WEEK 3 - Nanomedicine: A Smart Approach for Caner Chemotherapy Delivery Flashcards
(21 cards)
List 3 key challenges in cancer chemotherapy and drug delivery
Use of nanomedicines help overcome these
- Side effects
- chemo has non-selective toxicity = normal cells also affected
- pt exp: fatigue, N&V, hair loss, pain, bladder/bowel changes, dry mouth, skin changes, sexual function,
- changes to: blood, bone marrow, nerves, cognition
- Drug resistance
- developed by tumour cells
- Poor bioavaliability
- many cancer drugs require high dose due to poor solubility
What SE can Doxorubicin cause (reference to it MoA)
SE:
- enlarged heart (left side)
- heart failure
-
MoA
- Inhibits topoisomerase = stops the DNA repair mechanism
- Dox semiquinone binds to normal DNA and mitochondrial DNA
- binds to normal DNA and mitochondrial DNA
- have a lot of mitochondria in cardiac cells = not only cancer cells affected but cardiomyocytes (Cardiac muscle cells)
- Dox. is converted to dox. semiquinone = produces hydroxy radicals (in presence of Fe2+) = oxidative stress caused = DNA damage
NOTE: these 2 MoA are NOT specific to only cancer cells, also target healthy cells = SE
Explain difference between Nanotherapeutics, Nanotheranostics and Chemotherapy
Nanotherapeutics = tumour speciifc therapy
- delivery of drug directly to tumour
- reduced SE
Nanotheranostics = patient speicific therapy
- perosnalised medicine
- combines diagnosis and therapy
- diagnoses where tumour is + delivers drug to site
NOTE:
Chemotherapy = non-specific therapy = msot SE
- drug is delivered all over body
- targets disease but not specific tumour site
Explain use of nanomedicine
Use of nanomedicines help overcome challenges
Nanomeidicne - use of nanotechnology to diagnose and deliver drugs (e.g. treat / prevent disease)
- can be used fo delivery of other molecules e.g. genes, protons etc.
- Its popular due to limitations of current treatments
- e.g. chemo SE, unable to pass barriers - Systemic adminsitration typically (IV)
Target:
1. Leaky tumour vasculature
2. Poor lymphatic drainage in tumours
Explain the structure of normal vasculature
- Have tight endothelail junctions = no gaps = not leaky
- hence why dont normally see cells like ctDNA, cfDNA (tumours) in blood vessel
Explain the structural / functional abnormalities of tumour vasculature
- Have gaps in endothelial junctions = leaky
- caused by imbalance between pro and anti-angiogenic (vessel formation) signalling
- immature, hyperpermeable vasculature - Leaky vascualture = sign of tumour
- cells can move between gaps = metastasis
- hypoxia and low pH - Poor lymphatic drainage
- fluid accumulation = ↑ interstitial fluid pressure
Explain the role of Enhanced Permeability and Retention effect (EPR)
a.k.a. enhanced permeation and retention
EPR Effect - nanoparticles / macromolecules accumulate in tumour tissues due to leaky vascualture AND poor lymphatic drainage
- i.e. exploits tumour vasculature
Enhanced permability:
- Gaps allow nanoparticle to enter
gap is ~ 100-800nm
Retention:
- prolonged n.particle accumulation due to impaired drainage
Explain the role of the Enhanced Permeability and Retention (EPR) in nanomedicine delivery
List the 2 types of nanoparticle targeting strategies
- Passive = EPR Effect
- Active = Ligand-based interactions
Explain the 6 factors affecting EPR - passive targeting
A type of targeting strategy
- Tumour type & Heterogeneity
- EPR effect varies between diff. tumour types
- size of tumour, smaller = better permeability = better EPR effect / np diffusion
- heterogeneity of tumour affects accumulation - Vascular permability Extravasation and Blood flow
- tumours with ↑ leaky vasculature = ↑ EPR effect
- ↓ perfusion in hypoxic tumour = ↓ np delivery
- extravasation = movement of fluid - Interstital Fluid Pressure (IFP)
- have ↑ fluid due to poor drainage
- ↑ IFP in solid tumour ↓ np penetration into deep tumour regions - Physiochemical Properties
- size of np: 8-250nm
- smaller (<5) = cleared quicker and larger = poor penetration
- >250nm need EPR enhancers = ↑ permeability
- shape - use soft np = harder to be recognised as foreign
- charge = neutral or slightly -ive
- coating = use PEG
- prevents oponisation + ↑ circulation time - External Stimuli
- Stimuli-repsonsive np can ↑ EPR delivery - Patient specific factors
- genetics, meatbolism, immune response
- age, comorbodities
- tumour microenvironment
NOTE: np = nanoparticle
How does Opsonization affect the EPR Effect
Opsonin = a protien
Opsonization - attachment of protein (opsonin) to surface of np
- tells phagocytes to engulf molecule
- DO NOT WANT
MoA of Opsonization
1. Opsonin in bloodstream binds to np surface = coating
2. Np becomes recognisable to immune system = is targeted by phagocyte
3. Opsonin binds to specific receptor on phagocyte
4. Phagocyte engulfs np = phagocytosis
5. Np is internalised within phagosome
6. Np is cleared
Affects on EPR
- ↓ np circulation time
- ↓ targeting efficiency
- triggers immune repsonse
How can opsonization be minimised
Changing physiochemical properties of np
- Surface - coat np with PEG (pegylation)
- reduces protein adsorption + immune recognition
- PEG = non-toxic, water soluble polymer
- ↑ solubility, circulation time
- ↓ aggregation of np = maintain small size - Charge - make np surface neutral or slightly negative
- Size - keep np small, spherical, smooth surface
- irregualrly shaped molecules = immune recogn.
