Comparing monoclonal antibodies and small peptidic hormones for local targeting of malignant gliomas
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A Merlo1, J Mueller-Brand, H R Maecke
1Neurosurgery, Department of Surgery, University Hospitals, Basel, Switzerland. amerlo@uhbs.ch
Abstract:
Monoclonal antibodies, F(ab')2 fragments and peptidic vectors have been clinically tested for systemic and locoregional treatment of malignant gliomas. Since these brain-intrinsic neoplasms are characterized by relentless tumor cell infiltration of normal brain parenchyma, targeting agents require diffusive properties in order to reach invading tumor cell clusters that migrate along vascular clefts and axonal pathways. Tumor uptake was significantly improved by using small peptidic hormone receptors, e.g. modified octreotide, following systemic injections as compared to macromolecules which only led to limited stabilization of the disease. More importantly, biodistribution was found to be superior following direct intratumoral injection by using these small drug-like radioconjugates. Rapid and extensive distribution within 30 minutes was observed in large tumors, even crossing the corpus callosum in bihemispheric lesions following injection of 2-3 ml of the radiopharmakon injected into the center of non-resected tumors. Distribution was far more extensive after direct intratumoral injection as compared to intracavitary injection after surgical debulking. Increased interstitial pressure gradients and the much larger and chaotic structure of the interstitial space of a tumor compared to the extremely tight architecture of normal brain tissue might explain this unexpected biodistribution pattern. Peptidic hormone vectors might become useful agents to deliver radiopharmaceuticals into human invasive gliomas.
Insights
Small peptidic hormone vectors show promise for delivering radiopharmaceuticals to malignant gliomas. Direct intratumoral injection of these agents resulted in rapid and extensive tumor distribution, outperforming larger molecules.
Area of Science:
- Oncology
- Radiopharmacology
- Neuroscience
Background:
- Malignant gliomas infiltrate brain tissue, necessitating targeted therapies with good diffusion properties.
- Current treatments using macromolecules show limited efficacy due to poor tumor penetration.
- Small molecules like peptidic vectors offer potential for improved drug delivery.
Purpose of the Study:
- To evaluate the biodistribution and efficacy of small peptidic hormone vectors for malignant glioma treatment.
- To compare the distribution of peptidic vectors with larger molecules after systemic and locoregional administration.
- To investigate the potential of peptidic vectors as radiopharmaceutical delivery agents.
Main Methods:
- Clinical testing of monoclonal antibodies, F(ab')2 fragments, and peptidic vectors.
- Systemic and locoregional administration of targeting agents.
- Intratumoral and intracavitary injection of radioconjugates in non-resected tumors.
- Analysis of biodistribution and tumor uptake patterns.
Main Results:
- Small peptidic hormone receptors (e.g., modified octreotide) showed improved tumor uptake compared to macromolecules after systemic injection.
- Direct intratumoral injection of small radioconjugates led to rapid and extensive tumor distribution within 30 minutes.
- Distribution extended across the corpus callosum in bihemispheric lesions.
- Intratumoral injection demonstrated superior distribution compared to intracavitary injection post-surgery.
Conclusions:
- Small peptidic hormone vectors exhibit superior biodistribution in malignant gliomas compared to larger agents.
- Direct intratumoral injection of these radioconjugates facilitates rapid and widespread tumor targeting.
- Peptidic hormone vectors represent a promising strategy for delivering radiopharmaceuticals to invasive gliomas.
