Lecture 9 - nanomedicines and nanosimilars Flashcards
what is a nanomedicine?
nanomedicines are purposely designed systems for clinical applications,with at least one component at the nanoscale, resulting in reproducible properties and characteristics
what are systems that can eb cosndieretd nano medicines?
- Antibodies (but also biopharmaceuticals, so not covered here)
- Polymer-drug conjugates
- Nanoparticles
- Liposomes/Lipid nanoparticles
- Nanoemulsions
- Nanocrystals
- Nanocomplexes
what are attributes of nanomedicines
Because of the small size and high surface are to volume ratio of nanomedicines, formulation of drugs into nanomedicines can increase drug potency and efficacy.
This can be achieved by:
enhanced solubility and dissolution
enhanced drug delivery
expand on how increased drug potency and efface can be by enhanced solubility and dissolution
enhanced drug delivery
- Enhanced solubility and dissolution. Because of the high surface are to volume ratio offered by nanoparticles, the solubility and rate of dissolution can be increased.
- Enhanced drug delivery
The small particle size can prolong a drug’s residence in the systemic circulation, it can modify drug distribution and it may permit drug targeting and transport across biological barriers.
what are polymer-drug conjugates ?
Polymer-drug conjugates are seen as a new chemical entity in their own right and as their overall size is generally below 100 nm, these systems can be classified within the general area of nanotechnology.
describe building drug polymer conjugates
A large range of synthetic polyners can be produced in an appropriate quality and stability and can be custom made to have distinct characteristics:
- specified molecular weight,
- size,
- charge.
synthetic polymers are geenrally less immunogenic than naturally derived macromolecules
To produce polymer-drug conjugates for parenteral administration, water soluble polymers are used.
describe the water soluble backbone
This can include synthetic polymers but PEG is the most popular polymer; it is approved for human use and offers properties including low immunogenicity, antigenicity and toxicity.
PEG chains also offer high hydration and flexibility which is useful in improving solubility and drug delivery.
The ease with which PEG can be modified and conjugated to drugs and proteins also offers an advantage.
However, conjugation of PEG to proteins may also reduce their biological activity so the conjugation site of the PEG on the protein is an important consideration.
Within clinically approved products PEG molecular weights of 5000 to 40000 are used.
what is the rational for polymer conjugation ?
- Increase solubility: conjugation of low solubility drugs to water soluble polymers can improve solubility
- Enhanced Drug Delivery
- Protect against degradation after administration: the polymer chains block antibodies and enzyme binding
- Enhance bioavailability and plasma half-life: by conjugating to a polymer, the overall molecule size is increased, reducing excretion by the kidneys.
- Reduce aggregation, immunogenicity and antigenicity: the hydrophilic coating offered by the polymer increases solubility and can reduce protein-protein association.
- Promote targeting to specific organs, tissues or cells: the polymer coating can promote the Enhanced Permeability and Retention effect
how are proteins PEGylated?
PEGylation involves linking a polymer to a protein via a bridge between two cysteine residues in the protein.
Generally a 1:1 polymer-to-drug ratio is used.
PEG molecular weights of 5000 to 40000 used in clinical products
Disadvantage:
PEGylation of proteins may also reduce their biological activity so the conjugation site of the PEG on the protein is important.
describe the use of linkers in drug design, specifically in the context of drug conjugates.
The drug can be
directly covalently attached
Attached via a spacer/linker (more common)
The spacer linker overcomes the problem of the drug’s therapeutic action being blocked.
It can also facilitate controlled release of the drug from the carrier
Types of Linker Release Mechanisms:
Passive hydrolysis: Linkers like esters break down in the presence of water.
Enzymatic hydrolysis: Oligopeptide spacers are broken down by enzymes found in lysosomes, a type of cellular compartment.
pH-sensitive release: Certain spacers, such as N-cis-aconityl, are designed to release the drug when encountering specific pH levels, typically acidic environments.
what are solid nanoparticles?
Solid nanoparticles are solid constructs in the nanometre range, and can be prepared by a number of different manufacturing methods which generally involve either:
Size reduction (e.g. by milling)
Agglomeration (e.g. by precipitation)
what are various groups of solid nanaoaprticles?
Nanosized drug particle and nanocrystals
Nanocomplexes
Solid polymeric nanoparticles
Protein nanoparticles
what do nanosized drug particles effect?
