A:1016083113123. [DOI] [PubMed] [Google Scholar]
  • 23.Farokhzad OC, Dimitrakov JD, Karp JM, Khademhosseini A, Freeman MR, Langer R. Drug delivery systems in urology—getting “smarter”. Urology. 2006;68:463–469. doi: 10.1016/j.urology.2006.03.069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Au JL, Jang SH, Zheng J, et al. Determinants of drug delivery and transport to solid tumors. J Control Release. 2001;74:31–46. doi: 10.1016/S0168-3659(01)00308-X. [DOI] [PubMed] [Google Scholar]
  • 25.Piskin E. Biodegradable polymers as biomaterials. J Biomater Sci Polym Ed. 1995;6:775–795. doi: 10.1163/156856295x00175. [DOI] [PubMed] [Google Scholar]
  • 26.Yemisci M, Bozdag S, Cetin M, et al. Treatment of malignant gliomas with mitoxantrone-loaded poly (lactide-co-glycolide) microspheres. Neurosurgery. 2006;59:1296–1303. doi: 10.1227/01.NEU.0000245607.99946.8F. [DOI] [PubMed] [Google Scholar]
  • 27.Menei P, Montero-Menei C, Venier MC, Benoit JP. Drug delivery into the brain using poly(lactide-co-glycolide) microspheres. Expert Opin Drug Deliv. 2005;2:363–376. doi: 10.1517/17425247.2.2.363. [DOI] [PubMed] [Google Scholar]
  • 28.Stoeckemann K, Sandow J. Effects of the luteinizing-hormone-releasing hormone (LHRH) antagonist ramorelix (hoe013) and the LHRH agonist buserelin on dimethylbenz anthracene-induced mammary carcinoma: studies with slow-release formulations. J Cancer Res Clin Oncol. 1993;119:457–462. doi: 10.1007/BF01215925. [DOI] [PubMed] [Google Scholar]
  • 29.Santen RJ, Manni A, Harvey H. Gonadotropin releasing hormone (GnRH) analogs for the treatment of breast and prostatic carcinoma. Breast Cancer Res Treat. 1986;7:129–145. doi: 10.1007/BF01806244. [DOI] [PubMed] [Google Scholar]
  • 30.Blom JH, Hirdes WH, Schroder FH, et al. Pharmacokinetics and endocrine effects of the LHR analogue buserelin after subcutaneous implantation of a slow release preparation in prostatic cancer patients. Urol Res. 1989;17:43–46. doi: 10.1007/BF00261050. [DOI] [PubMed] [Google Scholar]
  • 31.Lowseth LA, Gerlach RF, Gillett NA, Muggenburg BA. Age-related changes in the prostate and testes of the beagle dog. Vet Pathol. 1990;27:347–353. doi: 10.1177/030098589002700507. [DOI] [PubMed] [Google Scholar]
  • 32.Zhou T, Lewis H, Foster RE, Schwendeman SP. Development of a multiple-drug delivery implant for intraocular management of proliferative vitreoretinopathy. J Control Release. 1998;55:281–295. doi: 10.1016/S0168-3659(98)00061-3. [DOI] [PubMed] [Google Scholar]
  • 33.Institute of Laboratory Animal Resources (US) Guide for the Care and Use of Laboratory Animals. Washington, DC: National Academy Press; 1996. [Google Scholar]
  • 34.Beijnen JH, Meenhorst PL, van Gijn R, Fromme M, Rosing H, Underberg WJ. HPLC determination of doxorubicin, doxorubicinol and four aglycone metabolites in plasma of AIDS patients. J Pharm Biomed Anal. 1991;9:995–1002. doi: 10.1016/0731-7085(91)80036-9. [DOI] [PubMed] [Google Scholar]
  • 35.Wassermann K, Bundgaard H. Kinetics of the acid-catalyzed hydrolysis of doxorubicin. Int J Pharm. 1983;14:73–78. doi: 10.1016/0378-5173(83)90115-1. [DOI] [Google Scholar]
  • 36.Chen CT, Au JL, Gan Y, Wientjes MG. Differential time dependency of antiproliferative and apoptotic effects of taxol in human prostate tumors. Urol Oncol. 1997;3:11–17. doi: 10.1016/s1078-1439(97)00016-1. [DOI] [PubMed] [Google Scholar]
  • 37.Bugat R, Robert J, Herrera A, et al. Clinical and pharmacokinetic study of 96-h infusions of doxorubicin in advanced cancer patients. Eur J Cancer Clin Oncol. 1989;25:505–511. doi: 10.1016/0277-5379(89)90264-2. [DOI] [PubMed] [Google Scholar]
  • 38.Hu L, Au JL, Wientjes MG. Computational modeling to predict effect of treatment schedule on drug delivery to prostate in humans. Clin Cancer Res. 2007;13:1278–1287. doi: 10.1158/1078-0432.CCR-06-1610. [DOI] [PubMed] [Google Scholar]
  • 39.Brem H. Polymers to treat brain tumours. Biomaterials. 1990;11:699–701. doi: 10.1016/0142-9612(90)90030-T. [DOI] [PubMed] [Google Scholar]
  • 40.Lesniak MS, Upadhyay U, Goodwin R, Tyler B, Brem H. Local delivery of doxorubicin for the treatment of malignant brain tumors in rats. Anticancer Res. 2005;25:3825–3831. [PMC free article] [PubMed] [Google Scholar]
  • 41.Fan H, Dash AK. Effect of cross-linking on the in vitro release kinetics of doxorubicin from gelatin implants. Int J Pharm. 2001;213:103–116. doi: 10.1016/S0378-5173(00)00651-7. [DOI] [PubMed] [Google Scholar]
  • 42.Vigevani A, Williamson M. Doxorubicin. In: Florey K, editor. Analytical Profiles of Drug Substances. New York, NY: Academic Press; 1980. [Google Scholar]
  • 43.Shenderova A, Burke TG, Schwendeman SP. Stabilization of 10-hydroxycamptothecin in poly(lactide-co-glycolide) microsphere delivery vehicles. Pharm Res. 1997;14:1406–1414. doi: 10.1023/A:1012172722246. [DOI] [PubMed] [Google Scholar]
  • 44.Sylvester J, Blasko JC, Grimm P, Ragde H. Interstitial implantation techniques in prostate cancer. J Surg Oncol. 1997;66:65–75. doi: 10.1002/(SICI)1096-9098(199709)66:1<65::AID-JSO13>3.0.CO;2-N. [DOI] [PubMed] [Google Scholar]
  • 45.Tapen EM, Blasko JC, Grimm PD, et al. Reduction of radioactive seed embolization to the lung following prostate brachytherapy. Int J Radiol Oncol Biol Phys. 1998;42:1063–1067. doi: 10.1016/S0360-3016(98)00353-8. [DOI] [PubMed] [Google Scholar]
  • 46.Mosby's Drug Consult. doxorubicin. Available at: www.mdconsult. com. Accessed May 29, 2007.
  • 47.Averbach A, Stuart OA, Chang D, Sugarbaker PH. Lattice intrahepatic doxorubicin with and without in-flow occlusion: a pharmacokinetic study of direct liver injection. Eur J Surg Oncol. 2000;26:73–79. doi: 10.1053/ejso.1999.0744. [DOI] [PubMed] [Google Scholar]
  • 48.Schrijvers DL. Extravasation: a dreaded complication of chemotherapy. Ann Oncol. 2003;14:iii26–iii30. doi: 10.1093/annonc/mdg744. [DOI] [PubMed] [Google Scholar]

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