(265b) Surface Engineering of Polymer Nanoparticles for Targeted Delivery to the Renal Endothelium

Targeted delivery of drug- or gene-based therapies to specific cellular populations maximizes the efficiency of treatment while reducing undesirable off-target effects in other tissues. Polymer nanoparticles (NPs) represent a tunable, biocompatible, and effective way to encapsulate therapeutics—transporting high quantities whilst protecting the cargo from the physiological environment. Incorporation of targeting ligands into polymer NPs helps increase local contact with and retention at cell types of interest, promoting favorable delivery outcomes for the payload.¹ In particular, targeting the renal endothelium would enhance treatments of kidney disease, which affects over 800 million people worldwide.² Given their high specificity toward a corresponding marker,³ antibodies (Abs) and fragments thereof represent a promising approach to targeting cells in the kidney. This research leverages advances in bioengineering with insights from materials science to immobilize Ab fragments onto the surfaces of poly(lactic acid)-block-poly(ethylene glycol) (PLA-PEG) or poly(amine-co-ester)-block-PEG (PACE-PEG) NPs, which can be used for drug delivery or nucleic acid therapy, respectively.

Whole Abs comprise the vast majority of clinically approved Abs and Ab conjugates worldwide,⁴ with inconsistencies in preparation, expense, and low stability posing major obstacles to clinical translation of fragmented Abs.³ This work used microscale reactions for high-throughput preparation and evaluation of endothelial cell–targeting anti-CD31 Ab fragments, facilitating optimization of cleaving conditions while minimizing materials usage. Half-Ab (hAb) fragments bear sulfhydryl groups for direct conjugation to maleimide-functionalized polymer NPs, covalently immobilizing the hAbs onto NP surfaces to resist potential displacement in blood sera. Flow cytometry revealed comparable binding activity across anti-CD31 hAb samples, significantly more than isotype hAb controls. Increased thiol content demonstrated a positive correlation with NP surface coverage and consequent binding of anti-CD31 hAb–NP conjugates to human umbilical vein endothelial cells (HUVECs). These results demonstrate a tunable strategy for preparation of Ab fragments from different parent Abs, as well as immobilization of targeting moieties onto nanocarrier surfaces without loss of binding activity.

References

1. G. T. Tietjen, L. G. Bracaglia, W. M. Saltzman, J. S. Pober. Trends Mol. Med. (2018), 24(7), 598–606.

2. C. P. Kovesdy. Kidney. Int. Suppl. (2022), 12(1), 7–11.

3. J. H. Lee,* D. V. Chapman,* W. M. Saltzman. BME Front. (2023), 4, 12.

4. X. Lyu, Q. Zhao, J. Hui, T. Wang, M. L, K. Wang, J. Zhang, J. Shentu, P. A. Dalby, H. Zhang, B. Liu. Antib. Ther. (2022), 5(4), 233–257.