[Audio] BME 695N: Engineering Nanomedical Systems (Fall 2007)

James Leary
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This course will cover the basic concepts of design of integrated nanomedical systems for diagnostics and therapeutics. Topics to be covered include: why nanomedical approaches are needed, cell targeting strategies, choice of core nanomaterials, technologies for testing composition and...

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    BME 695N Lecture 19: In vivo model systems to study nanomedical approaches to cancer detection and intervention

    With Deborah Knapp as guest lecturer.

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    BME 695N Lecture 21: FDA and EPA Regulatory Issues

    Outline:Introduction and overview How does the FDA think about nanomedical systems? The 2006 Nanotechnology Task Force Some details of the Nanotechnology Task Force Report General findings of the report Some initial recommendations of the Task Force Where the FDA may need to meet EPA on nanoscale materials Will FDA re-visit GRAS products containing nanomaterials?How will the FDA consider nanomedical systems? Nanomedical systems are integrated nanoscale drug and drug delivery devices Either a drug or a device? How about a "Combination Product"? Drug-Biologic combination productsEPA and other regulatory agency issues Assessing environmental impact of emerging nanotechnologies Concept of life cycle assessment (LCA) Toxicity of nanomaterials Some recommendations of the 2006 International Conference on Nanotechnology and Life Cycle AssessmentNanotechnologies and the workplace NIOSH – Formulating workplace safety standards for nanotechnology Protecting workers in the workplace Assessing hazards in the workplace Establishing a Nanotechnology Safety SystemThe future of nano-healthcare products

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    BME 695N Lecture 20: GMP and issues of quality control manufacture of nanodelivery systems

    Outline:Overview What does cGMP mean? Why GMP? Controlling processes means more predictable outcomes… Enforcement What can be learned from the semi-conductor industry clean-room and manufacturing? What doesn’t fit this paradigm?cGMP-level manufacturing Predictable methods lead to predictable products The CFR (Code of Federal Regulations) sections on GMPs What is covered under cGMP?Bionanomanufacturing So what is special about biomanufacturing? Nano-clean water necessary for nano-pharmaceuticals Contaminants at the nano-level Can you scale up the process?Some quality control issues – how to test Correctness of size – size matters! Composition – atomic level analyses Monodispersity versus agglomeration Order and correctness of layers Correctness of zeta potentials Does the nanomedical system contain the correct payload? Targeting (and mis-targeting) specificity and sensitivity

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    BME 695N Lecture 18: Designing nanodelivery systems for in-vivo use

    Outline:Overview – the in-vitro to ex-vivo to in-vivo paradigm In-vitro - importance of choosing suitable cell lines Ex-vivo – adding the complexity of in-vivo background while keeping the simplicity of in-vitro In-vivo - all the complexity of ex-vivo plus the “active” components of a real animalIn-vivo systems are open, “active” systems with multiple layers of complexity In-vitro and ex-vivo are mostly “closed” systems, but not absolutely What is an “open” system? Attempts to isolate open systemsLayers of complexity of in-vivo systems Human cells in nude mice – a mixture of in-vitro and in-vivo “Model” small animal systems Bbetter model larger animal systemsExamples of the in-vitro to in-vivo experimental pathway Kopelman group – multifunctional NPs for MRI and photodynamic therapy Langer group – aptamer-targeted NPs for cancer therapy in-vivo Leary group – peptide-guided NPs to human tumors in nude mice magnetic nanoparticles as MRI contrast agents in tissue phantoms

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    BME 695N Lecture 17: Assessing nanotoxicity at the single cell level

    Outline:Outline – the need for single cell measures of nanotoxicity There is more than one way for a cell to die... Necrosis" vs. "Apoptosis" There are other forms of "toxicity" Some other challenges in measuring toxicity of nanomaterialsNecrosis vs. Apoptosis mechanisms Necrosis is unplanned "cell injury" Apoptosis is planned "programmed cell death" Why it is important to distinguish between necrosis and apoptosisSingle cell assays for necrosis and apoptosis Dye exclusion assays for necrosis TUNEL assays for late apoptosis Annexin V assays for early apoptosis COMET assays for DNA damage and repair Light scatter assaysNanotoxicity in vivo – some additional challenges Single cell nanotoxicity, plus.... Accumulations of nanoparticles can change toxicity locally to tissues and organs Filtration issues of nanoparticles – size matters – toxicity to liver and lung

