caa a22 4500 477127770 CHVBK 20180405111655.0 cr unu---uuuuu 170330e19970801xx s 000 0 eng 10.1023/A:1012136925030 doi (NATIONALLICENCE)springer-10.1023/A:1012136925030 Liposome-Mediated Therapy of Intracranial Brain Tumors in a Rat Model [Elektronische Daten] [Uma Sharma, Amarnath Sharma, Robert Chau, Robert Straubinger] Purpose. Malignant brain tumors represent a serious therapeutic challenge, and survival often is low. We investigated the delivery of doxorubicin (DXR) to rat brain tumors in situ vialiposomes, to test the hypothesis that intact liposomes undergo deposition in intracranial tumor through a compromised blood-tumor vasculature. Both therapeutic effect and intra-tumor drug carrier distribution were evaluated to identify variables in carrier-mediated delivery having impact on therapy. Methods. The rat 9L gliosarcoma tumor was implanted orthotopically in Fischer 344 rats in the caudate-putamen region. The tumor-bearing rats were treated with DXR, either free or encapsulated in long-circulating, sterically-stabilized liposomes. Anti-tumor efficacy was assessed by survival time. In parallel, liposomes labeled with a fluorescent phospholipid analog were injected into tumor-bearing rats. At predetermined intervals, the brains were perfused with fixative, sectioned, and imaged with laser scanning confocal microscope (LSCM) to investigate the integrity of the tumor vascular bed and the intratumor deposition of liposomes. Results. Free DXR given in 3 weekly iv injections was ineffective in increasing the life span of tumor-bearing rats at cumulative doses ≤17 mg/kg, and at the highest dose (17 mg/kg) decreased survival slightly, compared to saline-treated controls. In contrast, DXR encapsulated in long-circulating liposomes mediated significant increases in life span at 17 mg/kg. Rats showed a 29% percent increase in median survival, respectively, compared to saline-control animals. The delay of treatment after tumor implantation was a major determinant of therapeutic effect. Fluorescent liposomes were deposited preferentially in tumor rather than normal brain, and were distributed non-uniformly, in close proximity to tumor blood vessels. Conclusions. Liposomes can be used to enhance delivery of drugs to brain tumors and increase therapeutic effect. The therapeutic effect may arise from release of drug from liposomes extravasated in discrete regions of the tumor vasculature and the extravascular space. Plenum Publishing Corporation, 1997 brain tumor nationallicence liposomes nationallicence drug delivery nationallicence doxorubicin nationallicence confocal fluorescence microscopy nationallicence Sharma Uma The Department of Pharmaceutics, University at Buffalo, State University of New York, 14260-1200, Amherst, New York aut Sharma Amarnath Eli Lilly and Co., 46202, Indianapolis, Indiana aut Chau Robert The Department of Pharmaceutics, University at Buffalo, State University of New York, 14260-1200, Amherst, New York aut Straubinger Robert Department of Pharmaceutics, State University of New York, 539 Cooke Hall, University at Buffalo, 14260-1200, Amherst, New York aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/8(1997-08-01), 992-998 0724-8741 14:8<992 1997 14 11095 https://doi.org/10.1023/A:1012136925030 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012136925030 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Sharma Uma The Department of Pharmaceutics, University at Buffalo, State University of New York, 14260-1200, Amherst, New York aut NATIONALLICENCE 700 1- Sharma Amarnath Eli Lilly and Co., 46202, Indianapolis, Indiana aut NATIONALLICENCE 700 1- Chau Robert The Department of Pharmaceutics, University at Buffalo, State University of New York, 14260-1200, Amherst, New York aut NATIONALLICENCE 700 1- Straubinger Robert Department of Pharmaceutics, State University of New York, 539 Cooke Hall, University at Buffalo, 14260-1200, Amherst, New York aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/8(1997-08-01), 992-998 0724-8741 14:8<992 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer