Howard E. Gendelman, MDLarson Professor of Medicine

and Infectious DiseasesChairman, Department of Pharmacology

and Experimental NeuroscienceDirector, Center of Neurovirology and Neurodegenerative

Disorders

Howard E. Gendelman, MDLarson Professor of Medicine

and Infectious DiseasesChairman, Department of Pharmacology

and Experimental NeuroscienceDirector, Center of Neurovirology and Neurodegenerative

Disorders

Perils of CNS drug deliveryPerils of CNS drug delivery

Points of discussionPoints 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

• 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

ImmunotoxicologyImmunotoxicology• 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

• 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

Immunotoxicity perilsImmunotoxicity 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.

• 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.

Blood-Brain BarrierBlood-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

• 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

BBB perilsBBB 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.

• 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.

Systemic effectsSystemic 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.

• 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.

Systemic toxicities and perilsSystemic 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

• 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

Therapeutic index and pharmacokinetics

Therapeutic index and pharmacokinetics

• Harmful interactions of nanoformu-

lations with biological systems

• Generation of reactive oxygen species

• Pulmonary toxicities

• Release of toxic chemicals

• Skin

• Harmful interactions of nanoformu-

lations with biological systems

• Generation of reactive oxygen species

• Pulmonary toxicities

• Release of toxic chemicals

• Skin

Model for CNS Drug Delivery: Significant promise but perilsModel for CNS Drug Delivery: Significant promise but perils

• neuroAIDS

• Macrophage-based drug delivery

• Potential versus perils

• neuroAIDS

• Macrophage-based drug delivery

• Potential versus perils

ConclusionsConclusions

• Toxicity and drug delivery

systems- Immunological responses

- Generation of neoantigens

- Systemic toxicities

- BBB function

- Neural impairments

- Cell membrane damage

• Toxicity and drug delivery

systems- Immunological responses

- Generation of neoantigens

- Systemic toxicities

- BBB function

- Neural impairments

- Cell membrane damage