Nanoparticles: A smart approach for cancer chemotherapy delivery

what is the mechanism of action of doxorubicin

• intercalation into DNA and mitochondrial DNA and disruption of topoisomerase-II-mediated DNA repair

• generation of free radicals and their damage to cellular membranes, DNA, and proteins

what effects does doxorubicin have on the heart

• leads to enlarged heart/ enlarged left ventricle due to non selective mechanism of action

• up to 75% of patients treated with doxorubicin will experience chronic health issues such as cardiotoxicity

how does doxorubicin cause damage to the heart

• reactive oxygen species cause apoptosis of normal cardiac cells, mitochondrial disruption, oxidative phosphorylation

• oxidative stress and lipid peroxidation

• reduction in ATP production in the mitochondria which impairs cardiac function

• iron related free radicals and the formation of doxorunicinol metabolite.

what is the difference in nanotherapeutics vs nano theranostics vs chemotherapy

• chemotherapy non specific, right drug right disease

• nanotherapeutics tumour specific, right drug to the right site at the right moment

• nanotheranostics - patient specific therapy, right drug to the right patient personalised medicine

• cancer is a very heterogenous disease need patient specific delivery

what is the definition of nanomedicine

• is the use of nanotechnology to diagnose, treat and prevent disease

• chemotherapy has side effects, bioavailability issues, can’t pass through cell membranes, liposomes can deliver drugs inside cell membranes, can be used for diagnosis, enhance MRI, enhance contrast properties

what is there an imbalance of in cancer vasculature

• there is an imbalance between pro and anti angiogenic signalling

describe the vasculature in cancer

• the tumour vasculature is immature, tortuous and hyperpermeable which leads to a complicated TME (low pH, hypoxia)

what causes leaky vasculature

• rapid tumour growth triggers the formation of new blood cells (angiogenesis) which are often poorly constructed with incomplete basement membranes and irregular junctions between endothelial cells leading to leakiness

what is the consequence of leaky vasculature

• fluid accumulation - there is leakage of fluid from the blood vessels and can build up pressure within the tumour impacting its growth and oxygen supply

• metastasis - leaky vessels allow cancer cells to easily escape into the bloodstream, facilitating the spread to distant organs

• drug deliver - characteristic can be exploited in cancer by using drugs designed to accumulate in the tumour due to leaky vasculature

why does poor lymphatic drainage occur in tumours

• the growing tumour mass can physically compress and obstruct the lymphatic vessels in the surrounding tissue preventing the normal flow of lymph fluid and lead to a build up of fluid within the tumour site this can also lead to cancer spreading through the compromised lymphatic system to nearby lymph nodes

• tumour growth and compression - tumour expands and physically squeezes the lymphatic vessels, hindering fluid drainage

• remodelling of lymphatic vessels - tumours remodel the vessels, disrupting function and promoting metastasis

• increased intersisital fluid pressure - blockage in vessels caused by the tumour leads to a buildup of fluid within the tumour tissue raising the IFP

• cancer cell dissemination - impaired lymphatic drainage can facilitate the spread of cancer to nearby lymph nodes so can travel through the compromised lympahtic system

what do tumour cells recruit in order to grow

• they recruit neo vasculature to ensure an adequate supply of nutrients and oxygen

• as they grow they recruit new vessels or engulf existing blood vessels

• imbalance of pro and anti angiogenic signalling creates an abnormal vascular network

how is tumour microvasculature different from microvasculature of normal tissues

• it does not have an organised, regular, branching order

• it shows disorganisation and lack of the conventional hierarchy of blood vessels

• arterioles, capillaries and venules are not identifiable, vessels are enlarged and often interconnected by bidirectional shunts

• inconsistent shape and diameter

how does the tumour create a complicated tumour microenvironment

• produce a large amount of hydrogen ions, lactate and pyruvate through glycolysis this creating an acidic microenvironment

• tumour vessles are more permeable than normal vessels and this leads to accumulation of vascular contents and enhanced IFP

