Drug delivery mechanisms

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PolysaccharideVirulence factorProtection

Plasmid

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Plasmid

PeptidoglycanStructural support

Pilli

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Plasma membrane

Cell wall

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biology4alevelblogspotcom

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bullDiffusion across membrane is decided by size of the molecule as well as its solubility in lipids(as lipids are the major components of the blayer)

bullThe lipid bilayer is permeable to a few small uncharged molecules likeoxygen (O2) and carbon dioxide (CO2)Thus they simply move across through diffusion

bullIons and hydrophilic moiety finds it difficult to move across and thus have protein which provide sites for such molecules but in the presence of a concentration gradient(since ATP is not used)

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UniportersbullGLUT1 ndash widely distributed glucose transporterbullGLUT4 - primary insulin regulated glucose transporter in muscle and adipose tissue

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Symporters

bullSGLT1 - Na+ glucose symporter in gut epitheliabull Important for transport of nutrients through intestinal epitheliumbull Amino acids are transported in similar manner

Antiporters

bullNHE-1 - Na+H+ antiporter in kidney and gut epithelia for regulation of systolic blood pressurebull3Na+Ca2+ antiporter in the heart for regulation of heart contractility

hyperphysicsphy-astrgsuedu

bullExamples leucocytes neutrophils and monocytes can engulf foreign substances like bacteria

bullAlso used in case of cell migration and adhesion related functions

bullExamples The uptake of extracellular fluids such as hormones and enzymes by the body cellsbullThe human egg cell takes up the nutrients present in the surrounding environment secreted by the other cellsbullUptake of nutrients by the cells containing microvilli present in the intestine

bullExamples Neurotransmittersreleased from the neuron cellsbullSecretion of pancreatic digestive enzymesbullRepairing wounds of the plasma membrane

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bull Drugs is a chemical substance used in the treatment cure prevention or diagnosis of disease or used to otherwise enhance physical or mental well-beingrdquo

bull This chemical substance can be polar (hydrophilic) non-polar (hydrophobic) and small or large in size

bull Drugs is a chemical substance used in the treatment cure prevention or diagnosis of disease or used to otherwise enhance physical or mental well-beingrdquo

bull This chemical substance can be polar (hydrophilic) non-polar (hydrophobic) and small or large in size

bull Drugrsquos transport across the membrane usually takes place through facilitated diffusion or receptor mediated delivery

bull Exchange of these chemicals also occur by active transport or other transport mechanisms depending upon the chemical nature of the drug and the target organ

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FirstThere are several barriers lining the organs which do not allow passage of the drug molecules or gene containing molecules simply through diffusions or active transports

Second Specific delivery of drug or gene to the targeted organ

Third Keeping the normal cells (un diseased) out of contact of the drug action or exposure to chemicals that the drug contains

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The word rdquotrans fectionrdquo is a blend of trans- and infectionGenetic material (such as super coiled plasmid DNA or siRNA constructs) or even proteins such as antibodies may be transfected

Transformation is the genetic alteration of a cell resulting from the direct uptake and incorporation of exogenous genetic material (exogenous DNA) from its surroundings and taken up through the cell

membrane(s)

Transformation is the genetic alteration of a cell resulting from the direct uptake and incorporation of exogenous genetic material (exogenous DNA) from its surroundings and taken up through the cell

membrane(s)

Transformation is the genetic alteration of a cell resulting from the direct uptake and incorporation of exogenous genetic material (exogenous DNA) from its surroundings and taken up through the cell

membrane(s)

Transfection is specifically used for eukaryotic cells

Transformation is the broader term used for both prokaryotes as well as eukaryotes

Transformation is the genetic alteration of a cell resulting from the direct uptake and incorporation of exogenous genetic material (exogenous DNA) from its surroundings and taken up through the cell

membrane(s)

Transfer of gene drug or any macromolecule into an eukaryotic cell is transfection

Transfer of gene of interest into any cell can be termed as transformation

Transformation is the genetic alteration of a cell resulting from the direct uptake and incorporation of exogenous genetic material (exogenous DNA) from its surroundings and taken up through the cell

membrane(s)

Transfer is done typically through non viral methods

Transfer is done usually with a viral vector or carrier

Electroporationmdashthe use of high-voltage electric shocks to introduce DNA into cells

It is a procedure that is gaining in popularity for standard gene transfer and also allows the generation of genetically modified mice

It can be used with most cell types and because it requires fewer steps can be easier than alternate techniques

It can be used for in vivo gene transfer particularly for surface or near surface tissue such as skin muscle and certain tumors or even internal tissues such as liver

