Shape-recovery of implanted shape-memory devices remotely triggered via image-guided ultrasound heating.

Shape-memory materials hold great potential to impart medical devices with functionalities useful during implantation, locomotion, drug delivery, and removal. However, their clinical translation is limited by a lack of non-invasive and precise methods to trigger and control the shape recovery, especially for devices implanted in deep tissues. In this study, the application of image-guided high-intensity focused ultrasound (HIFU) heating is tested. Magnetic resonance-guided HIFU triggered shape-recovery of a device made of polyurethane urea while monitoring its temperature by magnetic resonance thermometry. Deformation of the polyurethane urea in a live canine bladder (5 cm deep) is achieved with 8 seconds of ultrasound-guided HIFU with millimeter resolution energy focus. Tissue sections show no hyperthermic tissue injury. A conceptual application in ureteral stent shape-recovery reduces removal resistance. In conclusion, image-guided HIFU demonstrates deep energy penetration, safety and speed.

Multiblock Poly-ε-Caprolactones: One-Step Synthesis toward Programmable Properties.

Control of monomer sequence enables predictable structure-property relationships in versatile polymeric materials. The facile synthesis of multiblock copolymers (MBCPs) with controlled chain structure is highly challenging, particularly for those prepared via one-pot copolymerization of mixed monomers. Herein, poly-ε-caprolactone MBCPs, a series of thermoplastic elastomers with tailored thermal, mechanical, rheological, and degradable properties, are synthesized by Janus polymerization. Melting temperature, tensile strength, ductility, viscosity, and enzymatic degradability are governed by block length which is in turn dictated by the monomer-to-catalyst feed ratio. The relationships between the physicochemical properties and the architectures are investigated in detail.

A biodegradable, flexible photonic patch for in vivo phototherapy.

Diagnostic and therapeutic illumination on internal organs and tissues with high controllability and adaptability in terms of spectrum, area, depth, and intensity remains a major challenge. Here, we present a flexible, biodegradable photonic device called iCarP with a micrometer scale air gap between a refractive polyester patch and the embedded removable tapered optical fiber. ICarP combines the advantages of light diffraction by the tapered optical fiber, dual refractions in the air gap, and reflection inside the patch to obtain a bulb-like illumination, guiding light towards target tissue. We show that iCarP achieves large area, high intensity, wide spectrum, continuous or pulsatile, deeply penetrating illumination without puncturing the target tissues and demonstrate that it supports phototherapies with different photosensitizers. We find that the photonic device is compatible with thoracoscopy-based minimally invasive implantation onto beating hearts. These initial results show that iCarP could be a safe, precise and widely applicable device suitable for internal organs and tissue illumination and associated diagnosis and therapy.

A honeybee stinger-inspired self-interlocking microneedle patch and its application in myocardial infarction treatment.

Weak tissue adhesion remains a major challenge in clinical translation of microneedle patches. Mimicking the structural features of honeybee stingers, stiff polymeric microneedles with unidirectionally backward-facing barbs were fabricated and embedded into various elastomer films to produce self-interlocking microneedle patches. The spirality of the barbing pattern was adjusted to increase interlocking efficiency. In addition, the micro-bleeding caused by microneedle puncturing adhered the porous surface of the patch substrate to the target tissue via coagulation. In the demonstrative application of myocardial infarction treatment, the bioinspired microneedle patches firmly fixed on challenging beating hearts, significantly reduced cardiac wall stress and strain in the infarct, and maintained left ventricular function and morphology. In addition, the microneedle patch was minimally invasively implanted onto beating porcine heart in 10 minutes, free of sutures and adhesives. Therefore, the honeybee stinger-inspired microneedles could provide an adaptive and convenient means to implant patches for various medical applications. STATEMENT OF SIGNIFICANCE: Adhesion between tissue and microneedle patches with smooth microneedles is usually weak. We introduce a novel barbing method of fabricating unidirectionally backward facing barbs with controllable spirality on the microneedles on microneedle patches. The microneedle patches self-interlock on mechanically dynamic beating hearts, similar to honeybee stingers. The micro-bleeding and coagulation on the porous surface provide additional adhesion force. The microneedle patches attenuate left ventricular remodeling via mechanical support and are compatible with minimally invasive implantation.

Synthesis of cyclic graft polymeric prodrugs with heterogeneous grafts of hydrophilic OEG and reducibly conjugated CPT for controlled release.

Fabrication of cyclic graft (cg) copolymer-based polymeric prodrugs by conjugation of drug molecules to cg copolymers via a dynamic covalent bond capable of responding to biorelevant signals integrates simultaneously the merits of cg copolymers and polymeric prodrugs for enhanced stability of nanocarriers and precise modulation of drug release kinetics. To completely eliminate the compromised drug conjugation efficiency due to the steric hindrance of hydrophilic grafts, it will be useful to develop cg polymeric prodrugs with heterogeneous grafts composed of hydrophilic polymers and drug species, respectively. For this purpose, we reported in this study the synthesis of cyclic graft polymeric prodrugs with heterogeneous grafts of hydrophilic oligo (ethylene glycol) (OEG) and reducibly conjugated camptothecin (CPT), cg-poly(oligo(ethylene glycol) monomethyl ether methacrylate)-b-poly((2-hydroxyethyl methacrylate)-disulfide link-camptothecin) (cg-P(OEGMA)-b-P(HEMA-SS-CPT), cg-prodrugs), via an integrated strategy of a previously reported diblock copolymer-based template and post-polymerization intermolecular click conjugation of a reducible CPT prodrug. The micelles self-assembled from cg-prodrugs on one hand had sufficient salt stability due to the branched cg structure, and on the other hand showed a reduction-triggered cleavage of the disulfide link for a promoted CPT release. Most importantly, we uncovered two interesting phenomena of the cg-based polymeric prodrugs as delivery vehicles: (i) the dimensions of both self-assemblies formed by the cg and bottlegraft (bg) polymers depend substantially on the molecular size of the cg and bg polymers likely due to the steric hindrance of the grafted structures of the cg and bg molecules and relatively low aggregation number of the self-assembled structures, and (ii) cg-prodrug-based micelles exhibited greater in vitro cytotoxicity against cancer cells despite the lower drug loading content (DLC) than the bg-based analogues, which results primarily from the faster reduction-triggered degradation and drug release as well as the greater cellular uptake efficiency of the former micelle prodrugs. Taken together, the developed cg-prodrugs provide great potential for chemotherapy, and the aforementioned interesting results will definitely inspire more upcoming studies on the future design and development of novel cg polymers for biomedical applications.

