Anti-Cancer Drug Delivery Flashcards
(26 cards)
1
Q
- What is Cancer?
- What can cancer cells do?
- What is Metastasis?
A
- Uncontrolled cell division
- Cancer cells can invade nearby tissues
- Metastasis form by spreading through the bloodstream and lymphatic system to other parts of the body
2
Q
- What does Targeted Cancer Therapy identify?
- What does it find?
- What is developed?
A
- Identify differences between normal and cancer cells
- Find molecular targets that are associated with cancer to selectively kill tumour cells
- Develop anticancer agent (small molecule or antibody) for treatment
3
Q
What are current challeneges with traditional cytotoxic drugs and targeted chemotherapy?
A
- Poor solubility
- Rapid in vivo breakdown of free drug
- Tissue damage on extravastion
- Side effects
- Poor biodistribution and lack of selectivity for target tissue (high Vd leads to dose limiting side effects)
4
Q
How do we overcome the problems with traditional cytotoxic drugs and targeted chemotherapy?
A
Deliver cancer drugs specifically into cancer cells
5
Q
Pathophysiology of Tumour Tissue
- What do solid tumours depend on?
- When the size becomes approximately 2mm3 or greater, what do the cells reach?
- What does this drive?
A
- Solid tumours depend on ready supply of nutrients and oxygen
- When the size becomes approximately 2mm3 or greater, the cells reach a state of hypoxia
- This drives angiogenesis mostly in disorganised patterns with erratic and disorderly branched vessels
6
Q
Pathophysiology of Tumour Tissue (2)
- Dilated vessels with what?
- Tumour tissues show?
- Impaired lymphatic vessels lead to?
- These characteristics can be?
A
- Dilated vessels with irregular basement membrane and large inter-endothelial junctions
- Tumour tissues show hyper-vascular nature
- Impaired lymphatic vessels lead to poor drainage from the tumour interstitium
- These characteristics can be exploited for tumour-selective drug delivery
7
Q
Passive Targeting of Nanocarriers
- What is it and what does it result in?
- What size molecules?
- Impaired drainage leads to what?
- pH?
- Nanoparticles can also activate what?
A
- Refers to diffusing into the tumour via the EPR
- Large and small molecules can be targeted
- Impaired drainage leads to accumulation of the drug within the tumour
- Tumours have lower pH than the rest of the body, so nanoparticles can be used to only release the drug at this pH values
- Nanoparticles can also activate MMPs, causing the tumour matrix to disintegrate, helping the particles move through it easier
8
Q
Passive Targeting of Nanocarriers
- Size
- Permeability cut-off?
- EPR effect has been observed with?
A
- Permeability cut-off varies from 200-800nm
- EPR effect has been observed with liposomes, micelles, polymer drug conjugates, DNA polyplexes and antibodies up to 800 kDa
9
Q
Passive Targeting of Nanocarriers
- Surface Charge
- Negative charge?
- Positive charge?
A
- Blood vessels negatively charged on luminal surface due to carboxylate sugars and sulfate groups
- Positive charge on nanocarrier favours interaction with tumour blood vessel inhibiting entry back into systemic circulation
10
Q
Passive Targeting of Nanocarriers
- Longevity
- Removal of what by what?
- Protection achieved by?
A
- Fast removal of nanocarriers by macrophages and RES
- Protection can be achieved by grafting of polymers on the surface, most commonly PEG coating
11
Q
Discuss the Passive Targeting of Micelles
A
- Compound protected in the centre of micelle
- Micelle can migrate through the vasclature til EPR finds
- Ends up in cancer tissue and releases its compound
- Hydrophobic tail will direct to the core of the micelle
- Hydrophilic head will be at the surface on the outside
12
Q
Active Targeting of Nanocarriers
- What is active targeting?
- What must it first do?
A
- Active targeting utilises ligands such as antibodies, peptides, aptamers and small molecules (e.g. folic acid) to interact with tumour specific surface receptors
- However the particle must first passively diffuse into the tumour interstitium, before interacting with the cell itself via active targeting
- Therefore, active is a combination between passive and active
13
Q
What factors affective passive and active targeting?
