Deliver on a Promise: Hydrogen-Bonded Polymer Nanomedicine with a Precise Ratio of Chemodrug and Photosensitizer for Intelligent Cancer Therapy

The outcomes of combined cancer therapy are largely related to loading content and contribution of each therapeutic agent; however, fine-tuning the ratio of two coloaded components toward precise cancer therapy is a great challenge and still remains in its infancy. We herein develop a supramolecular polymer scaffold to optimize the coloading ratio of chemotherapeutic agent and photosensitizer through hydrogen-bonding (H-bonding) interaction, for maximizing the efficacy of intelligent cancer chemo/photodynamic therapies (CT/PDT). To do so, we first synthesize a thymine (THY)-functionalized tetraphenylporphyrin photosensitizer (i.e., TTPP), featuring the same molecular configuration of H-bonding array with chemotherapeutic carmofur (e.g., 1-hexylcarbamoyl-5-fluorouracil, HCFU). Meanwhile, a six-arm star-shaped amphiphilic polymer vehicle P(DAPA-co-DPMA-co-OEGMA)6 (poly(diaminopyridine acrylamide-co-2-(diisopropylamino)ethyl methacrylate-co-oligo(ethylene glycol) monomethyl ether methacrylate)6) is prepared, bearing hydrophilic and biocompatible POEGMA segment, along with hydrophobic PDAPA and PDPMA segments, characterizing the randomly dispersed dual functionalities, i.e., heterocomplementary H-bonding DAP motifs and pH-responsive protonation DPMA content. Thanks to the identical DAP/HCFU and DAP/TTPP H-bonding association capability, the incorporation of both HCFU and TTPP to six-arm star-shaped P(DAPA-co-DPMA-co-OEGMA)6 vehicle, with an optimized coloading ratio, can be straightforwardly realized by adjusting the feeding concentrations, thus yielding the hydrogen-bonded supramolecular nanoparticles (i.e., HCFU-TTPP-SPNs), demonstrating the codelivery of two components with the promise to optimize the combined CT/PDT efficacy

PhPOCl₂ as a potent catalyst for chlorination reaction of phenols with PCl₅

<p>Phenols are easily converted to the corresponding aryl chlorides by using phosphorus pentachloride (PCl₅) and a catalytic amount of phenylphosphonic dichloride (PhPOCl₂), which is a new efficient method for synthesis of aryl chloride in good yields.</p

Hydrogen-Bonded Polymer Nanomedicine with AIE Characteristic for Intelligent Cancer Therapy

One of the major goals of biomedical science is to pioneer advanced strategies toward precise and smart medicine. Hydrogen-bonding (H-bonding) assembly incorporated with an aggregation-induced emission (AIE) capability can serve as a powerful tool for developing supramolecular nanomedicine with clear tumor imaging and smart therapeutic performance. We here report a H-bonded polymeric nanoformulation with an AIE characteristic toward smart antitumor therapy. To do so, we first design a structurally novel tetraphenylethylene (TPE)-based H-bonding theranostic prodrug, TPE-(FUA)4, characterized by four chemotherapeutic fluorouracil-1-acetic acid (FUA) moieties arched to the TPE core. A six-arm star-shaped amphiphilic polymer vehicle, P(DAP-co-OEGEA)6, is prepared, bearing hydrophilic and biocompatible POEGEA (poly(oligo (ethylene glycol) ethyl acrylate) segments, along with a hydrophobic and H-bonding PDAP (poly(diaminopyridine acrylamide)) segment. Thanks to the establishment of the DAP/FUA H-bonding association, incorporating the TPE-(FUA)4 prodrug to the P(DAP-co-OEGEA)6 vehicle can yield H-bond cross-linked nanoparticles with interpenetrating networks. For the first time, AIE luminogens are interwoven into a six-arm star-shaped polymer via an intrinsic H-bonding array of the chemotherapeutic agent FUA, thus imposing an effective restriction of TPE molecular rotations. Concomitantly, encapsulated photothermal agent (IR780) via a hydrophobic interaction facilitates the formation of nanoassemblies, TPE-(FUA)4/IR780@P(DAP-co-OEGEA)6, featuring synergistic cancer chemo/photothermal therapy (CT/PTT). Our study can contribute a practical solution to fulfill biomedical requirements with a conductive advance in precision nanomedicine

Highly Sensitive Mechanochromic Photonic Hydrogels with Fast Reversibility and Mechanical Stability

