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BRAIN-SPECIFIC DRUG DELIVERY SYSTEM .pdf
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- 2. INTRODUCTION BLOOD-BRAIN BARRIER DRUG TRANSPORTMECHANISMS AT THE BBB STRATEGIES FOR BRAIN-SPECIFIC DRUG DELIVERY ADVANCED TECHNOLOGIES RECENT MARKETED AND CLINICAL TRIAL DRUGS REFERENCES 2
- 3. INTRODUCTION • The brainis protected by the blood-brain barrier (BBB)Delivering drugs to the brain is challenging due to the BBB’s selectivity. • Brain-specific drug delivery aims to overcome these barriers for effective treatment • Brain-specific delivery, also known as brain-targeted delivery, refers to the process of administering drugs or other therapeutic agents in a way that ensures they reach the brain in therapeutically effective concentrations while minimizing exposure to other parts of the body. 3
- 4. BLOOD-BRAIN BARRIER • Theblood brain barrier (BBB) is a natural protective layer of cells and capillaries creating a selective permeable barrier between the interstitium of the brain and the bloodstream. • It regulates the movement of molecules between the blood and the brain, carefully selecting certain molecules to reach one side or the other. • The BBB thus protects the brain from toxic compounds present in the bloodstream. • This protective barrier ensures a proper supply of nutrients to the brain by allowing molecules like oxygen or glucose to cross and reach the brain tissues 4
- 5. These flat cellsline the blood vessels in the brain and are tightly connected by tight junctions. They lack pores (fenestrations), reducing molecule exchange. Their high number of mitochondria provides energy for selective transport across the blood-brain barrier. These cells wrap around endothelial cells and share a basement membrane. They support tight junction formation, clear toxic substances, and help regulate cerebral blood flow, neuroinflammation, and blood vessel development. Astrocytes are star-shaped support cells with long extensions called end-feet that surround blood vessels. They regulate potassium ions and neurotransmitters, support neuron movement, and contribute to waste clearance and blood flow regulation. Tight junctions are protein complexes that seal the spaces between endothelial cells. They are much tighter in the brain than in other parts of the body, effectively limiting the passage of water, ions, and molecules into the brain tissue. This thin, supportive layer of extracellular matrix is shared by endothelial cells, pericytes, and astrocytes. It offers structural support and contributes to the overall barrier function of the blood-brain barrier. BLOOD-BRAIN BARRIER KEY COMPONENTS 5
- 6. Blood Brain DRUG TRANSPORT MECHANISMSAT THE BBB 6 Lipophilic diffusion Adsorptive- mediated Solute carrier Protein influx Transport Protein-mediated Receptor- mediated Paracellular transport
- 7. STRATEGIES FOR BRAIN-SPECIFICDRUG DELIVERY INVASIVE APPROACHES NON-INVASIVE APPROACHES 7
- 8. INVASIVE APPROACHES • Invasiveapproaches is a direct brain delivery techniques d)Intrathecal Delivery • Injection into the subarachnoid space of the spinal cord • Administered via lumbar puncture or catheter b)Convection-Enhanced Delivery(CED) • A modification of intracerebral injection • Uses positive pressure to distribute drugs over a wider area • Improves delivery of Large molecules a)Intracerebral • Drug is directly injected into brain tissue • Used in conditions like brain tumors or epilepsy • Bypass the BBB completely c)Intracerebroventricular Delivery • Injection into ventricles of the brain, where CSF circulates. • Distribution drug via CSF to the entire CNS. 8
- 9. NON-INVASIVE APPROACHES Non-invasive techniquesaim to deliver drugs to the brain without physically penetrating the skull or spinal cord. These methods bypass or exploit natural pathways of the blood-brain barrier. (BBB) using smart chemical, biological, or physiological approaches. NON- INVASIVE APPROACHES Chemical Modification (Prodrug Approach) Carrier- Mediated Transport (CMT) Receptor- Mediated Transport (RMT) Nanoparticl e-Based Delivery Intranasal Drug Delivery Exosome- Based Delivery 9
- 10. NON-INVASIVE APPROACHES Chemical Modification(Prodrug Approach) An inactive or less active compound (prodrug) is chemically modified to cross the BBB and later converted into the active drug inside the brain. Clinical Example: • L-DOPA (crosses BBB) → converted to Dopamine • Valacyclovir → Acyclovir (brain infections) 10
