Investigation of intravenous delivery of nanoliposomal topotecan for activity against orthotopic glioblastoma xenografts.

Achieving effective treatment outcomes for patients with glioblastoma (GBM) has been impeded by many obstacles, including the pharmacokinetic limitations of antitumor agents, such as topotecan (TPT). Here, we demonstrate that intravenous administration of a novel nanoliposomal formulation of TPT (nLS-TPT) extends the survival of mice with intracranial GBM xenografts, relative to administration of free TPT, because of improved biodistribution and pharmacokinetics of the liposome-formulated drug. In 3 distinct orthotopic GBM models, 3 weeks of biweekly intravenous therapy with nLS-TPT was sufficient to delay tumor growth and significantly extend animal survival, compared with treatment with free TPT (P ≤ .03 for each tumor tested). Analysis of intracranial tumors showed increased activation of cleaved caspase-3 and increased DNA fragmentation, both indicators of apoptotic response to treatment with nLS-TPT. These results demonstrate that intravenous delivery of nLS-TPT is a promising strategy in the treatment of GBM and support clinical investigation of this therapeutic approach.

[1]  C. James,et al.  Systemic and Local Drug Delivery for Treating Diseases of the Central Nervous System in Rodent Models , 2010, Journal of visualized experiments : JoVE.

[2]  M. Prados,et al.  Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. , 2010, Cancer research.

[3]  C. Rudin,et al.  A phase I study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in solid tumor malignancies , 2010, Cancer Chemotherapy and Pharmacology.

[4]  S. Gabriel,et al.  Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. , 2010, Cancer cell.

[5]  Ceirin M. Connolly-Ingram,et al.  Development of a highly stable and targetable nanoliposomal formulation of topotecan. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[6]  R. McLendon,et al.  Phase II trial of temozolomide (TMZ) plus irinotecan (CPT-11) in adults with newly diagnosed glioblastoma multiforme before radiotherapy , 2009, Journal of Neuro-Oncology.

[7]  Y. Ko,et al.  A phase III trial of topotecan and whole brain radiation therapy for patients with CNS-metastases due to lung cancer , 2009, British Journal of Cancer.

[8]  John W. Park,et al.  Pharmacokinetics and in vivo drug release rates in liposomal nanocarrier development. , 2008, Journal of pharmaceutical sciences.

[9]  Mitchel S Berger,et al.  Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors. , 2008, Neuro-oncology.

[10]  Yoji Yamashita,et al.  Canine model of convection-enhanced delivery of liposomes containing CPT-11 monitored with real-time magnetic resonance imaging: laboratory investigation. , 2008, Journal of neurosurgery.

[11]  M. Berger,et al.  Bioluminescence monitoring of intracranial glioblastoma xenograft: response to primary and salvage temozolomide therapy. , 2007, Journal of neurosurgery.

[12]  C. James,et al.  Identification of molecular characteristics correlated with glioblastoma sensitivity to EGFR kinase inhibition through use of an intracranial xenograft test panel , 2007, Molecular Cancer Therapeutics.

[13]  M. Berger,et al.  Convection-enhanced delivery of Ls-TPT enables an effective, continuous, low-dose chemotherapy against malignant glioma xenograft model. , 2006, Neuro-oncology.

[14]  John W. Park,et al.  Development of a highly active nanoliposomal irinotecan using a novel intraliposomal stabilization strategy. , 2006, Cancer research.

[15]  M. Berger,et al.  Novel nanoliposomal CPT-11 infused by convection-enhanced delivery in intracranial tumors: pharmacology and efficacy. , 2006, Cancer research.

[16]  Koji Yoshimoto,et al.  Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. , 2005, The New England journal of medicine.

[17]  C. James,et al.  Patient tumor EGFR and PDGFRA gene amplifications retained in an invasive intracranial xenograft model of glioblastoma multiforme. , 2005, Neuro-oncology.

[18]  R. Shoemaker,et al.  Schedule-dependent Inhibition of Hypoxia-inducible Factor-1α Protein Accumulation, Angiogenesis, and Tumor Growth by Topotecan in U251-HRE Glioblastoma Xenografts , 2004, Cancer Research.