We present a fast and efficient strategy for the preparation of photonic hydrogels for compression and organic solvent sensing by the self-assembly of monodisperse carbon-encapsulated Fe₃O₄ nanoparticles (NPs). The hydrogel film was composed of acrylamide (AM) and cross-linker <i>N</i>,<i>N</i>′-methylenebis­(acrylamide) (BIS), and the formed 1D NPs chain structure can be fixed within the hydrogels under a magnetic field by in situ photopolymerization. The resulting photonic hydrogels display vivid structural color which can be tuned by pressing and organic solvent treatment. The 0.2 kPa compression applied to the photonic hydrogels can be detected by the 37 nm blue shift of a reflection peak. Importantly, the photonic hydrogels can recover to their original state (<1 s) after being compressed on a pattern. Moreover, the sensitivity of mechanochromic photonic hydrogels can be adjusted by manipulating the concentration of monomers, and a large reflection peak shift (4.3 kPa, 200 nm) was observed. The detection range of the compression sensor can thus increase from 0–4.3 to 0–130.6 kPa. The photonic hydrogels are nearly monochromatic, with high sensitivity and stability and fast reversibility, and are potentially useful in displays, diagnostics, compression and solvent sensing

Crystal-Like Polymer Microdiscs

Here we describe a facile yet effective route for the fabrication of crystal-like polymer microdiscs with a huge bump at the surrounding edge through hydrodynamic instabilities of emulsion droplets containing hydrophobic polymer and cosurfactant <i>n</i>-octadecanol (OD). This strategy allows for the generation of polymer particles with tunable size and shape by tuning the cosurfactant concentration, emulsion droplet size, and/or solvent evaporation rate. The generation of polystyrene (PS) microdiscs is balanced by the interfacial instabilities of emulsion droplets, crystallization of OD, and capillary flow. Our approach can be extended to different hydrophobic polymers and allows for the functionalization of the discs with tunable chemical/physical properties by incorporating functional species. By introducing magnetic nanoparticles, we have been able to manipulate the spatial orientation of the magnetic microdiscs via an external magnetic field. We anticipate this simple and versatile route to be useful for the design and fabrication of well-defined microparticles for potential applications in the fields of targeting, separation, sensing, drug delivery, and formation of advanced materials

Emulsion Solvent Evaporation-Induced Self-Assembly of Block Copolymers Containing pH-Sensitive Block

A simple yet efficient method is developed to manipulate the self-assembly of pH-sensitive block copolymers (BCPs) confined in emulsion droplets. Addition of acid induces significant variation in morphological transition (e.g., structure and surface composition changes) of the polystyrene-<i>block</i>-poly­(4-vinylpyridine) (PS-<i>b</i>-P4VP) assemblies, due to the hydrophobic–hydrophilic transition of the pH-sensitive P4VP block via protonation. In the case of pH > p<i>K</i>a_(P4VP) (p<i>K</i>a _(P4VP) = 4.8), the BCPs can self-assemble into pupa-like particles because of the nearly neutral wetting of PS and P4VP blocks at the oil/water interface. As expected, onion-like particles obtained when pH is slightly lower than p<i>K</i>a_(P4VP) (e.g., pH = 3.00), due to the interfacial affinity to the weakly hydrophilic P4VP block. Interestingly, when pH was further decreased to ∼2.5, interfacial instability of the emulsion droplets was observed, and each emulsion droplet generated nanoscale assemblies including vesicles, worm-like and/or spherical micelles rather than a nanostructured microparticle. Furthermore, homopolymer with different molecular weights and addition ratio are employed to adjust the interactions among copolymer blocks. By this means, particles with hierarchical structures can be obtained. Moreover, owing to the kinetically controlled processing, we found that temperature and stirring speed, which can significantly affect the kinetics of the evaporation of organic solvent and the formation of particles, played a key role in the morphology of the assemblies. We believe that manipulation of the property for the aqueous phase is a promising strategy to rationally design and fabricate polymeric assemblies with desirable shapes and internal structures

Reversible Transformation of Nanostructured Polymer Particles

A reversible transformation of overall shape and internal structure as well as surface composition of nanostructured block copolymer particles is demonstrated by solvent-adsorption annealing. Polystyrene-<i>b</i>-poly­(4-vinylpyridine) (PS-<i>b</i>-P4VP) pupa-like particles with PS and P4VP lamellar domains alternatively stacked can be obtained by self-assembly of the block copolymer under 3D soft confinement. Chloroform, a good solvent for both blocks, is selected to swell and anneal the pupa-like particles suspended in aqueous media. Reversible transformation between pupa-like and onion-like structures of the particles can be readily tuned by simply adjusting the particle/aqueous solution interfacial property. Interestingly, poly­(vinyl alcohol) (PVA) concentration in the aqueous media plays a critical role in determining the particle morphology. High level of PVA concentration is favorable for pupa-like morphology, while extremely low concentration of PVA is favorable for the formation of onion-like particles. Moreover, the stimuli-response behavior of the particles can be highly suppressed through selective growth of Au nanoparticles within the P4VP domains. This strategy provides a new concept for the reversible transformation of nanostructured polymer particles, which will find potential applications in the field of sensing, detection, optical devices, drug delivery, and smart materials fabrication

Photothermal Effect-Triggered Drug Release from Hydrogen Bonding-Enhanced Polymeric Micelles

