Micro- and Nano- Micro- and Nano- TherapeuticsTherapeutics

Joseph F Chiang

Department of Chemistry and

Biochemistry

State University of New York College at Oneonta

Nanotechnology and Applications

October 16, 2004

Micro- and Nano-TherapeuticsMicro- and Nano-Therapeutics

Nanotechnology –to build matterNanotechnology –to build matter

from atoms/molecules-bottom-up from atoms/molecules-bottom-up technique. technique.

All matters were built historically All matters were built historically with top-down technique.with top-down technique.

Chemistry is a nanotechnology- Chemistry is a nanotechnology- combines atom/molecules to combines atom/molecules to build bulk materials. build bulk materials.

Characteristics of CommonCharacteristics of Common Routes of Drug Routes of Drug

AdministrationAdministration

Quantum Wells, Wire and DotsQuantum Wells, Wire and Dots Quantum wellsQuantum wells: if one dimension is : if one dimension is

reduced to nanoscale while the other reduced to nanoscale while the other two remain large.two remain large.

Quantum wires:Quantum wires: if 2 dimensions if 2 dimensions reduced to nanoscale while the third reduced to nanoscale while the third one remains large.one remains large.

Quantum dots: if all 3 dimensions Quantum dots: if all 3 dimensions reach nanoscalereach nanoscale

Approximate Sizes and Molecular Approximate Sizes and Molecular Weight of several ProteinsWeight of several Proteins

  d=size parameter of fundamental,d=size parameter of fundamental,  biological building block:biological building block:  d=.12(MW)d=.12(MW)1/3 1/3 (nm)(nm)  MW= molecular weight in unit of MW= molecular weight in unit of

dalton.dalton. 

  ProteinProtein MWMW Size Size __________________ Hemoglobin Hemoglobin 68KDa68KDa 4.5x7nm4.5x7nm

  LipoproteinLipoprotein 130KDa130KDa 20 nm 20 nm   -globulin-globulin 90KDa90KDa 4.3x26 nm4.3x26 nm

  FibrinogenFibrinogen 406KDa406KDa 4x76 nm4x76 nm

Polypeptide nanowire:Polypeptide nanowire:In a manner, In a manner,

amino acids amino acids

combinecombine

together in together in

chain by chain by

formation offormation of

peptide bond.peptide bond.

DNA double nanowire:DNA double nanowire:

Basic building block ofBasic building block of

DNA is nucleotide, it isDNA is nucleotide, it is

a five member ringa five member ring

deoxyribose withdeoxyribose with

phosphate group, aphosphate group, a

nucleic acid base R. nucleic acid base R.

Drug Delivery System TechnologiesDrug Delivery System Technologies

Oral Drug DeliveryOral Drug Delivery Injection Based Drug DeliveryInjection Based Drug Delivery Transdermal Drug DeliveryTransdermal Drug Delivery Bone Marrow InfusionBone Marrow Infusion

Organ System Specific DrugOrgan System Specific Drug

Delivery:Delivery:  a. Pulmonary Drug Deliverya. Pulmonary Drug Delivery  b. Nasal Delivery to Centralb. Nasal Delivery to Central  Nervous System(CNS)Nervous System(CNS)  c. Cardiovascular System(CV)c. Cardiovascular System(CV)  d. Gastro-Intestinal tract(GI)d. Gastro-Intestinal tract(GI)  e. Genito-Urinary Tract(GU)e. Genito-Urinary Tract(GU)  f. Ocular Drug Deliveryf. Ocular Drug Delivery

Control Release SystemsControl Release Systems Novel Packaging and Formulations:Novel Packaging and Formulations:  a. Fast Dissolving Tabletsa. Fast Dissolving Tablets  b. Chewable Tabletsb. Chewable Tablets  c. Solubility Enhancementc. Solubility Enhancement