• lymphatic vessels are dilated, leaky and discontinuous which diminishes their ability to deliver nutrients and remove waste products

what is the TME

• hypoxic and acid with high IPF promoting tumour development, immunosuppression and drug resustance

what are the clinical consequences of poor lymphatic drainage

• lymphadenopathy - when cancer cells spread to the lymph nodes via the lymphatic system, it can cause swollen lymph nodes which is a sign of cancer progression

• lymphedema - in some cases after cancer surgery that involves removing the lymph nodes, poor lymphatic drainage can lead to lymphedema which is characterised by swelling due to fluid build up in the affected area

• metastasis due to cancer cells travelling in the lymph nodes

what is the EPR effect

• it is a phenomenon where nanoparticles (drug carriers) and macromolecules preferably accumulate in tumor tissue due to leaky vasculature and poor lymphatic drainage

what does enhanced permeation allow

• large endothelial gaps (100-800nm) allow nanoparticles to extravasate

• cancer is heterogenous so endothelial gaps can be different between individuals

what does retention allow

• impaired lymphatic drainage, leads to prolonged nanoparticle accumulation

what does passive targeting of nanomedicine allow

• targeted drug delivery by liposomes, polymeric micelles, dendrimers,

• reduces systemic toxicity

what factors affect the EPR effect

1- tumour type and heterogenity

2- vascular permeability, extravasation and blood flow

3- intersistial fluid pressure

4- physiochemical properties: Size, shape, charge and coatings (to avoid opsonisation)

5- External stimuli, radiation, temperature, light, ppH

6- Patient specific factors

why does tumour type and heterogenity affect the epr effect

• epr effect varies between solid tumours (breast, pancreatic, glioblastoma) and hematologic malignancies

• heterogenous vascular architecture affects nanoparticle accumulation

how does Vascular Permeability, Extravasation, & Blood Flow affect epr

• Tumors with highly leaky vasculature (e.g., certain aggressive tumors) show a stronger EPR effect.

 

• Inadequate perfusion in hypoxic tumor regions reduces nanoparticle delivery.

how does  Interstitial Fluid Pressure (IFP) effect EPR effect

High IFP in solid tumors impedes nanoparticle penetration into deep tumor regions. Poor lymphatic drainage, fluid oozes out of the tumour

how do the physiochemical properties of the nanomedicine influence the EPR effect

• Size & Surface Properties: Optimal Size: 50–200 nm (smaller nanoparticles may be cleared rapidly, larger ones may have poor penetration).

 

• Charge & Hydrophobicity: Neutral or slightly negative particles avoid rapid clearance.

 

• Stealth Properties: Surface modification with polyethylene glycol (PEG) prevents opsonisation and enhances circulation time.

• IMPORTANT - avoid immune response and are not recognised as foreign body

how can stimuli sensitive nanoparticles affect the epr effect

Stimuli-responsive nanoparticles (pH-sensitive, enzyme-activated) can improve EPR-based delivery.

how can patient specific factors effect the EPR affect

• Individual Variability: Differences in genetics, metabolism, and immune response influence EPR.

 

• Age & Comorbidities: Elderly patients or those with cardiovascular diseases may have altered vascular function, affecting drug delivery.

 

• Immune System & Tumor Microenvironment: Macrophages & immune cells may recognise and clear nanoparticles, reducing EPR efficiency.

 

EPR depends on hypertension, blood pressure.

