Nanomedicine: A Smart Approach for Cancer Chemotherapy Delivery

Page 2: Intended Learning Outcomes

• Identify key challenges in cancer chemotherapy and drug delivery.

• Explain the structural and functional abnormalities of tumor vasculature.

• Describe the Enhanced Permeability and Retention (EPR) effect and its role in nanomedicine delivery.

• Describe different targeting strategies: passive and active.

• Understanding of stimuli-responsive nanomedicine.

• Review examples of clinically approved and investigational nanocarriers utilizing these strategies.

Page 3: Side Effects of Cancer Drugs

• General Overview: Side effects vary by individual and depend on the specific cancer drugs used.

  • Hair Loss/Thinning: Common side effect; coping strategies available.

  • Gastrointestinal Issues: Diarrhoea, constipation, and heartburn can occur; support options exist.

  • Immunosuppression: Increase in bruising, bleeding, and infection risk with some drugs; management available.

  • Fatigue: A significant side effect, but strategies to cope are available.

  • Oral Health: Some drugs can lead to dry mouth; treatments can provide relief.

  • Nausea: Common with many chemotherapy drugs; there are supportive treatments.

  • Changes to Appetite/Taste: Some patients experience altered appetite or taste preferences; coping mechanisms are available.

  • Dermatological Changes: Cancer drugs may affect skin and nails; remedies exist.

  • Sexual/Fertility Changes: Possible changes, with management options available.

  • Organ Function Changes: Monitoring of kidney, liver, heart, and lung function; regular tests by doctors.

  • Hormonal Changes: Consideration of sex hormones affected by cancer treatments.

  • Neurological Effects: Some drugs may lead to nerve dysfunction.

  • Cognitive Changes: Known as chemo brain or chemo fog, affecting memory and concentration.

• These occur because cancer drugs have non selective toxicity, meaning they can affect and damage cancerous and healthy cells- can lead to adverse effects like cardiotoxicity.

• tumour cells can also develop resistance to cancer drugs- this reduces treatment efficacy.

• Most anticancer drugs also have poor bioavailability- low solubility, need high doses, increases the risk of toxicity.

• Nanomedicine can be used to overcome these challenges.

Page 4: Chemotherapy - Doxorubicin

• Type: Anthracycline (related drugs include daunorubicin, idarubicin, and mitoxantrone).

• It inhibits topoisomerase- stops DNA repair mechanisms and DNA replication. Also produces reactive oxygen species.

• MOA- NADH turns to NAD, converting doxorubucun to docorubicin semiquinone. These molecules lead to the production of hydrogen peroxied.

• In the presence of iron, this goes through fenton reactioon and leads to formation of hydroxyl radicals - causes lipid peroxidstion/ oxidative stress.

• The doxorubicin semiquinolne intercalates with mitochondrial DNA. Bindings to mitochondrial DNA .

• The highest number of mitrochondria are in cardiac cells- heart muscles pump a lot of blood and require a lot of energy. This means that doxorubicin kills cancer cells, but also affects cardiomyocytes. This can cause enlarged hearts

• Doxorubicin, also known as Adriamycin, is a widely used anthracycline chemotherapeutic drug with potent activity against many cancers. Its effectiveness mainly comes from inhibiting DNA topoisomerase II, causing DNA double-strand breaks and blocking the cell cycle. However, its use is limited by cumulative cardiotoxicity, largely due to the production of reactive oxygen species (ROS) and oxidative stress, particularly in heart cells that are more vulnerable because of their high mitochondrial content.

  Doxorubicin also binds to mitochondrial DNA and cardiolipin in mitochondria, further contributing to ROS production. An iron chelator, dexrazoxane, is used to mitigate this cardiotoxicity by reducing iron-mediated ROS generation.

  Despite its potency, doxorubicin is not targeted to specific tumor markers, resulting in non-selective tissue distribution, a short half-life, and low tumor accumulation. Effective therapy often requires high doses, increasing the risk of side effects due to the drug’s lack of selectivity

• Side Effects: Non-selective mechanism leading to various side effects.

  • Examples include enlarged heart conditions noted in specific patient types (osteosarcoma, invasive ductal carcinoma).

  • Up to 75% of patients treated with dox sufffer chronic health iddues like heart failure.

