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 文獻名： Identification of a moderate affinity CD22 binding peptide and in vitro optimization of peptide-targeted nanoparticles for selective uptake by CD22+ B-cell malignancies

 

作者：Baksun Kim,a   Jaeho Shin,a   Tanyel Kiziltepeabc  and  Basar Bilgicer abc   

a Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA
b Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA

c Advanced Diagnostics and Therapeutics, University of Notre Dame, Notre Dame, IN 46556, USA

 

摘要：B cell malignancies, such as B cell leukemia and lymphoma, have CD22 overexpression with ∼7% of patients. A short CD22 binding peptide (PV3) with a moderate affinity (Kd ∼ 9 μM) was identified by screening multiple peptide candidates determined through analysis of CD22-epratuzumab complex crystal structure. PV3 binding specificity was confirmed via competitive binding inhibition, then was used as the targeting moiety on CD22-targeted liposomal nanoparticle (TNPPV3) formulations. To maximize the potential therapeutic outcome of TNPPV3 formulation, nanoparticle design parameters, such as peptide hydrophilicity, ethylene glycol linker length, valency, and particle size were optimized for maximum selective cellular uptake by CD22+ malignant cancer cells. The effects of altering design parameters one at a time on TNP uptake were evaluated using flow cytometry, and the optimal parameters for TNPPV3 were determined to be 8% peptide density, EG18 linker, and 3 lysines of 100 nm nanoparticles. This optimally designed TNPPV3 achieved ∼4 and 40-fold enhancement of cellular uptake by CD22+ Raji cells over CD22− Jurkat and MOLT-4 cells, respectively, demonstrating selectivity for malignant cells with CD22 overexpression. Overall, this study establishes PV3 to be CD22 binding peptide with proven effectiveness as a targeting element. In future, the optimal TNPPV3 formulation will potentially achieve maximal in vivo therapeutic outcomes by efficiently targeting CD22+ blood cancer cells in vivo.