Activated microglia targeting dendrimer–minocycline conjugate as therapeutics for neuroinflammation.
Open accessAbstract
Brain-related disorders have outmatched cancer and cardiovascular diseases worldwide as the leading cause of morbidity and mortality. The lack of effective therapies and the relatively dry central nervous system (CNS) drug pipeline pose formidable challenge. Superior, targeted delivery of current clinically approved drugs may offer significant potential. Minocycline has shown promise for the treatment of neurological diseases owing to its ability to penetrate the blood-brain barrier (BBB) and potency. Despite its potential in the clinic and in preclinical models, the high doses needed to affect a positive therapeutic response have led to side effects. Targeted delivery of minocycline to the injured site and injured cells in the brain can be highly beneficial. Systemically administered hydroxyl poly(amidoamine) (PAMAM) generation-6 (G6) dendrimers have a longer blood circulation time and have been shown to cross the impaired BBB. We have successfully prepared and characterized the in vitro efficacy and in vivo targeting ability of hydroxyl-G6 PAMAM dendrimer-9-amino-minocycline conjugate (D-mino). Minocycline is a challenging drug to carry out chemical transformations due to its inherent instability. We used a combination of a highly efficient and mild copper catalyzed azide-alkyne click reaction (CuAAC) along with microwave energy to conjugate 9-amino-minocycline (mino) to the dendrimer surface via enzyme responsive linkages. D-mino was further evaluated for anti-inflammatory and antioxidant activity in lipopolysaccharides-activated murine microglial cells. D-mino conjugates enhanced the intracellular availability of the drug due to their rapid uptake, suppressed inflammatory cytokine tumor necrosis factor α (TNF-α) production, and reduced oxidative stress by suppressing nitric oxide production, all significantly better than the free drug. Fluorescently labeled dendrimer conjugate (Cy5-D-mino) was systematically administered (intravenous, 55 mg/kg) on postnatal day 1 to rabbit kits with a clinically relevant phenotype of cerebral palsy. The in vivo imaging study indicates that Cy5-D-mino crossed the impaired blood-brain barrier and co-localized with activated microglia at the periventricular white matter areas, including the corpus callosum and the angle of the lateral ventricle, with significant implications for positive therapeutic outcomes. The enhanced efficacy of D-mino, when combined with the inherent neuroinflammation-targeting capability of the PAMAM dendrimers, may provide new opportunities for targeted drug delivery to treat neurological disorders.
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Fluorescently labeled dendrimer conjugate Cy5-D-mino crosses the blood-brain barrier more efficiently than free drug.
“fluorescently labeled dendrimer conjugate (Cy5–D-mino) crosses the blood brain barrier much efficiently than free drug”
From Nanotechnology: A Promising Approach for Delivery of Neuroprotective Drugs (2020) · cites this paper as Sharma et al., 2017
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Nanotechnology: A Promising Approach for Delivery of Neuroprotective Drugs
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- Authors
- Sharma, R., Kim, S.-Y., Sharma, A., Zhang, Z., Kambhampati, S. P., Kannan, S., & Kannan, R. M.
- Affiliations
- Johns Hopkins University (US)
- Kennedy Krieger Institute (US)
- Corresponding author
- Kannan, Rangaramanujam M.
- ORCID
- Venue
- Bioconjugate Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-10-27
- Volume
- 28
- Issue
- 11
- Pages
- 2874-2886
- ISSN
- 1043-1802 (ISSN-L)
- 1520-4812
- PMC
- PMC6023550
- OpenAlex
- W2761922521
- Cited by
- 100
- References
- 57
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 6 · 2023: 21 · 2022: 11 · 2021: 13 · 2020: 21 · 2019: 6 · 2018: 8
- FWCI
- 5.47
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Bioconjugate Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Child Health and Human Development (R01 HD076901)
- National Institute of Biomedical Imaging and Bioengineering (R01 EB018306)
- Topics
- Physical Sciences › Materials Science › Polymers and Plastics › Dendrimers and Hyperbranched Polymers
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- minocycline, PAMAM dendrimers, targeted drug delivery, blood-brain barrier, neuroinflammation, cerebral palsy, copper-catalyzed azide-alkyne cycloaddition, anti-TNF therapy, nitric oxide, oxidative stress, fluorescence imaging
- MeSH terms
- Animals, Anti-Inflammatory Agents, Cerebral Palsy, Drug Carriers, Inflammation, Minocycline, Rabbits, Drug Delivery Systems, Microglia, Dendrimers
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