Page 5: Nanomedicine Overview

Chemotherapy is non specific therapy- it targets the disease but not specific tumour sites. The whole body is exposed to the drug. this can lead to side effects as it damages healthy cells as well as cancer cells.

• Definition: Use of nanotechnology to provide specific therapy to tumors.

• Nanotherapeutics: Focus on tumor-specific therapy versus traditional nonspecific chemotherapy.

  • Importance of delivering the correct drug to the correct site at the right moment.

  • Nanotherapeutics can provide tumour specific therapy- using nanomedicine to deliver drugs directly to tumours, which reduces side effects.

• Nanotheranostics: Personalized therapy approach for targeted patient-specific therapy.

• This combines therapy and diagnostics into one approach. Uses nanoparticules that both treat and track tumours, allowing real-time monitoring of treatment efficacy.

Page 6: Popularity of Nanomedicine

• Market size projections: $230 billion by 2025, expanding to $620 billion by 2034.

• Reasons for popularity: Overcoming limitations of current treatments.

• Radiation therapy is used in more than half of all cancer patients- although it is one of the most effective treatment modalities, still anhuge challenge to alleviate short and long term toxicity.

• Same with chemotherapy

• traditional systemic administration of drugs has put all somatic cells at risk of toxicity.

• can reduce side effects and avoid drawbacks of chemotherapy by enclosing the drugs in a tiny compartment- absorbing drug into well designed pores/ mediums- provigind stabilised microenvironment - enabling active interaction within thr body, with the assistance of biomimicking membranes and releasing drigs after transport to desired sites- this is what nanotechnoligy tries to accomplish.

• Nanopraticle platforms for cancer treatmenr- liposomes, albumin, polymeric micelles. These rapidly cross the human biological barriers, even in targeted manner and continuously release the content to maintain appropriate blood conc of drug.

• 2 main unresolved issues in nanomedicine area-

• enhanced permeability and retention (EPR) given limited improvement in the survial outcomes in patients, even though EPR confirmed to dec risk of adverse effects and enhance efficacy during preclinical stages and animal model.

• Lots of nanomedicines/ materials used- plenty of organic ad inorganic nanocarriers but very few FDA approved.

Page 7: Cancer Vasculature Challenges

• Characteristics: Leaky tumor vasculature leading to fluid accumulation, metastasis, and difficulties in effective drug delivery.

• Immature Tumor Vasculature: Tends to be tortuous and hyperpermeable, resulting in a complicated tumor microenvironment (TME).

• NORMAL VASCULATURE- tight endothelial junctions, no gaps inbetween

• TUMOUR VASCULATURE- gaps in endothelial cells= leaky.

• this happend because of an imbalance in pro and anti angiogenic signalling.

• To grow, tumour cells recruit neovasculature to ensure supply of nutrients and oxygen. As they grow, they recruit new vessels/ engulf existing blood vessels. Imbalanceof pro and anti-angiogenic signalling within different parts of tumours creates abnormal vascular network- dilated, tortuous and saccular channels, w haphazard patterns of interconnection and branching.

• Tumour vasculature shows disorganisation. Arterioles, capillaries and venules are not identifiable. vessels are enlatged snd often interconnected by bidirectional shunts.

• The accompanyig lymphatic vessels are dilated, leaky and discontinuois- these reduce their ability to deliver nutrients and remove waste products.

• Tumour cells can produce a large amount of hydrogen ions, lactate and pyruvate (from glycolysis) this creates acidic microenvironment. These abnormalities create complicated TME - hypoxic and acod with high IFP- this promotes tumoir development, immunosuppression and drug resistance.

• inc in angiogenesis in tumours means the size increases, causing compression on lymohatic system- leading to poor lymphatic drainage.

• Lymphatics cant move, so thete is a lot of interstitial fluid pressure inside the tumour.

• Increased interstitial fluid pressure, as well as leaky vasculature, causes abnormal vessel formatin and hypoxia, because the continuous formation of blood vessels needs oxygen. and low pH- tumour vasculature is slightly acidic due to lactic acid formation.

• The rapid tumour growth in cancer triggers angiogenesis- poorly constructed w incomplete basement membranes and irregular junctions causing leakiness.

• Consequences of this - include fluid accumulation - leaking fluid from blood vessels can build up pressure within tumour, impacting growth and oxygen supply.

