exam 2 - nanoparticles and biologics

definition of biologics

a class of drugs that are derived from biological sources

what is the size range of biologics

500-1000 Da

what are two examples of biologics

tissue plasminogen activator and insulin

what are the ways that biologics have the capabilities to effectively treat diseases

action specificity, increased potency

what are the challenges to delivery of polypeptide drugs

1. large molecular mass proteins have a lower permeability across cell membranes

2. charged proteins will have a difficult time passing through membranes

3. enzymatic degredation by digestive proteases

4. immunogenicity against recombinant proteins

5. large molecular mass/cationic

what are the advantages to delivery of polypeptide drugs

1. protects drug from enzymatic degredation and decrease systemic clearance

2. increases solubility

3. controlled release and minimize undesirable side effects

4. improve biodistribution

5. lower immunogenicity

what is PEGylation

the process of covalent attachment of PEG to a protein or polypeptide

what are the three characteristics of PEGylated proteins

1. increases particle size and decreases kidney clearance

2. increases hydrophilicity

3. reduced proteolytic and enzymatic degredation

what are the pharmacokinetic properties of PEGylation

sustained absorption, increased half life, decreased systemic clearance

what are the pharmacodynamic properties of PEGylation

increased in-vivo antiviral activity, increased anti-tumor activity, improved response

how does PEGylation affect dosing interval

decreases dosing interval and increases patient compliance

key characteristics and challenges of nucleic acids

anionic and hydrophilic nature of the biomacromolecules

where is DNA found in

nucleus

where is mRNA found in

cytoplasm

what are vectors

carry nucleic acids to their site of action

are endolysosomal compartments acidic or basic

acidic

what is gene therapy

a clinical application of DNA molecules where the mutated copy of a gene is replaced with a healthy copy

what is strimvelis

gene therapy for SCID

what deficiency causes SCID

adenosine deaminase

what are the negatives of viral vectors

limited packaging capacity and immunogenicity

what are the extracellular barriers to nanoparticle delivery of nucleic acids

renal filtration, non-specific uptake by the liver/spleen, nuclease degredation

what are the intracellular barriers to nanoparticle delivery of nucleic acids

cellular entry, eadosomal escape, nuclear uptake

what types of molecules can lipid nanoparticles carry

DNA, ssRNA, mRNA, proteins and small molecules

what do lipid nanoparticles promote

formation of mRNA particles, escape from endoscopes, increased stability in circulation

what is a common example of lipid nanoparticle drug delivery systems

COVID-19 vaccine

what are the properties of the COVID-19 mRNA vaccine

provides instruction directly to immune system, efficiently creates specific immune system memory in a natural context, and mRNA can neither interact with nor integrate into DNA

what are nanoparticles

a type of colloidal drug delivery system ranging in size from 10-100 nm

what are the types of nanoparticles

liposomes and micelles

what are liposomes

bilayered lipid assemblies

what are micelles

aggregates of amphiphilic copolymers

what are the advantages of liposomes and micelles

they increase the amount of drug loading and increase overall drug solubility

what are the three key points of nanoparticles

they are not rapidly cleared by the kidneys, they circulate longer and accumulate better in tumors, and are internalized by cells via endocytosis

eight characteristics that make nanoparticles useful for anticancer drug delivery

1. greater drug loading capacity

2. can load multiple drug molecules and drug-drug combinations

3. can modify or tune drug release rate

4. circulate longer

5. can be modified with PEG

6. multivalency/drug targeting

7. enhanced permeability and retention effect

8. can overcome drug resistance and still deliver drug to cells

does PEGylation cause longer or shorter times in the blood

longer

how do nanoparticles enhance permeability for cancer cells

nanoparticles can permeate into leaky capillaries and accumulate in greater amounts in tumors

how can nanoparticles overcome drug resistance

they enter cells through endocytosis and avoid recognition by efflux pumps

how do nanoparticles achieve multivalency and drug targeting

nanoparticles can be internalized into cancer cells at higher amounts compared to the free drug due to the over expressed receptors in cancer cells

what happens to a nanoparticle when it is modified by PEG

decreased liver clearance, increased circulation time, increased half life

what are two product examples of nanoparticles and what do they treat

daunoxome - treats leukemias

ambisome - treats fungal infections

what are the two properties of micelles

circulate longer and has a slower clearance, improved therapeutic efficacy compared to the free drug

extracellular steps in nucleic acid delivery

inject, circulation, accumulation, penetration

intracellular steps in nucleic acid delivery

enter cells via endocytosis, endosomal/lysosomal escape, DNA goes to nucleus, RNA goes to cytoplasm

what groups binds to nucleic acids

amino