Age can affect the immune system

what can EPR enhancers do

• broaden the window to make blood vessels more permeable to nanoparticles

• charge can help avoid opsonisation, cationic attach more

• the harder the particles the easier to opsonise

what is pegylation

• chemical process that attached polyethylene glycol chains to molecules to improve their properties

• it is non toxic, water soluble polymer that is FDA approved

what are advantages of PEGylation

• prevents aggregation

• minimised opsonisation

• avoids phagocytosis

• prolonged circulation time

• immunogenicity decreases

what two clinical strategies can be used to improve the EPR effect

• physical approaches: use external, physical stimuli such as radiation or head to temporarily increase the permeability in tissue

• pharmacological approaches: rely on the administration of a drug to interfere with the tumour microenvironment for improved nanoparticle accumulation

what physical approaches are used to improve the EPR effect

• hyperthermia

• radiotherapy

• photodynamic therapy

• ultrasound

why is hyperthermia used to improve epr effect

• increases the gaps between vascular endothelial cells

why is radiotherapy used to improve the epr effect

• induces apoptosis in endothelial and tumour cells and enhances the expression of VEGF and FGF which in combination leads to vasculature leakiness

how does photodynamic therapy increase epr

• photosensitizers upon light illumination kill endothelial and tumour cells via the ROS production

• photosensitisers accumulate preferentially in cancer cells due to high affinity towards low density lipoproteins

how does ultrasound increase EPR

• physically opens the intercellular gaps on blood vessels by bubble- induced expansion and compression

how does VEGF work

• vascular endothelial growth factor causes blood vessels to lead by signalling endothelial cells to loose their tight junctions

how does fibroblast growth factors work

• promote vascular permeability meaning they can increase the leakage of fluid from vessels into surrounding tissue

what pharmacological strategies are used to improve the EPR effect

• vascular normalisers improve blood flow and reduce IFP

• remove clots and reduce IFP

• vascular mediators enhance the permeability of endothelial cells

• ECM degradation decreases the density of stroma

• tumour penetrating peptides enhance transcytosis through endothelial cells and endocytosis in cancer cells

what are examples of vascular modulators/ EPR enhancers

• angiotensin converting inhibnitors and angiotensin II induced hypertension

how does angiotension II help improve the EPR effect

• is a peptide hormone that increases blood pressure and is involved in the development of hypertension

what is active targeting

• it involves the modification or functionalisation of the nanoparticle with ligands to specifically target cancer cell markers

what are the advantages of active targeting

• more efficient (can increase the target concentration of drugs in target cells, more effective than passive targeting)

• more specific ( can target and identify and attach to specific cells, reducing damage to normal tissues)

• can treat disseminated locations (can help to treat metastatic lesions)

• can reduce side effects (reduced systemic toxicity by improving drug delivery)

• improve treatment efficacy

what cons of passive targeting

• low specificity

• toxicity/ side effects

what are cons of active targeting

• high cost

• short half life of biomarker/ ligand

• inability to target heterogenous tumour types

what are the 2 methods of uptake for nanoparticles

Nanoparticles that are functionalized with targeting ligands (e.g., antibodies and antibody fragments, nucleic acids aptamers, protein, peptides, and small molecules) can specifically bind to tumor-specific antigens or receptors expressed on the plasma membrane and enter tumor cells via clathrin-mediated endocytosis or other pathways, depending on their size, shape, charge, and surface modifications.

Alternatively, nanoparticles can be coated with plasma membranes derived from cancer cells, blood cells, or stem cells to achieve homotypic tumor targeting by taking advantage of the self-recognition and self-adherence capabilities of source cells, and can be taken up by tumor cells through membrane fusion

what is an example of a nanoparticle in clinic

CAELYX/ doxil

evades the immune system, prolongs half life, remains encapsulated until it reaches tumour, concentrates in tumour

Doxorubicin encapsulated in lipid liposome

what are challenges of nanomedicine

• bioparmaceutical properties, specific tumour targeting

• cost, repeatability, scaling up, clinical translational problems

• epr effect, off target effecrs, efficacy and toxicity vs free drug, personalised therapy

• uniformity and clarity on the regulation of nanodrugs

what are stimuli responsive nanoparticles in chemotherapy delivery

• ph responsive

• redox responsive

• mechanical

• magnetic hyperthermia

• photothermal therapy

• photodynamic therapy

what are the problems with pegylated liposomal doxorubicin

• reduced rate of heart failure, has the same side effects

• however the second dose the patients start to experience more side effects