Combination of Physicochemical Tropism and Affinity Moiety Targeting of Lipid Nanoparticles Enhances Organ Targeting

Abstract

Two camps have emerged for targeting nanoparticles to specific organs and cell types: affinity moiety targeting and physicochemical tropism. Here we directly compare and combine both using intravenous (IV) lipid nanoparticles (LNPs) designed to target the lungs. We utilized PECAM antibodies as affinity moieties and cationic lipids for physicochemical tropism. These methods yield nearly identical lung uptake, but aPECAM LNPs show higher endothelial specificity. LNPs combining these targeting methods had >2-fold higher lung uptake than either method alone and markedly enhanced epithelial uptake. To determine if lung uptake is because the lungs are the first organ downstream of IV injection, we compared IV vs intra-arterial (IA) injection into the carotid artery, finding that IA combined-targeting LNPs achieve 35% of the injected dose per gram (%ID/g) in the first-pass organ, the brain, among the highest reported. Thus, combining the affinity moiety and physicochemical strategies provides benefits that neither targeting method achieves alone.

Lipid nanoparticles-based RNA therapies for breast cancer treatment

“…As discussed above, the off-target effect associated with many nanomedicines remains a limitation that needs to be overcome, as it implies an increased dose of drug to achieve the desired therapeutic effect and reduces the bioavailability of the drug. Affinity targeting of the LNPs to the BC lesions can be easily achieved due to several chemical surface modifications [23,111]. By attaching smart molecules to the available functional groups of the lipids the selectivity and effectiveness can be certainly improved.…”