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bullInduction of membrane pores using ultrasound is exploited to facilitate entry of proteins nucleic acids and drugs into the cell

wwwintechopencom

bullThe microbubbles consist of lipid shell and perfluorocarbon gas on the inside The plasmid gene to be delivered resides in the shell

bullInduction of membrane pores using ultrasound is exploited to facilitate entry of proteins nucleic acids and drugs into the cell

wwwintechopencom

bullThe microbubbles consist of lipid shell and perfluorocarbon gas on the inside The plasmid gene to be delivered resides in the shell

bull After infusing the microbubbles with pDNA intravenously they are detected in the target organ by echography

bullUnder ultrasound exposure the microbubbles burst and the energy creates transient pores in membranes of surrounding cells and pDNAsare inserted into the cells

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bullMicroinjection is a well established technique used routinely for injection of animal cells tissues and embryos to insert genetic material such as DNA RNA proteins and macromolecules directly into animal cells or embryos a cell cytoplasm or nucleus

bullGenetic material is inserted via a needle which penetrates the cell membrane andor the nuclear envelope

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bullUse of a gene gun directly shoots a piece of DNA into the recipient plant tissuebull Tungsten or gold beads are coated in the gene of interest and fired through a stopping screen accelerated by Helium into the plant tissuebullThe particles pass through the plant cells leaving the DNA inside

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This method also alters the permeability of the cell membrane

bull Ca2+ interacts with the negatively charged phospholipid heads of the

cell membrane creating an electrostatically neutral situation

bull Lowering the temperature stabilizes the membrane making the

negatively charged phosphates easier to shield

bull Then a heat shock creates a temperature imbalance and thus a

current which helps get the DNA into the cell

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bullDevelopment of drug delivery systems for brain delivery is one of the most challenging research topics in pharmaceutical areas

bullThis is mainly due to the presence of the blood-brain barrier (BBB) which separates the blood from the cerebral parenchyma thus limiting the brain uptake of the majority of therapeutic agents

bullIt is a highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid (BECF) in the central nervous system (CNS)bull It is formed by capillary endothelial cells which are connected by tight junctions with an extremely high electrical resistivity bullIt allows the passage of water some gases and lipid soluble molecules by passive diffusion as well as the selective transport of molecules such as glucose and amino acids that are crucial to neural function bullIt prevents the entry of lipophilic potential neurotoxins from reaching to brain

bullIt should be controlled and not damage the barrier

bullDrug should be biodegradable specific and not toxic

bullThe drug load transported through the BBB should be adequate for reaching therapeutic concentrations in the brain

bullTherapeutic concentrations should be maintained for a sufficient duration of time for the desired efficacy

Characteristics of ideal drug delivery acrossthe BBB

Liposome = ldquoliposrdquo(means fat) + ldquosomardquo (means body)

When lipids are placed in contact with water the unfavorable interactions of the hydrophobic segments of the molecule with the solvent result in the self assembly of lipids often in the form of liposomes

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Hydrophobic drugs place themselves inside the bilayer of the liposome and hydrophilic drugs are entrapped within the aqueous core or at the bilayer interface

Liposomes can be surface functionalized to enable movement through PEGylation and to promote receptor-mediated endocytosis by using targeting ligands such as antibodies peptides proteins carbohydrates and various other small molecules

Chemotherapeutics or diagnostics can be encapsulated into the aqueous lumen incorporated into the lipid bilayer or conjugated to the liposome surface

Polyethylene glycol (PEG) density determines its structure at the liposome surfaceDensities below 9 -gt a mushroom-like globular structure above 9 -gt a more rigid extended brush-like morphology

Liposomes are composed of biodegradable biologically inert and non-immunogenic lipids

They produce no pyrogenic or antigenic reactions and possess limited toxicity

The ease of surface modification to bear the targetable properties make liposomes widely acceptable

The entrapment of the drugs both hydrophilic and hydrophobic into the liposomes is used to bypass the frequent generic toxicity associated with the drug as often seen in cancer drugs

The modification of liposomes permits a passive or active targeting of the tumor site

Specific modification effect enables an efficient drug payload into the malignant cell of tumors while the non-malignant cells become minimally impacted

Regenerative Medicine and Tissue Engineering for the Treatment of DiabetesBy Matsumoto S SoRelle JA and Shimoda M DOI 10577222808

Transfection by ElectroporationHuntington Potter PhD and Richard Heller PhD

Gene Therapy for Cardiovascular Disease Mediated by Ultrasound and MicrobubblesZhi-Yi Chen Yan Lin Feng Yang Lan Jiang Shu ping GeDisclosuresCardiovasc Ultrasound 201311(11)

Nanobiotechnology-Based Strategies for Crossing the BloodndashBrain BarrierKewal K Jain

Drug transport across the bloodndashbrain barrierWilliam M Pardridge

Liposomes as Potential Drug Carrier Systems for Drug DeliveryMelis Ccedilağdaş1 Ali Demir Sezer2 and Seyda Bucak3

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