Week 8 - Recent Advances in Drug Delivery to Cancer Flashcards
(32 cards)
What is paclitaxel and what is its clinical use?
- A taxane chemotherapeutic agent
- Targets microtubules, causing cell cycle arrest
- Used as 1st treatment for ovarian cancer and also in breast, lung, and pancreatic cancers.
Why is conventional paclitaxel formulation problematic?
Poor solubility and poor permeability
- use of co-solvent fixes this
- Paclitaxel is water-insoluble
- formulated with ethanol + Cremophor EL (polyoxyl castor oil), - Formulation can cause hypersensitivity, anaphylactic shock in up to 35% of patients
What is nab-paclitaxel and how does it address solubility issues?
Nanocarrier formulation of Paclitaxel
- N.particle formulation can overcome issues with convential Paclitaxel
Nab-paclitaxel (Abraxane) is:
- a solvent-free
- albumin-bound nanoparticle formulation of paclitaxel
- albumin has affintiy for paclitaxel due to hydrophobic pockets
- paclitaxel binds to albumin
- albumin aggregate = np formed
- improves solubility and ↓ hypersensitivity reactions
- shorter infusion time compared to original
NOTE:
- Used in MBC, NSCLC
How does nab-paclitaxel achieve tissue targeting?
Np naturally have passive targeting
- It exploits the EPR effect = can have passive targeting via tumour vasculature
= can enter tumour cell - Albumin ligand (gp60) binds to endothelial cells
- initiates caveolae-mediated transcytosis = enhance tissue penetration
What are the 4 biological barriers
NM - nanomedicine
- Cellular barriers
- Intravascular barriers
- have monocytes, macophages circulating that phagocytose NM
- opsoinisation - Endothelial barriers
- drug needs to pass through endothelial cells
- in cancer cells asculature is leaky = not big issue - Extravascular barriers
- enzymes, extracellular matrix, high interstial fluid pressure
How are NP formulated to overcome physical barriers
Structure:
- Ligand
- for active targeting to a specific receptor on cancer cell surface
- Linker
- cleaved in cancer cell to rerlease cargo / drug
- responds to microenvironment - Cargo / drug
- can be small molecule, nucleic acid, nanocarrier, cell Abs
What are the main endocytic pathways for nanoparticle uptake?
- Clathrin-mediated
- Caveolin-mediated
- Clathrin- and caveolin-independent pathways
- Phagocytosis
- Micropenocytosis
What is clathrin-mediated endocytosis?
A receptor-mediated pathway
- clathrin forms vesicles (~100 nm) to internalize NP
Ligands for Clathrin: transferrin, LDL, EGF
Clathrin = a coat protein
What is caveolin-mediated endocytosis?
Involves small (50–80 nm) caveolae that bypass lysosomes, trafficking directly to organelles like ER and Golgi. Ligands include folate and insulin.
What is Clathrin and Caveolin-independent endocytosis?
Pathway doesnt rely on ligands
- Small, membrane domains are used by NP
- Can avoid degradation
How does phagocytosis affect nanoparticle uptake?
Large NP (>500 nm) are engulfed by phagocytes = phagasome formed
- e.g., macrophages, neutrophils, dendritic cells
PEGylation is used to avoid immune clearance
- via opsoinisation
What is macropinocytosis and how is it relevant in cancer?
- Used for non-targeted drug delivery
- as doesn’t require specific receptor - Cells engulf extracellular fluid into a large vesicle
- Certain cancer cells (e.g. pancreatic, lung) show high activity of this = useful target
What is tissue targeting in drug delivery?
A type of targeted delivery
Targeting to specific cancer tissue
- use of passive or active targeting
- Designing NP to accumulate in specific tissues via:
- passive (EPR effect) OR
- active targeting using ligands
What is cellular targeting?
A type of targeted delivery
Active targeting
Attaching ligands (e.g., antibodies) to NP = will bind to specific receptors on cancer cells for internalization
What is organelle targeting?
A type of targeted delivery
Active targeting
NP that deliver drug directly to intracellular organelles
- e.g nucleus, mitochondria, ER, lysosomes for precise therapeutic action
Give an example of cell-targeted nanomedicine under clincal trial.
