Seutics 2 - Manickam

Define: Nanoparticles

• tiny particles that carry drug to where they need to go to be delivered for drug target

NPs are a typoe of colloidal drug delivery system. What is the size range that is pharmaceutically relevant?

10-100 nm

NPs consist of drug entity and polymers/lipids that assemble them into nanosized particles. What are the drug entities that it could be?

• small molecule drug

• peptide

• protein

• nucleic acid

What are the two major types of NPs?

1. liposomes

2. micelles

What structure is this?

Liposome

What structure is this?

Micelle

Define: Liposome

1. bilater lipid assemblies with hydrophilic center/core

   • contains amphilphilic molecules that make liposomes good for hydrophilic drug delivery

   • Core/center: hydrophilic

   • Middle bilayer: hydrophobic

Amphiphilic molecules

• head = hydrophilic

• tail = lipophilic/hydrophobic

Define: Micelle

• aggregates of amphiphilic copolymers with hydrophobic core

• hydrophobic core with hydrophilic shell (hydrophobic drug loaded in center)

What is the key advantage of micelles and liposomes as applied to drug solubility

• incr. amt of drug loading and it increases overall drug solubility in carriers

What are the three key messages regarding nanoparticles and their characteristics

1. NPs are not rapidly cleared via kidneys

2. NPs circulate longer and accumulate better in tumors

3. NPs are internalized by cells via endocytosis

Advantage of drug in nano particle

• greater probability for drug to get to target site

8 characteristics that make nanoparticles useful for anticancer drug delivery

1. greater drug loading capacity

2. can load multiple drug molecules for drug drug combinations

3. allow for modifying drug release rate

4. circulate longer, lesser elimination by kidneys

5. can be modified with PEG → decreases non specific uptake into liver and spleen and increase circulation times (PEGylation)

6. Multivalency/Drug targeting

7. Enhanced permeability and retention effect for anti cancer drug delivery

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

Advantage of PEGylation

• PEGylated particles are not rapidly cleared via liver therefore pegylated particles circulate for longer times

How are NPs affected by PEGylation?

1. normally opsonin on NPS will sent signals to machrophages and be cleared; however PEGylation adds PEG chains to NP and it reduces opsonin association

• opsonin are negatively charged particles

Define: Multivalency

• refers to NP surface mods using multiple copies of targeting ligand → leads to greater uptake and therefore more drug enters cell

What is meant by enhanced permeability and retention of NPs?

• NPs can extravasate/permeate into leaky capillaries and accumulate in greater amts in tumors

• NPs are retained longer due to reduced lymphatic drainage in tumors.

NPs can overcome surface efflux pump mediated drug resistance. NPs enter cells via ____ and avoid recognition by efflux pumps

endocytosis

What does PEG modification to NPs do?

PEG modification decreases liver clearance of NPS and therefore ..

• increase circulation times

• increase t1/2 → decreases clearance

NPs clear ___ compared to free drug

slower

PEG chains increase circulation _ _ of liposomes

half life

Micelles circulate _ and have a slower clearance

longer

Micelles have improved therapeutic effacy compared to _ drug

free

Small molecules are considered _ than 1000 Da

less

Large/macromolecule drugs are considered _ than 500-1000 Da

more

What are biologics

• class of drugs that are derived from biological sources

Proteins have a range of molecular masses and protein drugs act on specific __ __ / receptors in body

target sites

Biologics

• New class of treatments made from living organisms

• have capability to more effectively treat diseases

Why are biologics more capable to more effectively treat diseases?

1. action specificity

2. require lower/smaller doses compared to traditional small molecule APIs (INCREASED POTENCY)

5 challenges to delivery of polypeptide drugs

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

2. charged proteins (anionic vs cationic) will have a difficult time passing through membrane

3. enzymatic degradation by digestive proteases

4. immunogenicity against recombinant proteins

5. large molecular mass /cationic → will be hydrophilic

What are the advantages of oral protein and peptide delivery systems

1. protect drug from enzymatic degradation and decrease their systemic clearance

2. increase cargo solubility

3. controlled release and minimize undesirable side effects

4. improve biodistribution - decrease non specific uptake (by liver and spleen) and increase amts available for selective uptake by target cell/organ

5. lower immunogenicity

PEGylation is process of ___ ___ of PEG to a protein/polypeptide

covalent attachment

3 characteristics of PEGylated proteins

1. increase particle size = lower kidney clearance

2. increased H2O solubility (hydrophilicity) → for IV injections

3. reduced proteolytic / enzymatic degradation

PEGINTRON (PEGylated interferon alpha 2b) is used to treat ..

hepatitis from HCV infection

How does Interferon Alpha 2a affect PK and PD effects

modify with PEG

1. stays in blood longer and therefore increased absorption and sustained absorption

2. clearance is longer

3. increased t1/2

How does PEGylation affect dosing interval?

• decreases dosing interval and therefore increases pt compliance

What are nucleic acids

1. sugar

   • ribose (RNA)

   • Deoxyribose (DNA)

2. nucleotide bases

   • AUCG (RNA)

   • ATCG (DNA)

3. negatively charged phosphate backbone

What are the key characteristics of nucleic acids that are also the challenges for delivery?

• anionic and hydrophilic biomacromolecules

Where should drug be delivered if delivering DNA

cell nucleus

Where should drug be delivered if delivering mRNA

cytoplasm

DNA and mRNA delivery allows expression of __ ___

encoded protein

What are the steps in NA delivery

1. extracellular

   • particle injected

   • circulation

   • accumulation

   • penetration

2. intracellular

   • enters cell via edocytosis

   • endo/lysosomal escape

   • DNA → nucleus

   • RNA → cytoplasm

_ function to carry NA to their sites of action

vectors

Define: _ _ is the clinical application of DNA molecules → involvesreplacement of mutated copy of gene with a healthy/normal DNA copy

Gene therapy

Strimvelis is a gene therapy for treatment of ___

ADA-SCID

Limited packaging capacity of viral vectors and ____ are key concerns that drive need for safer alternatives for gene delivery

immunogenicity

3 main extracellular barriers/challenges to NP delivery of NAs

1. renal filtration

2. non specific uptake by liver/spleen

3. nuclease degradation

What are 3 main intracellular barriers/challenges to NP delivery of NAs

1. cellular entry

2. endosomal escape

3. nuclear uptake for DNA delivery

Polymers and lipids, or __, are used for NP formulation

Carriers

In nucleic acids, what funtional group binds to Phosphate grps

amines

Why do Liposomes carry nucleic acids

because of hydrophilic interior

What are the types of cargo that can be loaded into Lipid nanoparticles

1. ionizable cationic lipid

2. cholesterol

3. helper lipid

4. lipid anchored PEG

what do the cargo in LNPs promote?

1. formulation of mRNA loaded particles

2. allows escape from endosomes

3. increases stability in circulation