{"doi":"10.1002/anie.202503085","title":"A Modular Platform for Enhanced Drug Delivery to Glioblastoma Using Targeted Multidomain Protein Assemblies","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.","journal":"Angewandte Chemie International Edition","year":2025,"id":545135,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9481,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1302474,"name":"Aparajita Bhattacharya","orcid":"0009-0005-5340-9250","position":1,"is_corresponding":false},{"id":1302825,"name":"Frances Lee","orcid":null,"position":2,"is_corresponding":false},{"id":942251,"name":"Orin Mishkit","orcid":"0000-0002-0858-5053","position":3,"is_corresponding":false},{"id":1436003,"name":"Lucas Morales","orcid":null,"position":4,"is_corresponding":false},{"id":850828,"name":"James A. Tranos","orcid":"0000-0002-3521-029X","position":5,"is_corresponding":false},{"id":1224804,"name":"Heather Mao","orcid":null,"position":6,"is_corresponding":false},{"id":1237888,"name":"Neha Rahman","orcid":"0009-0009-4316-1369","position":7,"is_corresponding":false},{"id":402715,"name":"Joshua D. Frenster","orcid":"0000-0003-2401-1575","position":8,"is_corresponding":false},{"id":402719,"name":"Niklas Ravn-Boess","orcid":"0000-0001-6525-5942","position":9,"is_corresponding":false},{"id":1436004,"name":"Naomi Crook","orcid":null,"position":10,"is_corresponding":false},{"id":439531,"name":"Youssef Zaim Wadghiri","orcid":"0000-0001-7175-9397","position":11,"is_corresponding":false},{"id":402724,"name":"Dimitris G. Placantonakis","orcid":"0000-0003-1950-2978","position":12,"is_corresponding":false},{"id":826268,"name":"Jin Kim Montclare","orcid":"0000-0001-6857-3591","position":13,"is_corresponding":false},{"id":1302473,"name":"Andrew L. Wang","orcid":"0000-0003-4016-9460","position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":null,"created_at":"2026-07-19T02:53:17.418915Z","pmid":"40607714","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}