Targeted Drug Delivery:Targeted Drug Delivery:  a. Polymer and Collagen Systema. Polymer and Collagen System  b. Particle-based systemb. Particle-based system  1. Therapeutical Monoclonal 1. Therapeutical Monoclonal   antibodiesantibodies  2. Liposomes2. Liposomes  3. Microparticles3. Microparticles

4. Modified Blood Cells4. Modified Blood Cells  5. Nanoparticles5. Nanoparticles  6. Viral Assisted Intracellular Gene6. Viral Assisted Intracellular Gene  deliverydelivery  7. Non-Viral Intracellular Gene7. Non-Viral Intracellular Gene  deliverydelivery• Implant Drug Delivery SystemImplant Drug Delivery System

Goals of Nano-therapeuticsGoals of Nano-therapeutics

1. Ways to treat Disease1. Ways to treat Disease

2. Implants:

Requirements of Nano therapeutic Requirements of Nano therapeutic ApplicationsApplications

Devices should be non-invasiveDevices should be non-invasive Devices target therapeutics Devices target therapeutics

payloads to site of disease. payloads to site of disease. Devices should maximize Devices should maximize

therapeutic benefit and minimize therapeutic benefit and minimize undesired side effectundesired side effect

Characteristics of TherapeuticCharacteristics of Therapeutic

NanodevicesNanodevices::1. Biological molecule must retain 1. Biological molecule must retain

functions.functions.

2. Device function is the result of the2. Device function is the result of the

activities of device component.activities of device component.

3. The relative organization of device3. The relative organization of device

component drives device function.component drives device function.

4. Device function can be4. Device function can be

unprecedented in the biological unprecedented in the biological

world.world.

Characteristics of NanobiologicalCharacteristics of Nanobiological DeviceDevice1. 1. Minimally invasiveMinimally invasive2. Target sites of disease2. Target sites of disease3. Sense disease states in order to:3. Sense disease states in order to: - report conditions at the disease site to- report conditions at the disease site to clinicians;clinicians; - administer metered therapeutic - administer metered therapeutic interventions.interventions.4. Therapeutic function should be 4. Therapeutic function should be segregated into standard modulessegregated into standard modules5. Modules should be interchangeable to 5. Modules should be interchangeable to tune therapeutic functions.tune therapeutic functions.

BionanotechnologyBionanotechnology

Applications for design and constructApplications for design and construct

materials at nanoscale in materials at nanoscale in biotechnology field.biotechnology field.

Bionanotechnology-from natural Bionanotechnology-from natural enzyme to manipulate genetic code enzyme to manipulate genetic code in order to modify organisms. in order to modify organisms.

Biomaterials –result of application ofBiomaterials –result of application of

bionanotechnology.bionanotechnology.

Biomachines- to design molecular Biomachines- to design molecular machines at nanoscale, for example, machines at nanoscale, for example, study of cancer cells.study of cancer cells.

There are hundred-thousand differentThere are hundred-thousand different

nanomachines inside human body.nanomachines inside human body.

Purpose of Nano-therapeuticsPurpose of Nano-therapeuticsDiscussionsDiscussions

Focused on nanodevices rather than Focused on nanodevices rather than nanomaterials.nanomaterials.Purpose- serves as integral component Purpose- serves as integral component of drug delivery or other clinical of drug delivery or other clinical

devices.devices.Incorporating biological structure intoIncorporating biological structure intonanobiological devices: special nanobiological devices: special

challenge with traditional challenge with traditional engineering design engineering design

NanocontainersNanocontainers

To deliver drug directly to cells.To deliver drug directly to cells.

(The effective drug treatment is (The effective drug treatment is getting the medication to exactly the getting the medication to exactly the right spot)right spot)

Research report in “Science”:Research report in “Science”:

Methods to develop tiny containers of Methods to develop tiny containers of

nanocomposites to distribute drugs tonanocomposites to distribute drugs to

specific spot within individual cells. specific spot within individual cells.

