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Perils of CNS drug delivery

Perils of CNS drug delivery. Howard E. Gendelman, MD Larson Professor of Medicine and Infectious Diseases Chairman, Department of Pharmacology and Experimental Neuroscience Director, Center of Neurovirology and Neurodegenerative Disorders. Points of discussion.

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Perils of CNS drug delivery

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  1. Perils of CNS drug delivery Howard E. Gendelman, MDLarson Professor of Medicine and Infectious DiseasesChairman, Department of Pharmacology and Experimental NeuroscienceDirector, Center of Neurovirology and Neurodegenerative Disorders

  2. Points of discussion • Immune responses to foreign materials and neoantigens • Blood brain barrier (BBB) and neurotoxicity • Systemic (peripheral) toxicities, free radical formation • Cell membrane, toxic chemicals, free radicals, DNA damage, protein denaturation

  3. Immunotoxicology • Chemicals need to be evaluated for immune responses • These include genetic, neurotoxic, teratogenic, and nephrotoxic effects. • Epidemiological factors for carcinogens, biomarkers, and effects on the elderly. • The immune system is vulnerable to toxins. Lymphoid proliferation and differentiation can be affected along with thymocytes and bone marrow cells

  4. Immunotoxicity perils • Synthetic polymer-based drug-delivery systems were available for > 20 years but few are used in the clinic. • Control of in vivo administration and host responses. • Polymer-based systems with unpredictable and “potential” fatal responses. • Immunotoxicological responses occur to macromolecules.

  5. Blood-Brain Barrier • Delivery of therapeutic compounds is complicated by the BBB. • BBB limits entry of molecules > 400 daltons. • BBB delivery may permit entry of toxins. • Direct injection of drugs to CNS can cause neural and BBB injuries

  6. BBB perils • BBB restricts CNS delivery of drugs and cells. • The CNS poorly accessible to pharmaceutical agents. • CNS disease influences BBB function. • BBB contains drug-efflux-transporters (P-glycoprotein, multi-drug resistant protein, breast cancer resistant protein) that affects drug induced neurotoxic activities.

  7. Systemic effects • Modulation of the BBB (osmotic and chemical openings as transport/carrier systems) can improve CNS drug delivery but cause toxicity. • CNS delivery systems may not access diseased areas. • Toxicities are associated with drug conjugations such as liposomes and nanoparticles.

  8. Systemic toxicities and perils • Delivery systems may themselves provoke untoward biological responses and include: • Polymers - Nasal drug delivery • Liposomes - Peptides • Nanobiotechnologies • Polymeric micelles, polyion complex micelles • BBB modulation strategies and trans-porters including pluronic block copolymers

  9. Therapeutic index and pharmacokinetics • Harmful interactions of nanoformu-lations with biological systems • Generation of reactive oxygen species • Pulmonary toxicities • Release of toxic chemicals • Skin

  10. Model for CNS Drug Delivery: Significant promise but perils • neuroAIDS • Macrophage-based drug delivery • Potential versus perils

  11. Conclusions • Toxicity and drug delivery systems • Immunological responses • Generation of neoantigens • Systemic toxicities • BBB function • Neural impairments • Cell membrane damage

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