• Metastasis- leaky vessels allow easy escape of cancer cells into bloodstrea, where they can spread to other organs.

• Drug delivery- can be exploited in cancer treatments- use drugs that are designed to accumulate in the rumour due to leaky vasculature.

Key points-

•Tumor growth and compression:

•As a tumor expands, it can physically squeeze the lymphatic vessels, hindering the drainage of fluid. 

•Remodeling of lymphatic vessels:

•Tumors can also actively remodel the lymphatic vessels around them, further disrupting their function and promoting metastasis. 

•Increased interstitial fluid pressure:

•The blockage in lymphatic vessels caused by the tumor leads to a buildup of fluid within the tumor tissue, raising interstitial fluid pressure. 

•Cancer cell dissemination:

•This impaired lymphatic drainage can facilitate the spread of cancer cells to nearby lymph nodes, as they can more easily travel through the compromised lymphatic system. 

Clinical implications:

•Lymphadenopathy:

•When cancer cells spread to lymph nodes via the lymphatic system, it can cause swollen lymph nodes, which is often a sign of cancer progression. 

•Lymphedema:

•In some cases, particularly after cancer surgery that involves removing lymph nodes, poor lymphatic drainage can lead to lymphedema, a condition characterized by swelling due to fluid buildup in the affected area. 

Page 8: Enhanced Permeability and Retention (EPR) Effect

• Definition: EPR effect refers to the preferential accumulation of nanoparticles and macromolecules in tumor tissue due to their abnormal leaky vasculature and inefficient lymphatic drainage.
  This is the basis for passive targeting in nanomedicine, allowing drugs to concentrate in tumours w/o specific ligand-receptor interactions.

  • Enhanced Permeation: Caused by large endothelial gaps (100-800 nm).

  • Retention: Impaired lymphatic drainage facilitates prolonged accumulation of nanoparticles.

  • Role of EPR in Drug Delivery: Allows for targeted drug delivery, reducing systemic toxicity.

• Molecules larger than 40kDa show enhanced tumour accumulation via EPR- smaller molecules are rapidly cleared by renal filtration.

• Nanoparticle size- 10-800nm but changes from patient to patient because of tumour heterogeneity.

• Tumoir hetetrogeneity- EPR affect varies based on tumour type, location and vasculatisation.

• EPR mediated drug accumulation is passive targeting - doesnt need specific interaction sbetween the drug and tumour cells. nanoparticles passovelt extravasate through leaky tumour blood vessels. drug retention facilitated by poor lymphatic drainage - leads to prolonged drug exposure.

• active targeting involves ligand-receptir interactions (eg antibpdy-drug conjugates binding to tumour specific markers)

  • Limiatations of EPR effects. - tumour heterogeneity - affects extent of EPR effect., some tumours have low vascular permeability

• systemic admin is frequently used in nanomedicine - IV administered naoparticles transport directly w bloodstream and may eventually reach diseased tissues by exploiting EPR effect- upon accumulation, the nanoparticles will exert their fucntion inside the diseased tissues.

Page 9: Factors Influencing EPR Effect

1. Tumor Type and Heterogeneity

   EPR effect varies b/w solid tumours and hemetologic malignancies. Heterogenous vascular architecture affects nanoparticle accumulatuion.

2. Vascular Permeability, Extravasation, and Blood Flow

   Tumours with highly leaky vasculature show stronger EPR effect. inadequate perfusion in hypoxic regions reduces nanoparticle delivery.

3. Interstitial Fluid Pressure

   high IFP in solid tumours stops nanoparticle penetration into deep tumour regions.

4. Physicochemical Properties: Size 50-200nm - smaller are cleared rapidly, Shape, Charge and hydrophilicity- neutral/ slightly nefative particles can avoid rapid clearance, Coatings

5. External Stimuli: Radiation, Temperature, Light, pH- drug release mechansms- stimuli responsive nanopraticles can improve EPR based delivery

6. Patient-Specific Factors- individual variability - different genetics, metabolism, immune respinse- all influence EPR

   age and comorbidities- can alter vascular function and affect drug delivery

   immune system and tumour microenvironment— in some individuals macrophages and immune cells might recognise and clear nanoparticules, this reducing EPR efficacy.

