The use of submicron/nanoscale PLGA implants to deliver paclitaxel with enhanced pharmacokinetics and therapeutic efficacy in intracranial glioblastoma in mice.

Pharmacokinetics and therapeutic efficacy of submicron/nanoscale, intracranial implants were evaluated for treating malignant glioblastoma in mice. 9.1% (w/w) paclitaxel-loaded polylactide-co-glycolide (PLGA) nanofiber discs (F3) were fabricated and characterized for morphology and size distribution. Along with F3, three other formulations, 9.1% (w/w) paclitaxel-loaded PLGA submicron-fiber discs (F2), 16.7% (w/w) paclitaxel-loaded PLGA microspheres entrapped in hydrogel matrices (H80 and M80) were intracranially implanted in BALB/c mice and the coronal brain sections were analyzed for bio-distribution of paclitaxel on 14, 28 and 42 days post-implantation. BALB/c nude mice with intracranial human glioblastoma (U87 MG-luc2) were used in the therapeutic efficacy study. Animals were randomized to intracranial implantation of F3 and H80 with paclitaxel dose of 10mg/kg, placebo F3, placebo H80, weekly intratumoral injection of Taxol (10mg/kg) or no treatment and the treatment response was analyzed by bioluminescence imaging and histological (H&E, Ki-67) examinations. Enhanced, therapeutic paclitaxel penetration (approximately 1 microm) in the mouse brain up to 5mm from the implant site even after 42 days post-implantation from F3 and H80 was confirmed and deduced to be diffusion/elimination controlled. F3 and H80 demonstrated significant (approximately 30 fold) tumor inhibition and significantly low tumor proliferation index after 41 days of treatment in comparison to sham and placebo controls. The submicron/nanoscale implants are able to demonstrate optimal paclitaxel pharmacokinetics in the brain/tumor with significant tumor inhibition in a glioblastoma xenograft model in mice and hence could be potentially useful to treat highly recurrent GBM.

[1]  Chi-Hwa Wang,et al.  Self-Assembled Biodegradable Nanoparticles Developed by Direct Dialysis for the Delivery of Paclitaxel , 2005, Pharmaceutical Research.

[2]  H. Brem,et al.  Biodegradable polymer implants to treat brain tumors. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[3]  Chi-Hwa Wang,et al.  Biodegradable microfiber implants delivering paclitaxel for post-surgical chemotherapy against malignant glioma. , 2008, Biomaterials.

[4]  Henry Brem,et al.  Recent Advances in Brain Tumor Therapy: Local Intracerebral Drug Delivery by Polymers , 2004, Investigational New Drugs.

[5]  W. Saltzman,et al.  Pharmacokinetics of the Carmustine Implant , 2002, Clinical pharmacokinetics.

[6]  S. Piantadosi,et al.  Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas , 1995, The Lancet.

[7]  Lai Yeng Lee,et al.  Paclitaxel delivery from PLGA foams for controlled release in post-surgical chemotherapy against glioblastoma multiforme. , 2009, Biomaterials.

[8]  Edward F Chang,et al.  Focal cortical dysplasia: a review of pathological features, genetics, and surgical outcome. , 2006, Neurosurgical focus.

[9]  J. Benoit,et al.  Effect of stereotactic implantation of biodegradable 5-fluorouracil-loaded microspheres in healthy and C6 glioma-bearing rats. , 1996, Neurosurgery.

[10]  D. Rall,et al.  The Antitumor Agent, 1,3-bis(2-chloroethyl)-1-nitrosourea , 1966 .

[11]  J Verweij,et al.  Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. , 2001, European journal of cancer.

[12]  J. Benoit,et al.  Paclitaxel-loaded microparticles and implants for the treatment of brain cancer: preparation and physicochemical characterization. , 2006, International journal of pharmaceutics.

[13]  A. Göpferich,et al.  Efficacy of BCNU and paclitaxel loaded subcutaneous implants in the interstitial chemotherapy of U-87 MG human glioblastoma xenografts. , 2002, International journal of pharmaceutics.

