Synthetic Ionizable Colloidal Drug Aggregates Enable Endosomal Disruption.

Area of Science:

• Nanomedicine and Drug Delivery
• Cancer Therapeutics
• Physical Chemistry

Background:

• Colloidal drug aggregates form drug-rich nanoparticles but are often trapped in the endo-lysosomal pathway, limiting efficacy.
• Ionizable drugs can promote lysosomal escape but may cause phospholipidosis, a toxic condition.
• Existing strategies for lysosomal escape are limited by toxicity and efficacy.

Purpose of the Study:

• To investigate if tuning the acidity (pK$_{a}$) of drug nanoparticles can enable endosomal disruption.
• To develop a strategy for lysosomal escape that avoids phospholipidosis and minimizes toxicity.
• To synthesize and evaluate fulvestrant analogs with ionizable groups for improved cancer therapy.

Main Methods:

• Synthesis of 12 fulvestrant analogs with ionizable groups to modulate pH-dependent properties.
• Formation of lipid-stabilized fulvestrant analog colloids.
• Evaluation of colloid uptake by cancer cells and assessment of endo-lysosomal disruption mechanisms and toxicity.

Main Results:

• The pK$_{a}$ of the ionizable colloids influenced the mechanism of endosomal and lysosomal disruption.
• Four fulvestrant analogs with pK$_{a}$ values between 5.1 and 5.7 effectively disrupted endo-lysosomes.
• These selected analogs demonstrated disruption without causing measurable phospholipidosis.

Conclusions:

• Manipulating the pK$_{a}$ of colloid-forming drugs offers a tunable and generalizable strategy for endosomal disruption.
• This approach successfully achieves lysosomal escape while avoiding phospholipidosis and minimizing toxicity.
• The findings pave the way for developing safer and more effective nanoparticle-based cancer therapies.