(extravasatin- movement of fluid- lymph system

opsionisation - the particles not being reconguised as foreign bodies, preventing an immune response

extravasation - movement of fluid. )

Page 10: EPR Effect Visualization- factors affecting the EPR effect

• Normal vs. Suppressed EPR Effect: Differences in permeability depending on tumor size and heterogeneity.

• Nanoparticle Structure Impact: Different types of nanoparticles such as liposomes, micelles, and metallic nanoparticles differ in effectiveness based on their properties.

Heterogeneity of the EPR Effect

• EPR (Enhanced Permeability and Retention) Effect: Enables the accumulation of nanomedicines in tumor tissues due to leaky vasculature and poor lymphatic drainage.

• Heterogeneity Issue: The EPR effect is inconsistent across different tumors and even within the same tumor, particularly in large or necrotic tumors with occluded blood vessels. This variability hampers effective drug delivery.

• Causes: Blocked or embolized tumor vessels, thrombosis, and coagulation restrict blood flow, reducing the EPR effect.

• Potential Solutions: Enhancing the EPR effect by modulating tumor vasculature and leveraging biological processes like inflammation and cytokine activity could improve nanomedicine delivery.

Physicochemical Factors Impacting EPR Effect

1. Size:

   • Nanomedicines larger than 40-50 kDa (6-8 nm) avoid rapid renal clearance, ensuring longer circulation and better tumor accumulation.

   • Common sizes: 10–100 nm; larger particles (1-2 μm) like certain bacteria can also accumulate in tumors.

2. Surface Charge:

   • Positively charged particles bind endothelial cells but have rapid plasma clearance and low tumor accumulation.

   • Highly negatively charged particles circulate longer but are often cleared by the liver and spleen (RES).

   • Optimal charge: Neutral or slightly negative for better circulation and EPR effect.

3. Shape:

   • Shape affects accumulation and penetration. For example:

     • Worm-like micelles: Better drug loading and release; no consistent advantage in tumor accumulation.

     • Gold nanoparticles: Spheres accumulate more, but rods/cages penetrate deeper.

     • Rod-shaped particles: Show better accumulation with targeting ligands.

   • The best shape depends on the therapeutic goal (e.g., drug delivery vs. photothermal therapy).

4. Softness (Rigidity):

   • Softer nanoparticles show better tumor penetration and accumulation due to reduced immune clearance.

   • Medium rigidity liposomes may offer optimal tumor accumulation.

   • Rigid nanoparticles may be more effective in active targeting or transcytosis.

Other Factors:

• Biocompatibility: Essential for minimizing immune clearance and ensuring prolonged circulation.

• Clearance by RES/MPS: Opsonization triggers clearance by macrophages, reducing plasma half-life and impairing the EPR effect

Page 11: Opsonization and its effect on EPR Effect

• Opsonization Process: Plasma proteins eg immunoglobulins and complement proteins bind to nanoparticles in the bloodstream. THis marks them for recognition and clearance by the MPS- in liver and spleen.

• reduces circulation time- once they are optionised, nanoparticles are taken up by macrophages, which limits their bioavailability.

• it decreases targeting efficiency- as it interferes woth passive targeting (EPR effect) and active targeting.

• triggers immune respinses- some NPs induce an inflammatory response after opsonisation.

How to reduce opsonisation:

• PEGylation - PEG coatings create hydration shell which reduces protein adsoprtion anf immune recognition.

• surface change modification- neutral or slight nefatibe charges minimise non specific protein binding.

• Biometric coatings- cell membrane camouflaging reduces immune cleatance - eg using RBC membranes

• Hydrophillic surfaces- polymers, polysaccharides or zwitterionic coatings improve stealth properties.

• size, shape optimization- small and spherical NPs w smooth surfaces evade macrophage uptake better than large/ irregularlt shaped particles

Opsonisation and drug deluvery

• must be controlled to prolong circulatin time and enhance tumour accumulation via passive or active targeting

• stealth nanocarriers are designed to resist opsonisation and improve delivery efficacy.

• can be exploited to provide immune modulation therapy to enhance immune cell targeting.

Page 12: PEGylation

• Definition: PEGylation involves attaching polyethylene glycol (PEG) to drug carriers to enhance solubility and reduce immunogenicity.

• Benefit: Improves stability and circulation in the bloodstream.

