Approaches and Design Techniques to Alleviate Coagulation-Related Acute Side Effects of Lung-Targeted Nanocarriers

Lipid nanoparticles (LNPs) play a crucial role in drug delivery, enabling targeted drug administration to specific tissues.  LNPs tailored for lung-specific delivery often incorporate cationic (positively charged) lipids. Unfortunately, this inclusion has resulted in adverse effects, including inflammation, lethargy, and internal lung tissue damage. These unresolved side effects currently render such lung-targeted LNPs unsuitable for human therapeutic use.

Extensive mouse model testing in Dr. Brenner's lab has identified excessive coagulation occurs as a result of cationic LNP delivery and is the primary cause of these downstream acute side effects. Addressing this issue could involve several strategies: pre-treatment of patients with direct thrombin inhibitors such as Bivalirudin, limiting nanocarrier size to less than 100nm, and attaching anticoagulants such as PPACK to the LNP's surface. These measures effectively mitigate coagulation while preserving the lung-targeting capabilities of LNPs in mouse models.

• Pretreatment with Bivalirudin (an anticoagulant agent) prevents coagulation while sustaining the lung-targeting capacity of nanocarriers.
• Nanocarrier surface attachment of anticoagulant agents eliminates the need for a separate anticoagulant administration.
• Altering nanocarrier size to less than 100 nm reduces fibrinogen uptake in the lung, preventing coagulation and preserving lung-targeting specificity