Heterofunctional Polyester Dendrimers as Architecturally Tunable Platforms for Therapeutic Applications
Time: Fri 2026-01-09 10.00
Location: Kollegiesalen, Brinellvägen 8, Stockholm
Video link: https://kth-se.zoom.us/j/69760264313
Language: English
Subject area: Fibre and Polymer Science
Doctoral student: Arunika Singh , Ytbehandlingsteknik
Opponent: Professor Ling Peng, Equipe Labellisée Ligue Contre le Cancer Centre Interdisciplinaire de Nanoscience de Marseille Aix-Marseille University, CNRS, UMR 7325 CINaM 163, avenue de Luminy
Supervisor: Professor Michael Malkoch, Ytbehandlingsteknik; Doktor Natalia Sanz del Olmo, Ytbehandlingsteknik, University of Alcala, Faculty of Sciences, Department of Organic and Inorganic Chemistry, and Research Institute in Chemistry “Andrés M. Del Río” (IQAR), 28805 Madrid, Spain. Institute “Ramón y Cajal” for Health Research (IRYCIS), 28034 Madrid, Spain.
QC 2025-11-28
Embargo t.o.m. 2027-01-09 godkänt av skolchef Amelie Eriksson Karlström via e-post 2025-12-01.
Abstract
Dendrimers have emerged as versatile platforms in nanomedicine due to their well-defined architecture, monodispersity, and multivalent nature. However, conventional designs confine functional groups to the periphery, limiting their chemical and therapeutic diversity. This thesis presents heterofunctional polyester dendrimers (HFDs) based on a novel bromide-functional AB2C monomer as a multifunctional platform, combining molecular precision with clinical potential. The synthetic route follows divergent anhydride-mediated esterification, yielding monodisperse dendrimers (polydispersity ≤1.03) with internal bromide or azide groups and external hydroxyl functionalities. The biodegradable polyester scaffold undergoes controlled degradation over 30–96 h, balancing stability with biocompatibility. Orthogonal post-functionalization (azide-alkyne click chemistry and thiol-bromo coupling) enables selective incorporation of diverse payloads. Ammonium groups or apolar drugs like diclofenac can be embedded internally, while cationic groups or PEG chains are introduced onto the surface via esterification.
Systematic biological evaluation across antibacterial, gene delivery, and anticancer applications reveals a unifying principle: the therapeutic efficacy is governed by spatial distribution of functionalities rather than dendrimer generation. In antibacterial applications, dual-charge dendrimers display potent activity (MIC: 10–21 μM) against Gram-positive and Gram-negative pathogens with enhanced E. coli sensitivity, maintaining >85% mammalian cell viability (3–100-fold improvement over homofunctional counterparts). For gene therapy, the same cationic architecture achieves 93% RNase protection and 62% gene silencing in glioblastoma cells with minimal cytotoxicity. In anticancer applications, covalent diclofenac conjugation with PEGylation induces selective ROS-mediated cytotoxicity at 16–32-fold lower concentrations than free diclofenac, preserving >95% normal cell viability.
This work demonstrates that therapeutic performance can be decoupled from generation number through rational architectural design. The HFD platform defines transferable design principles for next-generation nanomedicine, uniting polymer versatility with molecular precision.