• To achieve effective delivery of systemically administered nanoparticles (NPs), maintaining prolonged circulation in the bloodstream is crucial. Proteins and peptides are typically degraded and cleared rapidly, so strategies like surface coating with inert polymers are used to extend their circulation time.

  PEGylation, the process of coating nanoparticles with polyethylene glycol (PEG), is the most common method for imparting "stealth" properties. PEG is FDA-classified as Generally Recognized as Safe (GRAS) and is widely used due to its ability to:

  • Prevent opsonization (binding of blood proteins that signal clearance)

  • Avoid recognition by macrophages and delay phagocytosis

  • Prolong systemic circulation time by forming a hydrophilic, hydrated barrier that prevents aggregation and interaction with blood components

  PEGylation introduces steric hindrance, creating a physical barrier that blocks unwanted interactions, including receptor binding and enzymatic degradation. Nanoparticles with steric shielding avoid macrophage recognitino, prolonging their half life in blood.

• Prevents opsionisation by introducing a hydration layer that physically blocks opsonin proteins from adsorbing onto nanoparticles.

Page 13: Clinical Strategies to Enhance EPR Effect

• Physical Strategies: Utilize external stimuli (e.g., radiation) to enhance vascular permeability in tumors.

• Pharmacological Strategies: Use drugs to modify tumor microenvironment for better nanoparticle accumulation.

Page 14: Physical Strategies Detailed

• Techniques: Hyperthermia, radiotherapy, photodynamic therapy, and ultrasound to enhance permeability of tumor vasculature.

• Hyperthermia- often in combination with other types of therapt. Can be applied to whole body, or localised. Mild increase in temperature of the tumour- heat dilates the blood vessels. this enhances vascular permeability so nanomedicines are more easily able to enter the tumour and stay there because of faulty lymphstics.

• Radiotherapy- one of the first line treatments of solid tumours. Enhances EPR effect by increasing vascular permeability by indicong endothelial cell apoptosis and increasing vascular endothelial growth factor and fibroblast growth factor gene expression. These decrease intratumoral pressure and enhance intratumoral drug penetration and distribution of nanoparticles.

• Photodynamic therapy- local or systemic administration of photosensitizers followed by light ittadiation at a certain wavelength. Whrn the photosensitisers are exposed to light, reactive oxygen species are generated, causinf cell death- leads to enhanced tumout vascular permeability, thus improved drug delivery to the tumour. photosensitisers accumulate preferentially in cancer cells bc of high affinity to low density lipoproteins (higher in cancer cells). Preferential accumulation helps limit cytotoxic effects of PDT to tumout sites that are lically illuminated

• Ultrasound- High tissue penetration depth, non invasive and easy to use. emhances epr effect by enhancing cell membrane permeability. Somoporation is the use of ultrasoound in conjunction w microbubbles or nanobubbles- expansion and compression of bubbles upon exposure to ultrasound leads to permeabilisation of the cell membranes and disrupts blood vessels to enhance drug delivery. Microbubbles often too big to pass through vessel themselves but enable passage of nanoparticles.

Page 15: Pharmacological Strategies Continued

• Terminologies: Vascular normalizers and mediators that impact endothelial permeability; tumor-penetrating peptides enhancing transcytosis.

• Tumour vascular normalisers - anti-angiogenic drugs initnially designed for oxygen and nutrient deprivation tumour tissues, but these agents demonstrate limited therapeutic benefit when used as a single agent in clinical settings. therefore a strategy to yse angiogenesis inhibitors as a tumour blood flow modulator to increase the delivery efficacy of nanoparticles has been developed. Vascular normalisers improve blood flow and reduce IFP.

• Small molecule tyrosine kinase inhbitors are also widelt investigated for vascular normalisation to promote epr mediated drug delivery

• Fibrinolytic cotherapy- hypercoagulative state of malignancy can occur in cancer patients- contributes to mortality- results from the tumour cells overexpressig tissue factors, producing tf bearing microparticles and secreting pro inflammatory cytokines and the cytokine activated endothelial cells and leukocytes overexpressing TFs, augmenting procoagulant molecule production , thus inducing platelet activatuin - resulting vascular occlusion contributes to heterogeneity of the EPR effect in tumour tissues- causes ineffective anticancer drug delivery, Fibrinolytics are good candidates to alleviate vascualr srewss ans restore tumour blood flow by degrading fibrins in occluded or compressed vessels.