[14]  P. Burger,et al.  Interstitial taxol delivered from a biodegradable polymer implant against experimental malignant glioma. , 1994, Cancer research.

[15]  W. Saltzman,et al.  Pharmacokinetics of interstitial delivery of carmustine, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer implant in the monkey brain. , 1998, Cancer research.

[16]  Susan M. Chang,et al.  A Phase II study of paclitaxel in patients with recurrent malignant glioma using different doses depending upon the concomitant use of anticonvulsants , 2001, Cancer.

[17]  M. Relling,et al.  Clinical Pharmacokinetics of Paclitaxel , 1994, Clinical pharmacokinetics.

[18]  J. Olson,et al.  Carboplatin-Loaded PLGA Microspheres for Intracerebral Implantation: In Vivo Characterization. , 1997, Drug delivery.

[19]  Christine Kratzel,et al.  Local chemotherapy of F98 rat glioblastoma with paclitaxel and carboplatin embedded in liquid crystalline cubic phases , 2004, Journal of Neuro-Oncology.

[20]  A. Olivi,et al.  Intratumoral chemotherapy. , 1995, Neurosurgery.

[21]  M. Zucchetti,et al.  Do anticancer agents reach the tumor target in the human brain? , 2004, Cancer Chemotherapy and Pharmacology.

[22]  Susan M. Chang,et al.  Intratumoral chemotherapy. Commentaries , 1995 .

[23]  H. Brem,et al.  Local delivery of doxorubicin for the treatment of malignant brain tumors in rats. , 2005, Anticancer research.

[24]  E. Goebel,et al.  Cerebral edema associated with Gliadel wafers: two case studies. , 2005, Neuro-oncology.

[25]  Madan Arora,et al.  Primary brain tumors in adults. , 2008, American family physician.

[26]  R. Schwartz,et al.  Primary brain tumors in adults. , 1992, Seminars in ultrasound, CT, and MR.

[27]  Willem Boogerd,et al.  Increased penetration of paclitaxel into the brain by inhibition of P-Glycoprotein. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[28]  M. Berger,et al.  Phase II study of paclitaxel in patients with recurrent malignant glioma. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  M. Samii,et al.  Biopolymer-mediated suramin chemotherapy in the treatment of experimental brain tumours , 2004, Acta oncologica.

[30]  Susan M. Chang,et al.  Standard treatment and experimental targeted drug therapy for recurrent glioblastoma multiforme. , 2006, Neurosurgical focus.

[31]  Xinguo Jiang,et al.  Aclarubicin‐loaded cationic albumin‐conjugated pegylated nanoparticle for glioma chemotherapy in rats , 2007, International journal of cancer.

[32]  K. Walter,et al.  Polilactofate microspheres for Paclitaxel delivery to central nervous system malignancies. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[33]  H. Brem,et al.  Local Delivery of Interleukin-2 and Adriamycin is Synergistic in the Treatment of Experimental Malignant Glioma , 2005, Journal of Neuro-Oncology.

[34]  William B. Krantz,et al.  Hydrogel Matrix Entrapping PLGA-Paclitaxel Microspheres: Drug Delivery with Near Zero-Order Release and Implantability Advantages for Malignant Brain Tumour Chemotherapy , 2009, Pharmaceutical Research.

[35]  Chi‐Hwa Wang,et al.  Microparticles developed by electrohydrodynamic atomization for the local delivery of anticancer drug to treat C6 glioma in vitro. , 2006, Biomaterials.

[36]  Kochi,et al.  High-dose chemotherapy with autologous hematopoietic stem-cell rescue for patients with malignant brain tumors. , 1999, Critical reviews in neurosurgery : CR.

[37]  Chi-Hwa Wang,et al.  Chemotherapeutic drug transport to brain tumor. , 2009, Journal of controlled release : official journal of the Controlled Release Society.