How can physical approaches improve EPR Effect
Most commonly used ~ 4 approaches
Use of external, physical stimuli to temporarily increase permeability in tumour tissue
4 Approaches:
1. Heat
- ↑ gaps between endothelial cells = ↑ leaky
- easier access to tumour site
- Radiothearpy
- induces apoptosis of tumour + surrounding endothelial cells = ↑ leakiness
- ↑ expression of VEGF and FGF (growth factor) - Photodynamic therapy
- photosensitisers + light produces reactive oxygen species
- kills endothelial and tumour cells - Ultrasound
- ↑ gaps between endothelail cells in vessels
- causes bubble induced expansion + compression
How can pharmacological approaches improve EPR Effect
Use of drug that interferes with tumour microenvironment to improve np accumulation
- Tumour vascular normalisers
- ↑ blood flow
- ↓ interstitial fluid pressure (IFP)
- e.g. anti-angiogenic drugs, tyrosine kinase inhibitors - Vascular mediators
- ↑ permeabilty of endothelilal cells
- EPR nehancer
- e.g. bradykinin, CO, heme-ocygenase-1, nitric oxide (NO), ACE inhibtiors - Extracelullar Matrix (ECM) Degradation
- overproduction of ECM proteins = major physical barrier to diffusion of np
- ↓ density of stroma - Tumour penetrating peptides
- ↑ trancytosis through endothelial cells
- ↑ endocytosis in cancer cells
- nutrient exchange rate contributes to uptake of np - Fibrinolytic co-therapy
- restore blood flow by degrading clots / fibrins in vessels
- ↓ IFP
Explain nanoparticle - active targeting
A type of targeting strategy ~ Ligand-based interactions
Modification of nanoparticles (with specific ligand attached) that recognise + bind to target markers expressed on cancer cell
BENEFITS:
- More efficient
- More speciifc
- Reduced SE
- Improves treatment efficacy
- Can treat disseminated locations
attache antibodies, peptides, small molecules, proteins, ligands e.g. attaching folate, HER2 antibody
MoA of Active targeting of cancer stem cells (CSC)
Enhances cell uptake + chemo. efficacy
CSCs cotnribute to tumour resistance, recurrence and metastasis
MoA
- Functionalse a np with targeting molecules that
- Targeting molecule binds specifically to CSCs markers expressed on surface of CSCs
- Np circulates in body + selectively binds to CSC marker
- Np accumulate at tumour site + internalise into the CSCs (receptor-mediated endocytsosis)
- Once inside CSC chemo drug is release = targeted cell death
- normal cells aren’t affected
Summary of active vs passive targetting
Advantage and disadvantages
On notes
Explain how nanomedicines move throughout body
- IV administration introduces np into bloodstream
- Systemic biodistribution of np
- if np is too small (<5nm) = cleared by kidnyes (renal clearance)
- if np is too big = cleared by spleen or RES
- drug released prematurely from np are metabolised + cleared by liver
- if np is recognised as foreign = cleared by macrophages (kupffer cells) - Tumour penetration
- np must escape blood vessels through gaps (EPR effect) = extravasation
- once np is in tumour it must withstand dense extracellular matrix + high IFP - Intra-tumoural Biodistribution
- np must enter tumour cell via endocytosis
- once in tumour np can release drug = therapeutic effect
List examples of clinically approved and investigational nanocarriers
- Have 15 approved cancer nanomedicines
Example:
1. Doxorubicin
2. Sacituzumab
- has a mAb on np surface that specifically targets Trop-2 (which is overexpressed in epithelial cancers)
- mAb is connected to drug via cleavable CL2A linker
- once linker is cleaved drug payload (SN-38 ~ Top-1 inhitbior) is released = apoptosis + DNA replication prevented
- released SN-38 can diffuse into neighbouting tumour cells
Doxil (Doxorubicin)
A liposome nanomedicine
- its pegylated = avoid immune response
- ↑ circulation time (t1/2) + drug accumulation in tumour
- doxorubicin sulfate encapsulated in an internal water phase surrounded by phospholipid bilayer shell enclosing
- remains encapsulated till reach tumour
- ↓ level of free doxorubicin = ↓ heart SE
- Drug can cross lipid bilayer in uncharged form
- Once drug becomes protonated = cant cross back
Issues with standard doxorubicin:
- Cardiotoxicity (affects mitcohondria)
- PEG doxorubicin has reduced effect / se
Issues with PEG doxorubicin:
- Hand-foot syndrome
- due to drug accumulation in hands and feet
- long t1/2 (half life) ↑ accumulation via EPR
- Local cytotoxicity, damaging endothelial cells
- Drug leaks from capilaires
What are the challenges in cancer nanomedicine
- Industry
- Costs, scaling up
- Repeatability, clinical translation problems - Clinics
- EPR effects
- Off taregt effects
- Efficacy & toxicity vs free drig
- Personalised therapy - Development
- Biopharmaceutical proeprties
- Specific tumour targeting - Regulation
- Uniformity and clearitiy on regulation