• Vascular mediarors involved in the EPR effect- bradykinin. critical mediator of inflammation- causes pain and edema. increased kinin generation by tumour cells through secretion of plasminogen activatior and other proteases. these cells subsequently activare the prekallikrein/ kallikrein cascade to generate bradykinin- facilitates endothelial cell, gap opening and enhances vasc permeability. Other vascular mediators- NO, CO, heme oxygenase-1.

• Extracellular matrix degradation- the overproduction and deposition ECM proteins at high density restricts dissusive and convective transport of drugs within the tumour. ecm degradation decreases the density of the stroma. This reduction in stroma density improves the distribution of therapeutic agents, allowing for more efficient tumor-targeted drug delivery and enhanced treatment efficacy.

• Tumour penetrating peptides- nutrient exchange rate across the tumour vasculature is high to cope with the aberrant tumour growth and nutritional demand of tumours. trans endothelial transport pathays are exploited by using ligands that target the receptors expressed on the tumour endothelial cells to actively extravasate the nanoparticles from blood to the tumour. Tumour penetrating peptides enhance transcytosis through endothelial cells and endocytosis in cancer cells.

Page 16: Pharmacological Modulators in EPR

• Examples: Nitric oxide and ACE inhibitors can enhance EPR effect, facilitating better delivery of treatments.

• ACE inhibitors - ACR is a central component of renin-angiotensin system that keeps BP high - converys angiotensin1 to angiotensin 2- vasoconstrictor. C terminal amino acid sequence of angiotensin 1 is similar to that of bradykinin so ace also degrades BK- resutlts in the inactivation of BK - giving reduced EPR effect. Using an ace inhubitor for HTN, degradation of BK might be blocked, leafing to increased pharmacological actions of kinin and an enhanced EPR effect.

• Tumour blood vessels lack a smooth muscle layer required for vasoconstriction, so these demonstrate poor response to angiotensin 2. When htn is generated by infucion of AT2, normal blood vessels constrict, but tumour vessels dont- they dilate and cell-cell gap junctions will open- increased blood flow and leakage out of tumour blood vessels- leaing to improved delivery of drugs to tumours.

Page 17: Active Targeting Benefits

• Active targeting - modification or functionalisation of the nanoparticle/ drug carrier with ligands to specifically target cancer cell markers. Actively directs nanoparticles to specific cells/ tissues improving drug accumulation and therapeutic efficacy.

• Advantages of Active Targeting:

  • Increased efficiency and specificity;

  • Ability to treat disseminated cancer locations;

  • Reduced side effects and improved therapeutic efficacy by using ligands on nanoparticles.

Page 18: Active Targeting of CSCs

• Mechanism: Modification of generic nanoparticles with targeting moieties (eg antibodies, peptides/ ligands) that bind specifically to cancer stem cell markers to improve therapy uptake and ensure selective delivery.

• Functionalised nanoparticles circulate in the body and selectively bind to CSCs (cancer stem cells) through receptor mediated endocytosis. Once inside the CSCs, chemotherapeutic drug is released, leading to targeted cell death while sparing normal cells.

• Advantages over passive targeting-

• higher specificity for CSCs

• reducing off target toxcitity

• overcomes EPR limitations by actively binding to tumout cells

• improved drug accumulation in resistant cancer cell populations, reducing tumoir relapse and metastasis.

Page 19: Active Targeting Moieties Classification

• Types of Targets:

  • Antibodies, Peptides, Proteins, Aptamers: Each with unique characteristics, advantages, and limitations regarding production costs and efficacy.

Page 20: Recap of Targeting Strategies

• Comparison: Active targeting nanoparticles provide more specificity compared to passive targeting techniques.

• ACTIVE TARGETING PROS

• high specificity , low toxicity/side effects

• ACTIVE TARGETING CONS

• high cost

• short shelf life of ligands/biomarkers

• inability to target heterogeneous tumour types

• PASSIVE TARGETING PROS

• affordable

• better stability

• can target heterigenous solid tumours

• PASSIVE TARGETING CONS

• Low specificity

• toxicity/ side effects depending on the nanomaterial

Page 21: Nanomedicine Journey in the Body

• Mechanism of Action: Details on renal clearance, tissue penetration, biodistribution, and the importance of overcoming barriers such as the protein corona.