Incorporation of noncovalent interactions into hydrophobic cores of polymeric micelles provides the micelles with enhanced physical stability and drug loading efficiency, however, it also creates obstacles for drug release due to the strong interactions between carriers and drugs. Herein, a series of amphiphilic block copolymers based on poly­(ethylene glycol)-<i>b</i>-poly­(l-lysine) (mPEG-<i>b</i>-PLL) with similar chemical structures, while different hydrogen bonding donors (urethane, urea, and thiourea groups) are synthesized, and their capacities for codelivery of anticancer drug (e.g., doxorubicin) and photothermal agent (e.g., indocyanine green) are investigated. The resulting hybrid micelles display decreased critical micelle concentrations (CMCs) and enhanced micelle stabilities due to the hydrogen bonding between urea groups in the polymers. Moreover, the strong hydrogen bonds between the urea/thiourea groups and drugs provide the carriers with enhanced drug loading efficiencies, decreased micelle sizes, however, slower drug release profiles as well. When exposed to the near-infrared laser irradiation, destabilization of the hydrogen bonding through photothermal effect triggers fast and controlled drug releases from the micelles, which dramatically promotes the aggregation of the drugs in the nuclei, resulting in an enhanced anticancer activity. These results demonstrate that the hydrogen bonding-enhanced micelles are promising carriers for controllable chemo-photothermal synergistic therapy

A Simple Route To Improve Inorganic Nanoparticles Loading Efficiency in Block Copolymer Micelles

The formation of well-defined polymer/inorganic nanoparticles (NPs) hybrid micelles with high loading of the NPs is critical to the development of nanomaterials with desired optical, electric, magnetic, and mechanical properties. Herein, we introduce a simple strategy to encapsulate monodisperse polystyrene (PS)-grafted Au NPs into the PS core of PS-<i>b</i>-poly­(4-vinylpyridine) (PS-<i>b</i>-PVP) micelles through block copolymer (BCP)-based supramolecular assembly. We demonstrate that selective incorporation of gold NPs into the PS cores during the assembly process can induce the formation of well-ordered hybrid micelles with spherical, cylindrical, or nanosheet morphologies. The number of NPs in each micelle can be effectively increased by simply increasing the content of NPs and adjusting the ratio of 3-<i>n</i>-pentadecylphenol (PDP) to the P4VP units accordingly. The balance between the NP loading (increasing the volume fraction of PS domain) and the PDP addition (increasing the volume fraction of PVP­(PDP) domain) maintains the same micellar morphology while achieving high NP loading. Moreover, strong enthalphic attraction of H-bonding between PDP and P4VP can increase the effective interaction parameter of the system to maintain the strong segregation, leading to the formation of ordered structures. The mass density of NPs in the hybrid micelles was further enhanced after removal of the added PDP from the supramolecules. No macrophase separation or order–order morphological transition was observed even when the volume fraction of PS-grafted NPs (φ_NP‑M) in the hybrid micelles reached 84.1 vol % (or 68 wt % on the ligand free NPs basis). Furthermore, we show that ordered clusters of NPs were generated within the spherical micelles when the φ_NP‑M reached 72.5 vol %. This directed supramolecular assembly provides an easy means to tailor the interactions between BCPs and NPs, thus generating ordered structures which can only be achieved when the loading of NPs is high enough. This approach is versatile and applicable to different types of NPs and different micellar aggregates and supramolecular pairs. It offers a new route for preparing hybrids with applications in the fields of molecular electronic devices, high-density data storage, nanomedicine, and biosensors

ABC Triblock Copolymer Particles with Tunable Shape and Internal Structure through 3D Confined Assembly

Here we present 3D confined assembly of polystyrene-<i>b</i>-polyisoprene-<i>b</i>-poly­(2-vinylpyridine) (PS-<i>b</i>-PI-<i>b</i>-P2VP) ABC triblock copolymers into particles with tunable shape and internal structures. Under weak confinement (i.e., ratio of the particle size to the periodicity dimension of the block copolymer <i>D</i>/<i>L</i>₀ > 4), surfactants in the suspension show significant influence on the morphology of the particles. Unique structures, such as onion-, bud-, and pupa-like particles, can be obtained by tailoring properties of the surfactants. Both particle shape and internal structure can be reversibly tuned through pathway independent solvent vapor absorption annealing. While under strong confinement (e.g., <i>D</i>/<i>L</i>₀ < 2), commensurability between <i>D</i> and <i>L</i>₀ will dominate the structure of the particles. Moreover, these structured particles with cross-linkable PI domain can be selectively cross-linked and disassembled into isolated nano-objects. Janus nanodiscs with PS and P2VP chains at different sides can be obtained from pupa-like particles. Such nanodiscs can act as surfactants to stabilize oil/water emulsion droplets. This strategy, combining 3D confinement, selective cross-linking, and disassembly, is believed to be a promising approach for constructing structured particles and unique nano-objects