W8 Nanoparticle Based Drug Delivery in Ca therapy- passive and active targeting (ZHM) Flashcards
Hypervascularisation: Healthy Vs Normal Tissue:
What are the differences? (angiogenesis)
Healthy tissue- Vascular endothelial growth factor (VEGF) promotes
angiogenesis in embryos and wound healing in adults
* Simple, organised arrangement of
arterioles, capillaries, and venules
Tumour tissue: VEGF allows tumour to grow beyond 1–2 mm with supply of nutrients and oxygen
* Disorganised and lack of conventional
hierarchy of blood vessels
=Increased number of blood vessels due to
angiogenesis (formation of new blood vessels)
Extravasation
Healthy tissue
* Normal cells’ vasculature is only permeable to particles smaller than 2 nm (very small particles)
Tumour tissue
* Vasculature pore sizes of most solid tumours range from 10 to 1000 nm, depending on the stage and type of cancer
=Leaky vasculature from blood vessels to tumour tissues
(anything travelling in blood has a chance to leak into tumour cells)
Impaired lymphatic drainage
- Healthy tissue
Interstitial fluid pressure ~ 0 mmHg - Tumour tissue
Interstitial fluid pressure reaches microvascular
pressure levels (a range of 10-40 mmHg)
=Impaired lymphatic drainage
What is Enhanced permeability and retention
(EPR)?
- Nanoparticles (~ < 100 nm) will remain inside healthy vessels but selectively leak into tumour tissue and accumulate there
This is passive targeting
Passive targeting facilitates deposition of nanoparticles within the tumour microenvironment, owing to distinctive characteristics inherent to the tumour cells, such as:
Formation of new blood vessels
Leaky vasculature
Impaired lymphatic drainage
EPR effect
All of the above
= All of the above
Passive targeting to active targeting history:
- EPR effect was discovered in 1986 → principle for the design of nanomedicines
- Doxil (doxorubicin in PEGylated liposomes) was the first nanomedicine approved by FDA in 1995 → approved the concept that prolonged systemic circulation time increased EPR-
based tumour accumulation - Abraxane (paclitaxel in albumin nanoparticles) was approved ten years later for metastatic breast cancer → confirmed the concept that active targeting strategies (binds to albumin-specific receptors) enhanced the EPR-based nanomedicine delivery
Active targeting:
What are the steps?
- Find tumor cell biomarker
- Find targeting moiety which are carrying drug payload
- Nanoparticles will look for biomarker on tumour cells to then attah themselves
- Overexpressed receptors on ca cells
Attach and then internalised into ca calls - Endoscope
Nanoparticle fabrication /
functionalisation
Materials examples?
shapes?
responsiveness?
shapes?
surface?
Organic, inorganic or polymeric
* Micelles, liposome, nanogel, dendrime, iron/silica, gold, mesoporous, polymer
characteristics:
* size, stiffness, porosity, topography
shape:
* Cube, rod, sphere, ellipse, plate, star
responsiveness:
* pH. temp, light, magnesium
surface:
* protein/peptide, antibody, carbohydrate, polymer
Proteins
examples:
- HER2 (human epidermal growth factor receptor 2) in breast cancer; EGFR (epidermal
growth factor receptor) in many cancers
-Nanoparticles conjugated with HER2-specific
affibody (ZHER2:342) or anti-EGFR antibody (cetuximab) - Transferrin receptors (TfR) with high expression on BBB endothelium
- Nanoparticles conjugated with transferrin for
receptor-mediated transcytosis across the BBB
Polysaccharides example:
- CD44 receptors overexpressed on various tumour cells
-Nanoparticles with hyaluronic acid (anionic
polysaccharide) can bind to CD44
Peptides examples:
Interleukin-4 receptors (IL-4R) overexpressed in lung cancer
-Nanoparticles conjugated with IL-4R-binding peptide-1 (CRKRLDRNC)
αv integrins specifically expressed on the endothelium of tumour vessels
-Nanoparticles conjugated with iRGD peptide
(internalisating peptide with RGD (Arg-Gly-Asp);
CRGDKRGPDEC) to penetrate tumour)
Aptamers:
- Short, single-stranded DNA or RNA (ssDNA or ssRNA) molecules, selectively bind to a specific target
- Nucleolin protein upregulated in many cancer cells
-Nanoparticles conjugated with AS-1411 aptamer can specifically recognise nucleolin - Tenascin‐C protein in extracellular matrix (ECM) in the tumour stroma
-Nanoparticles conjugated with GBI‐10 aptamer can target Tenascin-C
Small molecules
-
Folate receptors overexpressed on the surfaces of most solid tumour cells
-Nanoparticles conjugated with folic acid as the active ligand -
Sigma receptors overexpressed on many human tumours including melanoma
-Nanoparticles conjugated with anisamide, an agonist of sigma receptors
Which of the following is NOT an active targeting approach for cancer drug delivery?
Fabricating nanoparticles based on the CD44 receptor tumour-targeting properties of hyaluronic acid
Surface modification of nanoparticles with folic acid
The retention of polymeric nanoparticles in cancer tumour matrix
Synthesising integrin-targeted nanoparticles made of a chitosan-stabilised PLGA matrix
Decorating nanoparticles with anti-VEGF antibody
= The retention of polymeric nanoparticles in cancer tumour matrix
Stimuli-responsive drug release
* External stimuli examples?
* Internal stimuli examples?
- External stimuli
- Heat, Ultrasound, Light, Magnetic field
- Internal stimuli
- pH, redox, enzyme activity