• Systemic biodistribution after IV injection- IV administration introducrs nanoparticles into the bloodstream. therefore nanoparticles must remain stable in circulation without premature drug release. If theyre too small, they are excreted through the kidneys. Free drufs released prematurely from nanoparticles can be metabolised and cleared by the liver. If nanoparticles are recognised as foreign particles, macrophages in the liver clear them. Larger nanoparticles or those recognised by the immune system can be removed by the spleen or reticuloendothelial system.

Tumour penetration - extravasation - nanoparticles must escape the blood vesses through gaps between endothelial cells to reach the tumour- EPR effect.

Interstitial barriers- once in tumour, nanoparticles navigate through extracellular matrix composed of fibroblasts and stroma.

Tumours oftn have high interstitial pressure- can hinder movement of nanoparticles deeper into tissue.

Nanoparticles have to enter cancer cells via endocytosis- they need to release drug at right place and time for therapeutic effect.

Page 22: Uptake Mechanisms of Nanoparticles

• Mechanisms Detailed: Phagocytosis, clathrin-mediated endocytosis, caveolin-mediated endocytosis, and receptor-facilitated uptake.

Nanoparticles (NPs) can be engineered for tumor-specific targeting by functionalizing their surfaces with targeting ligands such as antibodies, antibody fragments, aptamers, proteins, peptides, carbohydrates, or small molecules. These ligands allow NPs to selectively bind to tumor-specific or overexpressed antigens and receptors on cancer cell membranes, enhancing tumor retention and cellular uptake. Once bound, NPs typically enter tumor cells through clathrin-mediated endocytosis or other internalization pathways, influenced by their size, shape, charge, and surface modifications.

An alternative strategy involves biomimetic targeting, where NPs are coated with plasma membranes derived from cancer cells, blood cells, or stem cells. This coating gives them homotypic (same type) or heterotypic (different type) adhesive properties, enabling tumor targeting through self-recognition and membrane fusion mechanisms. This natural camouflage approach has gained attention for its potential to improve tumor targeting efficiency.

Page 23: Historical Timeline of Cancer Nanomedicine

• Significant milestones from the discovery of EPR effect to FDA approvals and development of novel nanoparticle technologies.

• Currently 15 cancer nanomedicines approved globally. no actively targeted cancer nanomedicine has recieved regulatory approval.

Page 24: Market Overview of Cancer Nanomedicine

• Examples of Approved Products: Key details on nanoparticle-based drug delivery systems approved in various markets such as FDA and EMA; their materials and indications.

Page 25: Market Trends

• Future Projections: Detailed list of nanoparticle products in the market with their respective drug mechanisms and applications.

Page 26: Clinical Example - CAELYX/Doxil

• Overview of CAELYX: Demonstrated effectiveness in evading the immune system and prolonging half-life while remaining effective until reaching tumor sites.

• Doxil is liposomal formulation of doxorubicin- pegylated liposomal doxorubicin.

• reduction of cardiotoxicity because of the encapsulation of the drug, which protects the heart tissue from exposure during treatment.

• Evades immune system, significantly prolongs half life, remains encapsulated until it reaches tumour where it concentrates.

Page 27: Clinical Imaging of Kaposi Sarcoma

• Imaging Results: Observational studies in patients showing uptake of radiolabeled liposomes in consistent areas with tumor lesions.

Page 28: Patient Response to CAELYX Treatment

• Clinical Improvement: Changes observed in chest X-ray post-chemotherapy showing significant tumor reduction.

Page 29: Doxorubicin/Doxil in Breast Cancer

• Comparison of Formulations: Analysis of overall effectiveness and side effects, with a notable reduced rate of heart failure in certain formulations.

• Doxil has a much longer circlulation half life than doxorubicin. This facilitates greater uptake of PLD liposomes by tumour tissue - EPR. PLD accumulates selectiivelt in metastatic carcinoma tissue - 10fold higher intracellilar drig concs compared w normal tissue. Pegylated liposomal encapsulation also reduces plasma levels of free doxorubicin and reduce drug delivery in the heart- reduces cardiotoxicity.

• Hand-foot syndrome- common side effect of PLD occurs bc pharmacokinetics lead to drug accumulation in the skin capillaries- esp hands and feet.