Reducing the size of drug particles to within the nanosized range substantially increases the total surface area of the system, hence increasing solubility
This increases the dissolution and bioavailability
This high surface area can cause instability, to counteract this we can add surfactants
For oral drug delivery, are normally formulated into tablets or capsules.
what are example son products developed using drug nanaoarticles?
Aprepitant
Megesterol acetate
Sirolimus
Fenofibrate
describe nanocomplexes that are used in parenteral iron formulations
Parenteral iron formulations are colloidal systems with a complex structure that consists of a polynuclear iron (III)-hydroxide core surrounded by carbohydrate polymer coatings
These formulations are used when iron supplements given orally cannot be used or fail to provide therapeutic effect.
Parenteral iron formulations treat iron-deficiency anaemia in patients with chronic kidney disease. Carbohydrates such as sucrose, carboxymaltose, and dextran are used as polymer coatings of the polynuclear iron (III)-hydroxide core.
The average particle size in the formulation is 20–30 nm.
what are examples of nanoparticles used for iron deficiency ?
Ferric carboxymaltose
(Ferrinject)
Iron (III) isomaltoside
(Monofer)
Iron(III)-hydroxide dextran complex
(Ferrosat)
they are all liquid for injection
outline the use of abraxane as a solid protein nanoparticle
Nanoparticles can be prepared from proteins and there is an albumin-based system clinically available.
Abraxane is the first commercial product based on protein nanotechnology.
130 nm particles of albumin bound paclitaxel, supplied as a lyophilised powder
Approved for treatment of breast cancer in patients who don not respond to combination chemotherapy for metastatic disease.
It is the first Cremophor-free paclitaxel product.
what is the roel of cremaphor ?
Paclitaxel is available as Taxol® - a liquid formulation where paclitaxel is dissolved in polyethoxylated caster oil (Cremophor® EL) and ethanol (basically an emulsion).
However this formulation requires special infusion sets, prolonged infusion times (3 h), and premedication with corticosteroids and antihistamines to reduce the risk of hypersensitivity reactions.
Besides the toxicity issues, these delivery systems may reduce tumour penetration of the drug through the formation of large polar micelles.
what is the role of albumin ?
Physicochemical: albumin functions to coat the paclitaxel and stabilises the drug.
Albumin can do so due to its ability to reversibly non-covalently bind hydrophobic substances.
give an example for clinically approved liposome product improving solubility
Ambisome - AMphitorecicin B
there are SUV composed of hydrogenated soyphosphatidylcholine, cholesterol, disteraroylphosphatidyl glycerol and alpha tocopherol. These vesicles are less than 100 nm in size. Amphotericin B is intercalated within the liposome membrane
clinical indications; An antifungal agent given IV for the treatment of systemic fungal infections.
describe lipsome based product; doxorubicin
Caelyx/Doxil or
Doxorubicin.
80-100 nm sterically stabilised liposomes composed of
Pegylated distearoyl phosphatidyl ethanolamine,
hydrogenated soy phosphatidylcholine and cholesterol. used for
Advanced ovarian cancer
Advanced breast cancer
Aids-related Kaposi’s sarcoma.
describe DaunoXome liposome based products
Daunorubicin;
~45 nm sized liposomes composed of distearoyl phosphatidylcholine and cholesterol.
used in
Kaposi sarcoma
describe myocet liposome based product
Doxorubicin
150-190nm size liposomes composed of
egg phosphatidylcholine and cholesterol
First-line treatment of metastatic breast cancer in woman.
how are liposomes are used in tumor targeting for cancer treatment:
Liposomes can exploit the Enhanced Permeability and Retention effect (EPR effect)
This allows them to target the anticancer agents to tumour sites via passive targeting
To achieve this liposomes can be prepared with a pegylated surface and <100 nm in size.
why do we need long circulation ?
Enhanced circulation allows the liposomes to target tumour sites.
This is due to the unique blood vasculature within tumours.
- blood vessels in growing tumours are ‘leaky’ to circulating macromolecules and large particles
- allowing them easy access to the tumour’s interior.
what side effects do liposomes cause?
Hand-foot syndrome (palmar-plantar erythrodysesthesia or PPE):
Redness, swelling and sores on the palms of your hands and soles of your feet
Reports of 48% with Caelyx vs 2% with drug.
what is counselling to minimise side effects for lipsooem based products?
4 to 7 days after each infusion, keep hands and feet uncovered (avoid socks/gloves/tight-fitting shoes) and soaking them in cool water when possible.
Avoid exposing the skin to very hot water, eg saunas and jacuzzies, and avoid exercise that might cause damage to the skin, eg jogging.