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    BME 695N Lecture 16: Assessing drug efficacy at the single cell level

    Outline:Introduction and overviewNanomedical treatment at the single cell level requires evaluation at the single cell levelFor evaluation purposes, does structure reveal function?The difficulty of anything but simple functional assaysThe need for assays which at least show correlation to functional activityQuantitative single cell measurements of one or more proteins per cell by flow and image/confocal cytometryCell surface measures of protein expression on live, single cellsHigh-throughput flow cytometric screening of bioactive compoundsChallenges of measuring protein expression inside fixed, single cellsWhen location is important 2D or 3D imaging is required to get spatial location of proteinsinside cellsQuantitative multiparameter phospho-specific flow cytometryAttempts to measure "functional proteins" by detecting phosphorylationExample of phospho-specific, multiparameter flow cytometryExample of measuring single cell gene silencing by phospho-specific flow cytometryQuantitative measures of gene expression – the promises and the realitiesIs gene expression at the single cell level really possible?Is it even useful to measure a single gene's changes?Gene arrays of purified cell subpopulationsRNA amplification techniques to attempt to perform single cell gene arrays

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    BME 695N Lecture 15: Nanodelivery of therapeutic genes & molecular biosensor feedback control systems

    Outline:Introduction and overviewSome of the advantages of therapeutic genesSome of the advantages of molecular biosensor feedback control systemsWhy a nanodelivery approach is appropriateThe therapeutic gene approachWhat constitutes a "therapeutic gene" ?Transient versus stable expression modesMolecular feedback control systemsDrug delivery has traditionally not used feedback controlsWhy feedback control might be a very good idea!Positive or negative feedback?Molecular Biosensors as a component of a nanomedicine feedback control systemWhat is a molecular biosensor?How a molecular biosensor functions as a therapeutic gene switchBuilding integrated molecular biosensor/gene delivery systems –some examplesRequired componentsExample of a ribozyme/antivirus systemExample of an ARE biosensor/DNA repair system

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    BME 695N Lecture 14: Challenges of proper drug dosing with nanodelivery systems

    Outline:Overview of drug dosing problemProblems of scaling up doses from animal systemsBasing dosing on size, area, weight of recipientVast differences between adults in terms of genetics, metabolismDosing in children – children are NOT smaller adults!Pharmacokinetics – drug distribution, metabolism, excretion, breakdownConventional dosing assumes drug goes everywhere in the bodyTargeted therapies – a model for future nanomedical systems?From the animal dosing to human clinical trialsImportance of picking an appropriate animal model systemDoes drug dosing really scale?The human guinea pig in clinical trials and beyondSome drug dosing methodsAttempts to scale up on basis of areaAttempts to scale up on weight/volumeAttempts to use control engineering principlesGenetic responses to drug dosingAll humans are not genomically equivalent!Predicting on basis of family tree responsesSNPs, chips, and beyond…predicting individual drug responseAfter the $ 1000 individual genome scan… more closely tailored individual therapiesDosing in the era of directed therapies – a future model for nanomedical systems?How directed therapies change the dosing equationCurrent generation directed antibody therapies dosingSome typical side effects of directed therapiesNanomedical systems are the next generation of directed therapiesMost directed therapies are nonlinear processesCurrent and pending FDA approved directed therapiesSome examples of how a few directed therapies workComplement directed cytotoxicityADCC-mediated adaptive immunity switchAntibody-directed enzyme producing therapyOther ways of controlling dose locallyMagnetic field release of drugsLight-triggered release of drugs

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This course will cover the basic concepts of design of integrated nanomedical systems for diagnostics and therapeutics. Topics to be covered include: why nanomedical approaches are needed, cell targeting strategies, choice of core nanomaterials, technologies for testing composition and...

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