Radoslav Aavic at McGill has developed Radoslav Aavic at McGill has developed two types of polymers- Micelle: two types of polymers- Micelle: Hydrophobic end facing inward, Hydrophobic end facing inward, Hydrophilic end facing outwardHydrophilic end facing outward

Dimension: 20-45 nm.Dimension: 20-45 nm.Using fluorescent light to tack the Using fluorescent light to tack the

micelle’s journey and discovered the micelle’s journey and discovered the tiny container could pass through the tiny container could pass through the wall of a rat cell, but did not enter the wall of a rat cell, but did not enter the cell’s nucleus. It also did not penetrate cell’s nucleus. It also did not penetrate other part of the cell, as mitochondria. other part of the cell, as mitochondria.

Nanoceramic drug delivery Nanoceramic drug delivery systemsystem

  1. Reducing toxicity to non-diseased1. Reducing toxicity to non-diseased  cells cells   2. Increasing drug efficiency2. Increasing drug efficiency  3. Being able to target and control 3. Being able to target and control   drug release with high precisiondrug release with high precision  (Several anti-cancer drugs fail in (Several anti-cancer drugs fail in

their desired clinical activity due to their desired clinical activity due to lack of specific target delivery.)lack of specific target delivery.)

  An Example:An Example:

  Glass microsphere of 17YGlass microsphere of 17Y22OO33-19Al-19Al22OO33--64SiO64SiO22(mol %) composition, 20-30 (mol %) composition, 20-30 m m diameter-effective for targeted diameter-effective for targeted radiotherapy of liver cancer( radiotherapy of liver cancer( 8989Y is Y is non-radioactive, can be activated by non-radioactive, can be activated by neutron bombardment to neutron bombardment to 9090Y, a Y, a --emitter(temitter(t½½=64.1 h)=64.1 h)

NanomedicineNanomedicine

One of the great promises of One of the great promises of nanotechnology- to increase control nanotechnology- to increase control of our personal health.of our personal health.

Understanding of disease-open the Understanding of disease-open the door to therapy for treating disease.door to therapy for treating disease.

  Nanotherapeutic is one the Nanotherapeutic is one the nanotechnology applications in nanotechnology applications in treating disease.treating disease.

Nanotherapeutic devices are Nanotherapeutic devices are created to find the target and to created to find the target and to correct it.correct it.

Immunotoxins-one component Immunotoxins-one component binds to target cells, the other binds to target cells, the other component is the poison that kills component is the poison that kills the cell. the cell.

Liposomes-artificial membranes, Liposomes-artificial membranes, under specific conditions forming under specific conditions forming small, closed vesicles composed of small, closed vesicles composed of a lipid bilayer that encloses a small a lipid bilayer that encloses a small droplet of water.droplet of water.

  Liposome size-20 nm-10Liposome size-20 nm-10m to m to deliver drug.deliver drug.

Gene Therapy- with understanding Gene Therapy- with understanding of human genome, one can of human genome, one can understand and correct genetic understand and correct genetic defect.defect.

Therapy is to correct a missing or Therapy is to correct a missing or defect protein.defect protein.

Current ApplicationsCurrent Applications

Injection of the spheres into a diseased Injection of the spheres into a diseased liver through the hepatic artery liver through the hepatic artery where they are entrapped in small where they are entrapped in small blood vessels to block blood supply blood vessels to block blood supply to cancer cells andto cancer cells and

irradiating irradiating ββ ray to cancerous cells. ray to cancerous cells.

An Example:An Example:

The development of Targeted Nano The development of Targeted Nano Therapeutics(TNT):Therapeutics(TNT):

( by Triton BioSystem with Army ( by Triton BioSystem with Army Research Lab) Research Lab)

(Continue)(Continue)

The TNT system attacks cancer in 3 The TNT system attacks cancer in 3 steps.steps.