Size
A
- If nanoparticle too large, might not get into tumour tissue
14
Q
Polymeric Nanoparticles
- Size
- How do they work?
- What’s improved?
- What stops interaction with plasma proteins?
A
- Size = ~ 100nm
- Incorporated into the core of polymeric nanoparticles, providing protection from metabolism by enzymes and avoiding interaction with healthy tissue and organs
- The circulation half life is improved as a result of decreased renal secretion and hindered uptake by RES
- A PEG shell on the surface stops interaction with plasma proteins to avoid recognition by RES
15
Q
What are the Types of Building Polymeric Blocks?
A
- Targeting Ligand
- Shell-Forming Polymer
- Linkage between polymeric blocks
- Core-forming polymer
16
Q
Types of Building Polymeric Blocks: Shell-Forming Polymer
A
- PEG
- Biocompatible
- Polyacrylic acid
- pH responsive
17
Q
Types of Building Polymeric Blocks: Linkage between Polymeric Blocks
A
- Ester
- Amide
- Disulfide
- Hydrazone (pH sensitive)
18
Q
Types of Building Polymeric Blocks: Targeting Ligands
A
- Small molecules, sugar, CHO, growth factors, vitamins
- Biomacromolecules, antibodies, antibody fragments, aptamers, proteins, peptides
19
Q
Composition of Multifunctional Nanoparticles
A
- Core
- Shell
- Cargoes
20
Q
Composition of Multifunctional Nanoparticles: Core
A
- Hydrophobic
- Can be stabilised by anionic interactions
- Cationic interactions used to bind the SiRNA molecule
- Drug-conjugate can be packed into core
- Unimolecular structures
- Crosslinking stabilises entire nanoparticle
21
Q
Composition of Multifunctional Nanoparticles: Cargoes
A
- This transporter can be
- Chemotherapeutics
- Nucleic acids
- Proteins
- Peptides
- Imaging probes - diagnostic purposes
22
Q
Methods for Preparation of Polymeric Nanoparticles
A
- Self-assembly of Block Copolypeptides
- Polymers than can be used in Emulsification
- Ultrasonic or handheld homogenisation
- Microfluidic homogenisation
- Particle replication in non-wetting templates (PRINT)
- Cast solution with polymer and drug, remove solvent by heat
- Cover with perfluoropolyether elastomeric mold, pass through heated nip roll with splitting
- Place on film, pass through heated nip roll, cool, harvest nanoparticles
23
Q
Polymeric Nanoparticles for Passive Cancer Targeting: 2 Major Endocytic Processes?
A
- Phagocytosis
- Particles > 1 mcm
- Macrophages, neutrophils, dendritic cells
- Pinocytosis
- Adsorptive pinocytosis through non-specific adsorption of nanoparticles
- Receptor mediated endocytosis of nanoparticles
24
Q
Passive Targeting - PEG configurations on a polymeric nanoparticle
- Low Surface Coverage of PEG?
- High surface coverage and lack of mobility of the PEG chains?
A
- Low Surface Coverage of PEG chains leads to a configuration where most of the chains are located closer to the particle surface
- High surface coverage and lack of mobility of the PEG chains lead to the ‘brush’ configuration where most of the chains are extended away from the surface
- Increased longevity
25
Polymeric nanoparticles for active cancer targeting
* Receptor density in comparison to healthy cells
* Multivalent binding
* High receptor density on cancer cells in contrast to healthy cells
* Multivalent binding of nanoparticles to the surface of cancer cells
* If you take a nanoparticle with a lot of ligands, it can attach to several receptors at the same time providing a much higher affinity
26
Functional Design of Polymeric Nanoparticles for Cancer Targeting Types
* External Stimuli triggered drug release
* Tumour pH - triggered drug release
* Tumour pH-triggered nanoparticle deshielding or charge conversion to facilitate tumour cell uptake
* Internal stimuli triggered drug release
