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

Abstract

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 watersoluble 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.

Crown Macromolecular Derivatives: Stepwise Design of New Types of Polyfunctionalized Phosphorus Dendrimers

“…5-Hydroxyisophthalaldehyde can be prepared in two steps (Scheme ) in the gram scale from commercially available dimethyl 5-hydroxylisophthalate 2 . The first experiment concerns the reaction of hexachlorocyclotriphosphazene 1 with the 5-hydroxyisophthalaldehyde 13 affording in higher then previously described yield (85%) the dendrimer 14 bearing 12 aldehyde groups in one step (Scheme , top).…”

PSMA-Targeted Nanotheranostics for Imaging and Radiotherapy of Prostate Cancer

“…The size of the nanocarriers, whether targeted or non-targeted, has a profound influence on their in vivo tumor accumulation and retention. As previously discussed, to improve bioavailability and target-specific tumor uptake, the size of the nanocarriers should be larger than 5 nm [ 74 , 75 ]. However, with the nanocarrier size above 12 nm, EPR-mediated passive accumulation becomes more prominent and PSMA-targeted uptake is suppressed ( Figure 3 A) [ 4 , 58 ].…”

Divergent Synthesis of Biocompatible Nearly Monodisperse Multi‐Functional Poly(ethylene glycol) Periodic Copolymers

“…[30,31] For ATRP and RAFT, PEG based ATRP initiators and PEG based CTAs are used respectively to prepare targeted copolymers. [32][33][34][35] In almost all cases, copolymers of PEG are reported with a dispersity of 1.1-1.5, which is a typical of living radical polymerizations. Hydroxyl end terminal PEGs are known to be used as micro initiator for further copolymerization with functional caprolactones.…”