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Liposome-mediated therapy of intracranial brain tumors in a rat model
U S Sharma1, A Sharma, R I Chau
1Department of Pharmaceuties, University at Buffalo, State University of New York, Amherst 14260-1200, USA.
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 via liposomes, 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 < or = 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.
Insights
Liposomes effectively deliver doxorubicin (DXR) to rat brain tumors, significantly increasing survival rates. This drug delivery method enhances therapeutic effects by targeting tumor vasculature for improved treatment outcomes.
Area of Science:
- Oncology
- Nanotechnology
- Pharmacology
Background:
- Malignant brain tumors pose significant therapeutic challenges with low survival rates.
- Effective drug delivery to intracranial tumors is limited by the blood-brain barrier and tumor vasculature.
Purpose of the Study:
- To investigate liposome-mediated delivery of doxorubicin (DXR) to rat brain tumors.
- To test the hypothesis that intact liposomes deposit in tumors via compromised vasculature.
- To evaluate therapeutic effects and drug carrier distribution for optimized delivery.
Main Methods:
- Orthotopic 9L gliosarcoma rat model used.
- Treatment with free DXR versus DXR encapsulated in long-circulating liposomes.
- Anti-tumor efficacy assessed by survival time; liposome deposition studied using fluorescently labeled liposomes and confocal microscopy.
Main Results:
- Free DXR was ineffective; liposomal DXR significantly increased median survival by 29% at 17 mg/kg.
- Liposomes preferentially deposited in tumors over normal brain tissue.
- Liposome distribution was non-uniform and concentrated near tumor blood vessels.
Conclusions:
- Liposomes enhance drug delivery and therapeutic efficacy for brain tumors.
- Therapeutic effects likely result from drug release from liposomes extravasated within tumor vasculature and surrounding spaces.
