Cyclotriphosphazene-Based Star Copolymers as Structurally Tunable Nanocarriers with Programmable Biodegradability

Myriad nanocarriers have been developed to improve the therapeutic index of low-molecular-weight drugs for cancer treatment, but many have suboptimal size and/or are too stable for optimal penetration into tumors and their subsequent excretion from the body. To address this challenge, we developed a series of novel nanocarriers based on star polymers consisting of hydrophilic poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) or poly(ethylene glycol) (PEG) polymer arms attached to hexavalent cyclotriphosphazene (CTP)-derived cores through either stable or stimuli-responsive linkers. The star polymers were assembled using either "grafting from" or "grafting onto" approaches and characterized by quantitative arm substitution at the core. The resulting star polymers were precisely defined water-soluble nanomaterials with a suitable hydrodynamic size (∼10–25 nm) for tumor uptake; those with stimuli-responsive linkers exhibited programmable pH- or cathepsin-mediated degradability. Finally, low-molecular-weight drugs—an anthracycline-based cancerostatic and an imidazoquinoline-based immunostimulant—were linked to exemplary CTP-based star polymers to demonstrate their suitability for drug delivery.