1. The patient receives a simple 1. The patient receives a simple infusion containing trillions of infusion containing trillions of bioprobes, each of which is a bioprobes, each of which is a nanoscale magnetic sphere bound nanoscale magnetic sphere bound to an antibody,to an antibody,

2. The bioprobes will seek and attach 2. The bioprobes will seek and attach to cancer cells in the bloodstream,to cancer cells in the bloodstream,

(Continued)(Continued)

3. The physician will switch on the 3. The physician will switch on the magnetic field in the region of the magnetic field in the region of the cancer. This will cause the bioprobes cancer. This will cause the bioprobes to heat up to kill the cancer cells to heat up to kill the cancer cells within minutes.within minutes.

Another example:Another example:

A tumor or cancerous cell can be destroyed A tumor or cancerous cell can be destroyed at 43at 43ooC. Normal cells can be kept alive at C. Normal cells can be kept alive at ~49~49ooC.C.

When ferri- or ferro-magnetite materials are When ferri- or ferro-magnetite materials are implanted, heating at alternating magnetic implanted, heating at alternating magnetic field can kill the cancerous cells. If the field can kill the cancerous cells. If the pore of the magnetic materials is pore of the magnetic materials is decreased to nanoscale, cancer cells can decreased to nanoscale, cancer cells can be destroyed. be destroyed.

Use of ferromagnetic glass ceramic Use of ferromagnetic glass ceramic

containing 36 wt% of containing 36 wt% of magentite(Femagentite(Fe33OO44), 200nm ), 200nm diameter in CaO-SiOdiameter in CaO-SiO22 matrix. matrix.

The cancerous cells in the canal of The cancerous cells in the canal of rabbit tibia were destroyed when rabbit tibia were destroyed when the device is inserted into tibia the device is inserted into tibia and placed under an alternating and placed under an alternating magnetic field of 300 Oe at 100 magnetic field of 300 Oe at 100 KHz.(Kokubo, et al.) KHz.(Kokubo, et al.)

1. Nanotherapeutic Device in Oncology1. Nanotherapeutic Device in Oncology

Existing therepies-surgical, resection, Existing therepies-surgical, resection, radiotherapy, and chemotherapy- radiotherapy, and chemotherapy- unfavorable.unfavorable.Nanotherapeutic devices can be specifically Nanotherapeutic devices can be specifically delivered to tumor by virtue of the size, delivered to tumor by virtue of the size, Therapeutic devices with cytoxins can not Therapeutic devices with cytoxins can not leave the normal cells, but can leak to tumor leave the normal cells, but can leak to tumor

cells.cells.

2. Cardiovascular Application of 2. Cardiovascular Application of Nanotherepeutics:Nanotherepeutics:

Current tissue engineering Current tissue engineering approaches involve synthesis of 3-D, approaches involve synthesis of 3-D, porous scaffolds that allow, adhesion, porous scaffolds that allow, adhesion, growth, and proliferation of seeded growth, and proliferation of seeded cells to generate functional vessel.cells to generate functional vessel.

MEMS technology and nanoscale MEMS technology and nanoscale control of molecular events control of molecular events &interaction has been applied to the &interaction has been applied to the development of cardiovascular development of cardiovascular sensors. sensors.

3. Nanotherapeutics & Specific3. Nanotherapeutics & Specific Host Host Immune ResponsesImmune Responses

4. Nanotherapeutic Vaccines4. Nanotherapeutic Vaccines

5. Antibody Response to 5. Antibody Response to Therapeutic Devices.Therapeutic Devices.6. Special Device Application.6. Special Device Application.

  a. Biosensors detect glucose level a. Biosensors detect glucose level for management of Diabetes:for management of Diabetes:

  Implanted sensors and non-Implanted sensors and non-invasive sensors are invasive sensors are underdevelopment to monitor underdevelopment to monitor glucose level with glucose oxidase glucose level with glucose oxidase which combine glucose and Owhich combine glucose and O22 to to form gluconic acid and Hform gluconic acid and H22OO22. Pt . Pt electrode is used to measure Helectrode is used to measure H22OO2 2

level.level.