- 11. Carrier-Mediated Transport (CMT) Thatutilizes specific transporter proteins present on the blood-brain barrier (BBB) to carry small, drug-like molecules into the brain. Mechanism • The BBB contains specialized transporters GLUT1,LAT1,SVCT2 • Transporters recognize and carry the drug into the brain just like a nutrient. Example L-DOPA is transported via LAT1 transporter NON-INVASIVE APPROACHES 11
- 12. NON-INVASIVE APPROACHES Receptor-Mediated Transport(RMT) That uses specific receptors on the blood-brain barrier (BBB) to transport large therapeutic molecules like proteins, peptides, or antibodies into the brain. Mechanism of Action • Drugs are linked to ligands (or antibodies) that can bind to specific receptors on the BBB(TfR, IR, LDLR). • The receptor-ligand complex is internalized by endocytosis. • The drug is then transported across endothelial cells and released on the brain side (transcytosis). Example : • Monoclonal antibody delivery in Alzheimer's disease clinical trials. • TfR-targeted nanoparticles for glioblastoma treatment. 12
- 13. NON-INVASIVE APPROACHES Intranasal drugdelivery Intranasal drug delivery is a non-invasive technique where drugs are administered through the nasal cavity to reach the brain via olfactory and trigeminal nerve pathways, bypassing the blood-brain barrier (BBB). Mechanism of Action Drug is transported directly to the brain via: • Olfactory nerve (to olfactory bulb) • Trigeminal nerve (to brainstem and spinal cord) Example • Insulin-Alzheimer's disease (clinical trials) • Ketamine-Depression (FDA approved nasal spray) 13
- 14. NON-INVASIVE APPROACHES Nanocarriers inNon-Invasive Delivery Nanocarriers are nano-sized drug delivery systems (typically 1–100 nm) designed to encapsulate or attach drugs, protect them from degradation, and enhance their delivery to the brain — often through non-invasive routes like intravenous, oral, or intranasal Nanocarriers help transport drugs across or bypass the BBB using: • Passive diffusion • Active targeting (e.g., receptor-mediated transport) • Intranasal pathway Example • Doxorubicin-Brain cancer (glioblastoma)- Liposomes, SLNs • Rivastigmine-Alzheimer’s treatment-Chitosan NPs (intranasal) • Paclitaxel-Brain tumor targeting-PEGylated NPs 14
- 15. Advanced Technologies inBrain-Specific Drug Delivery EXOSOME AI AND MACHINE LEARNING GENE EDITING and CRRISPR 3D PRINTED NANO CARRIER SYSTEM FOCUSED ULTRASOUND 15
- 16. ADVANCED TECHNOLOGIES INBRAIN-SPECIFIC DRUG DELIVERY Technology Key Advantage Brain-Specific Benefit Exosome-based delivery Natural, immune-evasive Easily crosses BBB AI-driven modeling Predictive, fast Optimizes nanocarrier design CRISPR/gene editing delivery Genetic correction Treats root causes of brain diseases Focused ultrasound & MENPs External control Temporarily opens BBB safely 3D printed delivery systems Customizable Personalized brain-targeted therapies 16
- 17. RECENT MARKETED ANDCLINICAL TRIAL DRUGS Drug Name Technology Used Status Disease Targeted Aducanumab Ligand-targeted antibody (RMT) Marketed Alzheimer’s Nasal Insulin Intranasal delivery Phase II/III Alzheimer’s NBTXR3 Radiation-activated nanoparticles Trials Brain tumors ExoThera Exosome delivery of RNA/protein Preclinical Glioblastoma, neuroinflammation AI-designed drugs AI modeling & BBB prediction Preclinical CNS disorders DNL310 Antibody-fusion transport system Phase II/III Hunter syndrome FUS + Doxorubicin Focused ultrasound BBB opening Clinical Trial Brain tumors ONCR-177 Oncolytic virus in nanoparticle platform Trials Glioblastoma 17
- 18. • Pardridge, W.M.(2012). Drug transport across the blood–brain barrier. J. Cereb. Blood Flow Metab., 32(11), 1959–1972. • Banks, W.A. (2016). From blood–brain barrier to blood–brain interface: new opportunities for CNS drug delivery. Nat. Rev. Drug Discov., 15(4), 275–292. • Patel, M.M., & Patel, B.M. (2017). Crossing the blood–brain barrier: recent advances in drug delivery to the brain. CNS Drugs, 31(2), 109–133. • Chen, Y., & Liu, L. (2012). Modern methods for delivery of drugs across the blood–brain barrier. Adv. Drug Deliv. Rev., 64(7), 640–665. • Jafari, M. et al. (2022). Artificial intelligence in targeted brain drug delivery: Concepts and challenges. J. Pharm. Sci., 111(1), 15–30. • ClinicalTrials.gov. (2024). A Study of Focused Ultrasound with Doxorubicin for Glioblastoma. Available at: https://clinicaltrials.gov/ • FDA. (2021). Approval of Aducanumab for Alzheimer's Disease. U.S. Food and Drug Administration. Available at: https://www.fda.gov 18