Near-Infrared Fluorescent Micelles from Poly(norbornene) Brush Triblock Copolymers for Nanotheranostics

Abstract

This contribution describes the design and synthesis of multifunctional micelles based on amphiphilic brush block copolymers (BBCPs) for imaging and selective drug delivery of natural anticancer compounds. Well-defined BBCPs were synthesized via one-pot multi-step sequential grafting-through ring-opening metathesis polymerization (ROMP) of norbornene-based macroinitiators. The norbornenes employed contain a poly(ethylene glycol) methyl ether chain, an alkyl bromide chain, and/or a near-infrared (NIR) fluorescent cyanine dye. After block copolymerization, post-polymerization transformations using bromide−azide substitution, followed by the strain-promoted azide−alkyne cycloaddition (SPAAC) allowed for the functionalization of the BBCPs with the piplartine (PPT) moiety, a natural product with well-documented cytotoxicity against cancer cell lines, via an ester linker between the drug and the polymer side chain. The amphiphilic BBCPs self-assembled in aqueous media into nano-sized spherical micelles with neutral surface charges, as confirmed by dynamic light scattering analysis and transmission electron microscopy. During self-assembly, paclitaxel (PTX) could be effectively encapsulated into the hydrophobic core to form stable PTX-loaded micelles with high loading capacities and encapsulation efficiencies. The NIR fluorescent dye-containing micelles exhibited remarkable photophysical properties, excellent colloidal stability under physiological conditions, and a pH-induced disassembly under slightly acidic conditions, allowing for the release of the drug in a controlled manner. The in vitro studies demonstrated that the micelles without the drug (blank micelles) are biocompatible at concentrations of up to 1 mg mL −1 and present a high cellular internalization capacity toward MCF-7 cancer cells. The drug-functionalized micelles showed in vitro cytotoxicity comparable to free PPT and PTX against MCF-7 and PC3 cancer cells, confirming efficient drug release into the tumor environment upon cellular internalization. Furthermore, the drug-functionalized micelles exhibited higher selectivity than the pristine drugs and preferential cellular uptake in human cancer cell lines (MCF-7 and PC3) when compared to the normal breast cell line (MCF10A). This study provides an efficient strategy for the development of versatile polymeric nanosystems for drug delivery and image-guided diagnostics. Notably, the easy functionalization of BBCP side chains via SPAAC opens up the possibility for the preparation of a library of multifunctional systems containing other drugs or functionalities, such as target groups for recognition.

Molecular polymer bottlebrushes in nanomedicine: therapeutic and diagnostic applications

“…Combining sophisticated (triggerable) drug/gene delivery mechanisms (as discussed in this article) with advances in imaging probes 207–209 may allow MPBs to become the ideal platform for theranostic applications. 210 The future for polymer science is bright, 211 and MPB research this is expected to contribute progressively to best-in-class nanomaterials in the years to come. The sharp increase in publications featuring MPBs and the plentiful and diverse applications of MPBs that emerged in recent years, indicate that this area of research in only going to grow in years to come.…”

Cyclophanediene and Cyclophanetriene‐Based Conjugated Polymers

“…These copolymers containing different blocks are useful for material science, as amphiphilic block copolymers can arrange into various nanostructures, resulting potentially in varied conductivity and tunable optoelectronic properties. [131][132][133] Additionally, amphiphilic polymers have been used in applications such as drug delivery [134,135] and as catalytic nanoreactors. [136][137][138] PPVcontaining amphiphilic diblock copolymers have previously been reported in literature, synthesized by non-living methods, and the PPV blocks exhibited liquid crystallinity with electrical and optical properties.…”

Sulfonated Block Copolymers: Synthesis, Chemical Modification, Self-Assembly Morphologies, and Recent Applications

“…The photoacoustic effect and the near-infrared (NIR) response of nanometer-sized micelles based on poly(ethylene glycol) (PEG) methyl ether- block -poly(DL lactide) (PEG2000–PDLLAx) have been used as indicators to target tumors in living animals [ 129 ]. The fluorescence property of amphiphilic brush copolymers (BBCPs) based on poly(norbornene), PEG, an alkyl bromide chain and cyanine dye, as NIR indicator, have been employed for imaging and selective drug delivery of natural anticancer compounds [ 130 ]. P3HT, hydrophilic poly(triethylene glycol allene) (PHA), and poly(phenyl isocyanide) (PPI) were polymerized to form triblock copolymers with tunable white-light emissions in different states such as solution, gel, and solid state [ 131 ].…”