WEEK 3 FLASHCARDS

Why do conventional chemotherapeutics come with a lot of side effects

because they are not very specific and kill all rapidly dividing cells.

MOA doxorubicin

inhibits DNA topoisomerase, causing DNA strand breaks and blocking cell cycle.

Also produces ROS and oxidative stress

important side effect with doxorubicin

cardiotoxicity

• binds to mitochondrial DNA and contributes to ROS production. Cardiac cells rich in mitochondria and are particularly vulnerable to damage from oxidative stress.

characteristics of cancer vasculature

• leaky, leading to fluid accumulation

• hyperpermeable

• gaps in endothelial cells bc of imbalance in pro and anti angiogenic signalling

• complicated tumour microenvironment

• hypoxic

• increased interstitial fluid pressure

what is the EPR effect

preferential accumulation of nenoparticles in tumour tissue because of their leaky vasculature and inefficient lymphatic drainage.

Factors that affect the EPR effect

• tumour type and heterogeneity - varies between solid tumours and hemetological malignancy

• vascular permeability and blood flow - highly leaky vasculature - enhanced EPR

• interstitial fluid pressure

• physicochemical properties

• external stimuli - temp, light, pH

• patient specific factors - genetics etc.

what is opsionisation

proteins called opsionins attach to a molecule, marking it for destruction by the immune system.

consequences of opsionisation for drug delivery

• can reduce circulation time of drugs

• decreases targeting efficiency

• triggers immune responses.

how to reduce opsionisation? how does this work

PEGylation - PEG coating of nanoparticles to introduce a hydration layer that blocks opsonin proteins from adsorbing onto nanoparticles through steric hinderance

physical strategies to enhance EPR effect

• hyperthermia- mild inc in temp of tumour, dilates blood vessels, enhancing permeability.

• radiotherapy - inc vas permeability by inducing endothelial cell apoptosis.

• photodynamic therapy - generates ROS, causes cell death.

• ultrasound- increased vascular permeability

Pharmacological strategies to enhance EPR effect.

• Tumour vascular normalisers

• fibrinolytic cotherapy - malignancy can result in hypercoagulative state in some patients. Fibrinolytics alleviate vascular stress and restore blood flow bt degrading fibirins in occluded vessels.

• extracellular matrix degradation

• tumour penetrating peptides - enhance transcytosis through endothelial cells in cancer cells.

• inproving blood flow, reducing clots, inproving IFP

examples of pharmacological modulators in epr

• nitric oxide

• ACE inhibitors - block degradation of bradykinin, increased effect of kinin and enhanced EPR effect.

what is active targeting

modification of nanoparticle with ligands to specifically target cancer cell markers.

advantages of active targeting

increased specificity

reduced side effects and increased therapeutic efficacy.

overcomes EPR limitations by actively binding to tumour cells.

examples of types of targets in active targeting

antibodies

peptides

proteins

cons of active targeting

high cost

short shelf life of ligands

inability ot targrt heterogeneous tumous

passive targeting pros

affordable

better stability

can target heterogeneous solid tumours

passive targeting cons

low specificity

toxicity depending on nanomaterial

nanomedicine journey in body

• IV injection, systemic distribution

• NPs need to be stable enough to keep drug inside until they reach their target.

• nanoparticles must escape blood vessels through gaps between endothelial cells to reach the tumour through EPR effect

• once in tumour, NPs travel through ECM.

• enter cancer cells via endocytosis.

uptake mechanisms of nanoparticles

• once bound to target ligand, NPs enter tumour cells through clathrin-mediated endocytosis, or biomimeting targeting

• biomimeting targeting - NPs coated with plasma membranes from cells to target tumour through self-recognition through camouflage.

Benefits of pegylated liposomal doxorubicin

reduced cardiotoxicity because of encapsulation of the drug which protects heart tissue from exposure during treatment.

challenges in cancer nanomedicine

• lacking global consensus of definitions of nanomedicine

• unclear regulatory pathways

• variability in nanomaterial properties

• balancing innovation and safety

examppes of stimuli responsive nanoparticles mechanisms

• pH responsive

• redox responsive

• magnetic hyperthermia

• photothermal therapy

• photodynamic therapy

types of radiotherapy

• external beam

• internal

• molecular

how does radiation cause DNA damage

• ionising radiation creates DNA lesions :

• base damage

• alkali labile sites

• single strand breaks

• double strand breaks

when can tumours be resistant to radiotherapy

the amount of damage caused by radiotherapy is enhanced if oxygen is present due to toxic oxidative stress, so hypoxic tumours can be resistant to radiation treatment.

side effects of radiotherapy

• tiredness

• skin reactions

• haor loss in treatment area

• emotional effects

• head and neck radio- swallowing issues

• some pts do not experience toxicity.

side effects of pelvic radiotherapy

oedema

sode effects of chest radiotherapy

effect on lung function

side effects of brain radiotherapy

cognitive and neurological effects

what are the advantages of proton beam therapy

• sparing of normal tissues

• lower risk of secondart cancers and normal tissue toxicities

complications of external beam radiation

• doses of radiation to healthy tissues

• need multiple beam angles to minimise doses to normal tissues.

• risk of long term consequences eg radiation induced cancers in later life.

what is brachytherapy

• internal radiotherapy

• implant little seeds of radioactivity into tumours- low energy rays emitted as they decay and can only get so far so are localised to tumours.

what is radiopharmaceutical therapy

external beam and targeted radionucelotide - need understanding of tumour biology and positioning.

can be delivered in various forms

combining chemotherapy with radiotherapy

• damage to DNA from radiotherapy and inhibition of DNA repair pathways enhances the efficacy of radiotherapy.

what is the therapeutic ratio

• the relativje expected benefit of a combined treatment taking into account the effects on the tumour and normal tissue.

• more thna 1= treatment more beneficial than toxic and vice versa.

• need to balance tumour response to treatment with toxicity before starting treatment.

what is scope of practice

activities that a HCP performs within their professional role.

HCPs should recognise and work within their limits of knowledge and skills.

competence meaning

• the ability to perform tasks successfully

what are the stages of competence

• unconscious incompetence

• conscious incompetence

• conscious competence

• unconscious competence

what factors affect the scope of practice

• clinical condition and stage of prescribing

• sector, location of practice

• pt age and communication difficulties

• complexity of cases and individual pharmacist experience, confidence and state of mind.

factors influencing the prescribing process

• medicine

• context

• prescriber

• patient