SGT-53
- a cationic liposome with p53 DNA
- p53 = tumour supressor gene
- genes are diff. to deliver as they are macromolecules, hydrophilic, can’t cross cell membrane, degraded by nucleases = need to protect gene
- lioposome = phospolipid bilayer
- gene encapsulated in core
- cationinc helps fusion with membrane
- has a transferrin receptor-targeting antibody (TfRscFv)
- used for tumor-selective delivery
- good tolerability, no advrse SE
How does SGT-53 enter cells?
Via transferrin receptor (TfR) -mediated endocytosis
- transferin (protein) helps with cellular uptake of iron
- cancer cells consume a lot of iron due to rapid prolifeartion
- cancer cells overexpress TfR = NP can bind to it via transferin antibody
List 4 Organelle Targeting Strategies
- Target endosomes and lysosomes
- endosome engluf particles forming vesicle
- if NP remains in endometriosis for long / no endosomal escape, endosome becomes lysosome (↓ pH)
- lysosome degrade (via lysosymes)
- AIM: make NP escape from endosme to prevent degradation
- VIA: Pore formation, proton sponge, swelling polymers (in low pH) - Nucleus targeting
- VIA: functionalise NP with ligands (e.g. TAT peptide)
- Ligand interacts with NPC = uptake of NP
- Nucleus have double layered membrane that have Nuclear pore complex (NPC)
- NPC filters molecules based on size (>10 = NO entry, NM bigger than this)
- Mitochondria targeting
- VIA: passive targeting (use lipophilic, cationinc NP) as mitochondira is -ively charged
- Functionalise NP with TPP (lipophilic, cationic strcuture)
- VIA: active targeting, attach MTS ligands (interact with mito. receptor)
- Mitochondria has 2 membranes, similar to nucleus (size exclusion) - Targeting Endoplasmic Reticulum and Golgi
- VIA: functionalise NP with ligands
- e.g. cysteine, sulfonyl ligand, KDEL protein
NOTE:
- Important to maintain homeostasis of organelles
List 5 Advanced Responsiveness to Improve Targeted Delivery
(Stimuli Responsive NP Methods)
- pH responsive
- pH of cancer cells are slighlty more acidic than normal cells
- drug release in pH of cancer cell - Enzyme responsive
- drug release in response to certain enzymes that are overlyexpressed in cancer cells
- Redox responsive
- have reactive oxygen species in cancer cell - Magnetic Hyperthermia
- Light - Photothermal
NOTE:
Used to make sure drug is released in only cancer cells
What are pH-responsive nanocarriers?
Nanoparticles that release drugs in acidic (low pH) environments like:
- tumors (pH 5.5~6)
- lysosomes (pH ~4.5)
How Achieved:
- Using acid-labile linkers
- drug released when exposed to acid / low pH
- Charge-shifting
- NP in tact in physiological pH
- once pH drops drug disassembles = drug release
- pH responsive linkers
- shell that is responsive to pH = dissasembles or swells = drug released
What are enzyme-responsive nanocarriers?
Nanocarriers that release drugs in response to tumor-specific enzymes e.g. MMPs
- Certain enzymes are overexpressed in the tumor microenvironment
How Achieved:
- Use of MMP2 to shield NP
- MMP dependent changes
- allows increase uptake of drug
What is redox-responsive nanomedicine?
Not approved, Clinical trials ONLY
Use redox-sensitive bonds that cleave in high glutathione (GSH) / reactive oxygen species conditions of tumor cells
- e.g., clevable disulfide, diselenide bonds
- In cancer cells have many reactive species + imbalance in glutathione levels (reduced and oxidised)
- leads to glutathione depletion and lipid peroxidation
What is magnetic hyperthermia?
Uses magnetic nanoparticles (SPIONs) activated by an alternating magnetic field to generate heat and kill tumor cells.
- Expose iron NP to alternating magnetic fields, NP starts vibrating = heat production
HOW Achieved:
- Iron NP are selectively uptaken by cancer cells
- To get cytotoxicty of drug need to expose it to alternating magnetic field
- Once exposed NP vibrates = heat = apoptosis
What is light photothermal therapy?
Uses nanomaterials to convert light into heat (>41°C) to selectively kill cancer cells while sparing healthy tissue.
How Achieved:
- NP produces heat when exposed to (absorb) light
- Heat in cancer cell = death
NOTE:
- need to prevent damage to normal / healthy surrounding tissue
