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Updated: Jun 10, 2026
Delivery of Therapeutic siRNA to the CNS Using Cationic and Anionic Liposomes
Published on: July 23, 2016
On the future development of optimally-sized lipid-insoluble systemic therapies for CNS solid tumors and other
1National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD, USA. hemantsarin74@gmail.com
Abstract:
It remains a challenge to deliver effective concentrations of therapeutics into CNS pathologies, which is primarily due to the fact that current and investigational CNS therapeutics are suboptimally-sized to accumulate to effective concentrations in individual diseased CNS tissue cells. The blood-CNS barrier of blood capillary microvasculature within neuropathologic tissues is known to be permeable to lipid-insoluble macromolecules in a wide-spectrum of neuropathologies. In the case of CNS solid tumor tissue blood capillaries, the physiological upper limit of pore size to the transcapillary passage of spherical lipid-insoluble macromolecules is approximately 12 nanometers, and systemically administered imageable dendrimer nanoparticles within the 7 to 10 nanometer size range accumulate to therapeutic concentrations in solid tumors since this size range of particles maintain peak blood concentrations for several hours. In preliminary pre-clinical studies, it has recently been shown that one intravenous dose of small molecule chemotherapy-conjugated imageable dendrimer nanoparticles within the 7 to 10 nanometer size range, with doxorubicin bound to the particle exterior via acid-labile covalent linkages, is effective at regressing orthotopic rodent malignant gliomas. Although it is foreseeable that such drug-conjugated imageable nanoparticles within the 7 to 10 nanometer size range will be effective theranostic agents for the concurrent treatment (i.e. neutron capture therapy) and imaging (i.e. magnetic resonance) of solid tumor disease, the issue of maintaining a neutralized particle exterior following the attachment of cationic drugs will need to be addressed to eliminate cationic charge-mediated nanoparticle toxicity to blood capillary walls. In this review, the ultrastructural basis for blood capillary microvascular permeability to lipid-insoluble macromolecules is discussed, and the importance of delineating the precise physiologic upper limits of pore size in the blood capillary microvasculature of other CNS pathologies, including neurodegenerative, inflammatory and ischemic CNS diseases, is emphasized. The discussion herein will serve as guide for the future development of optimally-sized, non-toxic and non-immunogenic lipid-insoluble systemic therapies, which should be the focus of future patent applications and patents on CNS drug development.
Insights
Optimally-sized nanoparticles (7-10 nm) show promise for delivering therapeutics across the blood-CNS barrier to treat brain pathologies like malignant gliomas. Further research is needed to ensure non-toxic, non-immunogenic delivery systems.
Area of Science:
- Nanotechnology
- Neuroscience
- Oncology
Background:
- Delivering therapeutics to the central nervous system (CNS) is challenging due to suboptimal drug sizes.
- The blood-CNS barrier in neuropathologies allows passage of lipid-insoluble macromolecules.
- Blood capillary pore size in CNS tumors limits passage to ~12 nm.
Purpose of the Study:
- To review the ultrastructural basis of blood capillary permeability in the CNS.
- To emphasize the need for precise pore size delineation in various CNS pathologies.
- To guide the development of optimally-sized, non-toxic CNS therapies.
Main Methods:
- Review of literature on blood-CNS barrier permeability.
- Analysis of nanoparticle size and accumulation in CNS solid tumors.
- Discussion of pre-clinical studies using chemotherapy-conjugated dendrimer nanoparticles.
Main Results:
- Imageable dendrimer nanoparticles (7-10 nm) accumulate in solid tumors and regress malignant gliomas in rodents.
- This size range maintains therapeutic concentrations in blood for hours.
- Cationic drug conjugation requires neutralization to prevent toxicity.
Conclusions:
- Optimally-sized (7-10 nm) lipid-insoluble nanoparticles are promising for CNS drug delivery.
- Future CNS therapies should focus on non-toxic, non-immunogenic, and optimally-sized nanoparticles.
- Further research is needed to define pore size limits in diverse CNS diseases for targeted therapy development.