[19]  M. Berger,et al.  Extensive Distribution of Liposomes in Rodent Brains and Brain Tumors Following Convection-Enhanced Delivery , 2004, Journal of Neuro-Oncology.

[20]  M. Berger,et al.  Distribution of Liposomes into Brain and Rat Brain Tumor Models by Convection-Enhanced Delivery Monitored with Magnetic Resonance Imaging , 2004, Cancer Research.

[21]  P. Cullis,et al.  Drug Delivery Systems: Entering the Mainstream , 2004, Science.

[22]  B. Fisher,et al.  Phase II study of topotecan plus cranial radiation for glioblastoma multiforme: results of Radiation Therapy Oncology Group 9513. , 2002, International journal of radiation oncology, biology, physics.

[23]  M. Bally,et al.  Liposomal encapsulation of topotecan enhances anticancer efficacy in murine and human xenograft models. , 2000, Cancer research.

[24]  D. Papahadjopoulos,et al.  Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. , 1999, Pharmacological reviews.

[25]  R. McLendon,et al.  Topotecan treatment of adults with primary malignant glioma , 1999, Cancer.

[26]  A. Lissoni,et al.  Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  N. Freudenberg,et al.  Infiltration of lung carcinomas with macrophages of the 27E10-positive phenotype. , 1997, Lung cancer.

[28]  J. Carmichael,et al.  126 Evaluation of topotecan (Hycamtin™) in relapsed small cell lung cancer (SCLC). A multicentre phase II study , 1997 .

[29]  A Gordon,et al.  Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  E. Eisenhauer,et al.  Phase II study of topotecan in patients with recurrent malignant glioma , 1996 .

[31]  T. Burke,et al.  Reduced albumin binding promotes the stability and activity of topotecan in human blood. , 1995, Biochemistry.

[32]  S. Baker,et al.  Cerebrospinal fluid pharmacokinetics and penetration of continuous infusion topotecan in children with central nervous system tumors , 1995, Cancer Chemotherapy and Pharmacology.

[33]  X. Gao,et al.  Stabilization of topotecan in low pH liposomes composed of distearoylphosphatidylcholine. , 1994, Journal of pharmaceutical sciences.

[34]  D. Harron.  Clinical pharmacokinetics: Concepts and applications (2nd edn.) , 1989 .

[35]  S. Bryson.  Clinical Pharmacokinetics: Concepts and applications. , 1983 .

[36]  G. R. Bartlett.  Phosphorus assay in column chromatography. , 1959, The Journal of biological chemistry.

[37]  John W. Park,et al.  Convection-enhanced delivery of a topoisomerase I inhibitor (nanoliposomal topotecan) and a topoisomerase II inhibitor (pegylated liposomal doxorubicin) in intracranial brain tumor xenografts. , 2007, Neuro-oncology.

[38]  C. Calatozzolo,et al.  In vitro effects of topotecan and ionizing radiation on TRAIL/Apo2L-mediated apoptosis in malignant glioma , 2004, Journal of Neuro-Oncology.

[39]  G. Ross,et al.  Long-term survival in a phase III, randomised study of topotecan versus paclitaxel in advanced epithelial ovarian carcinoma. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[40]  M. Moroni,et al.  5-Methyltetrahydrofolate or 5-formyltetrahydrofolic acid to modulate 5-fluorouracil’s cytotoxic activity in vivo? A phase II study in patients with advanced colon cancer , 1996, Cancer Chemotherapy and Pharmacology.

[41]  E. Eisenhauer,et al.  Phase II study of topotecan in patients with recurrent malignant glioma. National Clinical Institute of Canada Clinical Trials Group. , 1996, Annals of oncology : official journal of the European Society for Medical Oncology.

[42]  S. Sallan,et al.  Phase II evaluation of topotecan for pediatric central nervous system tumors. , 1996, Cancer.

[43]  Malcolm Rowland,et al.  Clinical pharmacokinetics : concepts and applications , 1989 .