  b. A biosensor using hemolysin to b. A biosensor using hemolysin to detect short strand of DNA. detect short strand of DNA. Hemolysin is embedded in a Hemolysin is embedded in a membrane separating 2 chambers membrane separating 2 chambers which draws ions from one to which draws ions from one to another. When nanopores are another. When nanopores are blocked, an abrupt change in blocked, an abrupt change in current is detected(Chamber current is detected(Chamber dimensions: one with 3-4 nm in dimensions: one with 3-4 nm in diameter and the other with 1.4 diameter and the other with 1.4 nm in diameter).nm in diameter).

  c. Antibodies used as a biosensor c. Antibodies used as a biosensor for blood type tester-composed of for blood type tester-composed of a collection of antibodies that a collection of antibodies that recognize specific sugars on the recognize specific sugars on the surface of red blood cells. The surface of red blood cells. The antibody is added to the blood, antibody is added to the blood, and if the particular blood type is and if the particular blood type is present in the cells, the antibody is present in the cells, the antibody is bind to the surface, sticky cells bind to the surface, sticky cells together. The result is that a together. The result is that a clumping of cells can be detected clumping of cells can be detected by human eye. by human eye.

Soft LithographySoft Lithography

Synthesis of Poly (amido) amine Synthesis of Poly (amido) amine (PAMAM) (Bottom-Up Approach)(PAMAM) (Bottom-Up Approach)

Top-down Approach:Top-down Approach:

  Carbon nanotubes can be synthesized Carbon nanotubes can be synthesized with a top-down approach from graphitewith a top-down approach from graphite

  sheets in an electric arc oven by sheets in an electric arc oven by   metal catalyzed polymerization method.metal catalyzed polymerization method.

Bottom-up Approach:Bottom-up Approach:

  Proteins are synthesized from lowerProteins are synthesized from lower  molecular weight amino acid molecular weight amino acid

precursors by chemically or precursors by chemically or biologically mediatedbiologically mediated

  Polymerization.Polymerization.

Micro and Nanotechnology in Drug DeliveryMicro and Nanotechnology in Drug Delivery

Synthesis and Preparations of Synthesis and Preparations of nanoporous inorganic & organic platformsnanoporous inorganic & organic platforms

Use of biomolecules for targeting, Use of biomolecules for targeting, adhesion, and biointerfacingadhesion, and biointerfacing

Nanofabricated & micropatterned drug Nanofabricated & micropatterned drug delivery devicedelivery device

Formation & fabrication of Formation & fabrication of nanoparticulate system modified with nanoparticulate system modified with natural biological ligands. natural biological ligands.

Present Focuses of Therapeutic Present Focuses of Therapeutic Delivery SystemDelivery System

  Patients & PhysiciansPatients & Physicians Improve drug delivery Improve drug delivery

and efficacyand efficacy Enhance drug stabilityEnhance drug stability Increase complianceIncrease compliance Potential for local Potential for local

delivery-decrease site-delivery-decrease site-effecteffect

How Can Micro and How Can Micro and Nanotechnology Help?Nanotechnology Help?

  Micro and nanofabrication allow for:Micro and nanofabrication allow for:

Control for shapeControl for shape

Control for sizeControl for size

Asymmetrical 3D designAsymmetrical 3D design

Oral Drug DeliveryOral Drug Delivery

The Current Drug DeliveryThe Current Drug Delivery

System Market Size:System Market Size:

$50 billions for 2003,$50 billions for 2003,

$67 billions for 2006( projected to $67 billions for 2006( projected to grow)grow)

The total pharmaceutical market is The total pharmaceutical market is

$250 billions in 2001.$250 billions in 2001.

