A Modular Platform for Enhanced Drug Delivery to Glioblastoma Using Targeted Multidomain Protein Assemblies
Abstract
Abstract Protein‐based nanocarriers bear highly desirable properties such as biodegradability and the ability to facilitate passage through biological barriers such as the blood–brain‐barrier. Using modular protein engineering, we develop a strategy for iteratively improving the delivery efficacy of hydrophobic small molecules for the treatment of glioblastoma multiforme (GBM). By increasing the multiplicity m of the coiled‐coil and RGD peptide targeting regions from 1 to 2, we can increase both the hydrodynamic micellar size and drug loading capacity of the targeted multidomain protein assembly (TMPA) relative to its predecessor thermoresponsive assembled protein (TRAP). An upper limit of m is likely determined by steric interactions. TMPA shows a 1.7‐fold increase in doxorubicin (Dox) encapsulation compared to TRAP and demonstrates a 1.3‐fold improvement in uptake by U87 human GBM cells. Near‐infrared (NIR) dye‐labelled TMPA (NIR‐TMPA) is intravenously administered to mice orthotopically implanted with GBM cells and to control mice. Pharmacokinetic analysis using a 2‐compartment pharmacokinetic model reveals a significantly prolonged distribution‐phase (short‐phase) half‐life in tumor‐bearing mice compared to control, while the elimination‐phase (slow‐phase) half‐life remains comparable between groups. This suggests altered early‐phase kinetics likely due to tumor‐associated sequestration or retention. The resulting increased area under the concentration‐time curve (AUC) in tumor‐bearing mice supports enhanced accumulation or slower clearance. Ex vivo fluorescence imaging of organs and 3D reconstructions of whole mouse heads further corroboratesa preferential localization of NIR‐TMPA in tumor regions. These findings highlight the potential of TMPA and its future derivatives for targeted GBM therapy.
Article Details
Authors (14)
Andrew L. Wang
Department of Chemical and Biomolecular Engineering New York University Tandon School of Engineering 6 MetroTech Center Brooklyn NY 11201 USA
Aparajita Bhattacharya
Department of Chemical and Biomolecular Engineering New York University Tandon School of Engineering 6 MetroTech Center Brooklyn NY 11201 USA
Frances Lee
Department of Chemical and Biomolecular Engineering New York University Tandon School of Engineering 6 MetroTech Center Brooklyn NY 11201 USA
Orin Mishkit
Department of Radiology Bernard & Irene Schwartz Center for Biomedical Imaging and Center for Advanced Imaging Innovation and Research New York University Grossman School of Medicine 550 1<sup>st</sup> Avenue New York NY 10016 USA
Lucas Morales
Department of Chemical and Biomolecular Engineering New York University Tandon School of Engineering 6 MetroTech Center Brooklyn NY 11201 USA
James A. Tranos
Department of Radiology Bernard & Irene Schwartz Center for Biomedical Imaging and Center for Advanced Imaging Innovation and Research New York University Grossman School of Medicine 550 1<sup>st</sup> Avenue New York NY 10016 USA
Heather Mao
Department of Chemical and Biomolecular Engineering New York University Tandon School of Engineering 6 MetroTech Center Brooklyn NY 11201 USA
Neha Rahman
Department of Radiology Bernard & Irene Schwartz Center for Biomedical Imaging and Center for Advanced Imaging Innovation and Research New York University Grossman School of Medicine 550 1<sup>st</sup> Avenue New York NY 10016 USA
Joshua D. Frenster
Department of Neurosurgery New York University Grossman School of Medicine 550 1<sup>st</sup> Avenue New York NY 10016 USA
Niklas Ravn‐Boess
Department of Neurosurgery New York University Grossman School of Medicine 550 1<sup>st</sup> Avenue New York NY 10016 USA
Naomi Crook
Department of Chemical and Biomolecular Engineering New York University Tandon School of Engineering 6 MetroTech Center Brooklyn NY 11201 USA
Youssef Z. Wadghiri
Department of Radiology Bernard & Irene Schwartz Center for Biomedical Imaging and Center for Advanced Imaging Innovation and Research New York University Grossman School of Medicine 550 1<sup>st</sup> Avenue New York NY 10016 USA
Dimitris G. Placantonakis
Perlmutter Cancer Center, New York University Langone Health
Jin Kim Montclare
Department of Chemical and Biomolecular Engineering New York University Tandon School of Engineering 6 MetroTech Center Brooklyn NY 11201 USA