• Long plasma half life due to pegylatin which enhances tumour accumulation via enhances permeability and retention effect, but it can also accumulate int he skin - esp areas subject to mechanical stress.

Drug leakage from capillaries- small liposomal size allows extravasation in tissues with high vascular permeability incl hands and feet. Mechanical pressure nd heat further increase local blood flow and vascular permeability - leads to passove leakage of doxorubicin into the dermis.

Direct cytotoxicity and inflammation- once doxorubicin is released from liposomes, it causes local cytotoxicity - damaging keratinocytes and endothelial cells. Thid triggers inflammation, erythema, swelling , pain - characteristic of hand foot syndrome.

Page 30: Market Projections for Liposomal Doxorubicin

• Market Growth Estimates: Expected growth rates in the liposomal doxorubicin market highlighting various formulations.

Page 31: Active Targeting Example in Clinic

• Case Study: Details on Trodelvy, an antibody-drug conjugate for triple-negative breast cancer, its mechanism, and recent success.

• Triple negative breast cancer - aggressive and metastatic due to the lack of 3 receptors. difficult to target.

• Sacituzumab-Govitecan= antibody drug conjugate designed for active targeting in triple neg breast cancer and other solid tumours.

• Human monoclonal antibody specifically targetd trop 2 - overexpressed in multiple epithelial cancers- antibody enables precise delivery of cytotoxic payload to trop 2 expressing tumour cells.

• Linker- hydrophillic ph sensitive linker that connects the antibody to the drug payload. This gets cleaved near to tumour side where pH is slightly acidic compared to normal tissue- ensures stable circ in bloodstream bit releases payload upon internalisation into the tumour cell.

• Payload- SN-38 is a topoisomerase 1 inhibitor , prevents DNA replication and induces apoptosis in rapidly dividing cancer cells. Highly effective in killing tumour cells. Higher drug to antibody ration compared to others.

• MOA- Target Recognition & Binding: The monoclonal antibody specifically binds to Trop-2 on the tumor cell surface.

• Internalization & Payload Release: The antibody-drug conjugate (ADC)-Trop-2 complex is internalized via endocytosis, where the pH-sensitive linker breaks down inside the cell, releasing SN-38.

• Cytotoxic Effect: SN-38 inhibits topoisomerase I, leading to DNA damage, cell cycle arrest (at G2/M phase), and apoptosis.

• Bystander Effect: Released SN-38 can diffuse into nearby tumor cells, boosting anti-tumor effects even in heterogeneous tumors.

Page 32: Clinical Trials for Actively Targeted Nanomedicines

• Current Trends: Discussion of lipid-based nanocarriers in clinical trials for cancer treatment.

• All still in clinical trials. none approved yet.

Page 33: Challenges in Cancer Nanomedicine

• Overview on Challenges: Biopharmaceutical properties, specific tumor targeting, and scaling-up strategies; EPR effect considerations and the 5R rule of patient stratification.

• Lack of Global Consensus: Different countries have varying definitions and regulatory frameworks for nanomedicines, creating confusion and barriers to international collaboration and market access.

• Varying Definitions and Classifications: Regulatory bodies like the FDA and EMA classify nanomedicines differently, affecting approval processes and required documentation.

• Unclear Regulatory Pathways: Nanomedicines often don't fit neatly into existing categories (drugs, devices, biologics), causing confusion about applicable guidelines and data requirements.

• Variability in Nanomaterial Properties: Differences in size, shape, and surface characteristics make it difficult to establish uniform regulatory standards for safety and efficacy.

• Insufficient Guidance for Industry: Existing regulatory guidelines are often too general, lacking specifics on long-term safety, manufacturing, and post-market surveillance, which slows development.

• Evolving Scientific Understanding: Rapid advancements in nanomedicine outpace regulatory updates, leaving guidelines outdated or unclear.

• Balancing Innovation and Safety: Striking a balance between encouraging innovation and ensuring safety is challenging, as unclear or stringent regulations can discourage investment and delay new treatments

Page 34: Stimuli-Responsive Nanoparticles

• Responsive Mechanisms:

• pH responsive

• redox responsive

• mechanical

• magnetic hyperthermia

• photothermal therapy

• photodynamic theraqpy