Chemotherapy Challenges & Nanomedicine

 What is the main limitation of conventional chemotherapy like doxorubicin?

It has a non‑selective mechanism, damaging healthy tissues and causing severe side‑effects (e.g., cardiotoxicity).

Why is cardiotoxicity a major issue with doxorubicin?

It accumulates in cardiac tissue and generates ROS → irreversible dose‑dependent heart damage.

Define nanomedicine.

 The use of nanotechnology to diagnose, treat, and prevent disease.

Why is nanomedicine increasingly popular?

It overcomes chemotherapy limitations such as poor barrier penetration and high systemic toxicity

What key abnormalities exist in tumour vasculature?

 immature, tortuous, hyperpermeable, with poor lymphatic drainage.

What is the tumour microenvironment (TME) like?

Hypoxic, acidic (low pH), high interstitial pressure, dense stroma.

What is the Enhanced Permeability and Retention (EPR) effect?

 Preferential accumulation of nanoparticles in tumours due to leaky vasculature and poor lymphatic drainage.

What is opsonisation?

Binding of plasma proteins (opsonins) to nanoparticles → recognition and clearance by macrophages.

 How does PEGylation improve nanoparticle circulation?

PEG reduces opsonisation, creating a stealth layer that prolongs half‑life.

How does hyperthermia enhance EPR?

It increases endothelial gaps, improving nanoparticle extravasation.

Why does tumour heterogeneity limit the effectiveness of the EPR effect?

Because tumours vary in vascular density, perfusion, stromal density, and endothelial gap size, meaning EPR is inconsistent across patients and tumour types.

How does PEGylation improve pharmacokinetics beyond reducing opsonisation?

•  PEGylation increases hydrodynamic radius

• reduces renal clearance, prolongs circulation half‑life

• stabilises nanoparticles against aggregation.

Why does Angiotensin II (AT‑II) increase nanomedicine accumulation in tumours?

AT‑II induces transient hypertension, increasing tumour blood flow and driving nanoparticles across leaky vasculature via pressure‑dependent extravasation.

Why do actively targeted nanoparticles still rely on the EPR effect?

 Ligands can only bind receptors after nanoparticles extravasate into tumour tissue; thus EPR is required for initial tumour entry,

 How does CAELYX®/Doxil® achieve reduced cardiotoxicity compared to free doxorubicin?

PEGylated liposomes retain doxorubicin inside the carrier, preventing cardiac exposure and directing accumulation to tumours via EPR.

What makes SN‑38 a powerful payload in Trodelvy®?

 SN‑38 is the active metabolite of irinotecan, a potent Topoisomerase I inhibitor, giving high cytotoxicity once released inside Trop‑2‑expressing cells.

Mechanism of action for doxorubicin for causing toxicity

• NADH turns to NAD, converting doxorubicin into doxorubicin semiquinone

• These semiquinone molecules lead to the production of hydrogen peroxide

• In the presence of iron, this goes through a Fenton reaction and leads to the formation of hydroxyl radicals which causes lipid peroxidation/ oxidative stress

• Doxorubicin semiquinone intercalates with mitochondrial DNA

• This reactive oxygen species causes cardiac muscles

• The highest number of mitochondria are in cardiac cells as the heart must pump much blood and needs much energy

• Therefore, doxorubicin kills cancer cells, but it also affects cardiomyocytes (causing enlarged hearts and heart failure) - risk of heart attack and heart failure increases drastically.