Nanotech MedicineNanotech MedicineNCI has launched a five-year initiative to NCI has launched a five-year initiative to

enlist nanotechnolgy to fight cancer.enlist nanotechnolgy to fight cancer.

$144 millions for the next five years to $144 millions for the next five years to support the initiative.support the initiative.

$90 millions will go toward funding several $90 millions will go toward funding several Centers of Cancer Nanotechnlogy Centers of Cancer Nanotechnlogy Excellence.Excellence.

$38 millions for targeted research grant in $38 millions for targeted research grant in the nanotech to fight against cancerthe nanotech to fight against cancer

$16 millions set aside to train scientists to $16 millions set aside to train scientists to work in this multidisciplinary environment.work in this multidisciplinary environment.

Nanoceramics for Gene & Drug Nanoceramics for Gene & Drug DeliveryDelivery

Layered double hydroxides(LDHs)-Layered double hydroxides(LDHs)-

Gene or drug delivery into biologicalGene or drug delivery into biological

cells-a gene or drug delivery carriercells-a gene or drug delivery carrier

Composition of LDHs:Composition of LDHs:

M(II)M(II)1-x1-xM(III)M(III)xx(OH)(OH)22(A(An-n-))x/nx/nyHyH22O,O,

Where M(II)-divalent cationWhere M(II)-divalent cation

M(III)-trivalent cation,M(III)-trivalent cation,

A =interlayer anion,A =interlayer anion,

n-=charge on the interlayer ion.n-=charge on the interlayer ion.

(Inorganic or organic anions can be (Inorganic or organic anions can be introduced between hydroxide layer introduced between hydroxide layer

by ion exchange or precipitation.) by ion exchange or precipitation.)

Bio-LDH NanohybridsBio-LDH Nanohybrids

Biofunctional molecules- nucleosideBiofunctional molecules- nucleoside

monophosphates, ATP, DNA, monophosphates, ATP, DNA,

flourescein-5-isothiocyanate, etc canflourescein-5-isothiocyanate, etc can

be intercalated into hydroxide layer be intercalated into hydroxide layer

To form bio-LDH nanohybridsTo form bio-LDH nanohybrids

Controlled Release of Interlayer Controlled Release of Interlayer

Biomolecules:Biomolecules:

The miomolecules stored in LDH’s The miomolecules stored in LDH’s

can be released under acidic condition.can be released under acidic condition.

Preparation of Nanoparticles of LDHsPreparation of Nanoparticles of LDHs

The particlesThe particles

prepared inprepared in

nanoscale for nanoscale for

IntravenousIntravenous

injection. injection.

  Number of Issued and Pending Patents and Number of Number of Issued and Pending Patents and Number of papers relating to Nanotube Applicationspapers relating to Nanotube Applications

  ________________________________________________________________________________________  TopicsTopics IssuedIssued PendingPending PapersPapers  ProductionProduction 5959 9292 1189 1189  Field-emission-relatedField-emission-related  devicesdevices 3030 5858 394 394  ElectronicsElectronics 1111 2727 360 360  Composites, fibersComposites, fibers 7 7 3636 111 111  Sensors, probes,detectorsSensors, probes,detectors 7 7 2323 129 129  Hydrogen storage, fuel cellsHydrogen storage, fuel cells 4 4 2 2 63 63  Batteries, capacitorsBatteries, capacitors 4 4 3 3 3 3   OtherOther 30 30 33 33 3776 3776  ______________________________________________________________________________________________________________________  TotalTotal 152152 274274 6026 6026

 

Identity Badge under skinIdentity Badge under skin

FDA has approved “VeriChips” FDA has approved “VeriChips” manufactured by Applied Digital manufactured by Applied Digital Solution (Delray, Florida) to market Solution (Delray, Florida) to market implantable microchips under skin.implantable microchips under skin.

An under-the–skin ID to access An under-the–skin ID to access medical information. medical information.