Synthesis of stimuli-responsive nanosized ring-like colloids and cyclic polymers via a dual-template approach.

Ring-like particles have received considerable attention due to their unique interior cavity and properties. However, the preparation of stimuli-responsive nanosized rings with internal size smaller than 100 nm remains unexplored likely due to the challenges encountered in their synthesis. The successful fulfillment of this target will not only significantly enrich the family of ring-like nanoparticles but also build a connection that bridges ring-like nanoparticles and cyclic polymers. For this purpose, we report in this study a controlled synthesis of stimuli-responsive ring-like colloids and cyclic polymers using both star-shaped polymers and ß-cyclodextrin (ß-CD) as the dual templates. The first template comprising star-shaped polymers generated a ring-like structure and adoption of ß-CD as the second template further restricted the ring thickness to the height of a ß-CD, leading to the generation of stimuli-responsive nanosized ring-like colloids with ring thickness less than 1 nm, which shifted the ring-like structure to cyclic polymers with reversible cross-linked disulfide bridges. The reported "dual-template" approach is thus a valuable alternative to the current synthetic strategies toward stimuli-responsive ring-like colloids and cyclic polymers.

Synthesis of Thermosensitive Conjugated Triblock Copolymers by Sequential Click Couplings for Drug Delivery and Cell Imaging.

The elegant integration of an excellent light-emitting segment and a biorelevant signal-responsive moiety could generate advanced polymeric delivery systems with simultaneously favorable diagnostic and therapeutic functions with respect to cancer theranostics. Although polymeric delivery systems based on fluorescent polyfluorene (PF) or thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm) have been extensively developed, the preparation of a ternary polymer formulation composed of a PF block, a PNIPAAm sequence, and a hydrophilic moiety remains rarely explored likely because of the difficulty in integrating different synthesis strategies for polymer synthesis. To this end, herein we reported the design and controlled synthesis of a PF- and PNIPAAm-based amphiphilic triblock copolymer, PF11-b-PNIPAAm120-b-poly(oligo(ethylene glycol) monomethyl ether methacrylate)17 (PF11-b-PNIPAAm120-b-POEGMA17), with a well-defined structure by a strategy of sequential click couplings between Suzuki-coupling-generated PF and atom-transfer radical polymerization (ATRP)-produced PNIPAAm and POEGMA. The as-prepared triblock copolymers can self-assemble into micelles with a core-shell-corona (CSC) structure that is composed of an inner hydrophobic core of the PF moiety for fluorescent tracking and drug encapsulation, a thermosensitive middle shell of PNIPAAm block for thermomodulated drug loading and release, and a hydrophilic outer corona of the POEGMA segment for micelle stabilization. Interestingly, the doxorubicin (DOX)-loaded micelles prepared at 25 °C had a greater drug loading capacity than the analogues fabricated at 37 °C due to the better stability of the former formulation, leading to its higher in vitro cytotoxicity in HeLa cells. Together with the integration of a localized hyperthermia-triggered drug release profile and efficiently intracellular trafficking of the nanocarriers by monitoring the fluorescence of the PF moiety, this formulation demonstrates a great potential for cancer theranostics.

Drug-DNA adducts as biomarkers for metabolic activation of the nitro-aromatic nitrogen mustard prodrug PR-104A.

PR-104A is a clinical-stage nitrogen mustard prodrug that is activated for DNA alkylation by reduction of a nitro group to the corresponding hydroxylamine (PR-104H) or amine (PR-104M). Metabolic reduction is catalysed by flavoreductases such as cytochrome P450 oxidoreductase (POR) under hypoxia, or by aldo-ketoreductase 1C3 (AKR1C3) independently of hypoxia. The unstable reduced metabolites are challenging to measure in biological samples, and biomarkers of the metabolic activation of PR-104A have not been used in the clinical evaluation of PR-104 to date. Here, we employ a selected reaction monitoring mass spectrometry assay for DNA crosslinks to assess the capacity of human cancer cells to bioactivate PR-104A. We also test whether the more abundant DNA monoadducts could be used for the same purpose. DNA monoadducts and crosslinks from PR-104A itself, and from its reduced metabolites, accumulated over 4 h in AKR1C3-expressing TF1 erythroleukaemia cells under hypoxia, whereas intracellular concentrations of unstable PR-104H and PR-104M reached steady state within 1 h. We then varied rates of PR-104A reduction by manipulating hypoxia or reductase expression in a panel of cell lines, in which AKR1C3 and POR were quantified by targeted proteomics. Hypoxia or reductase overexpression induced large increases in PR-104A sensitivity (inhibition of proliferation), DNA damage response (γH2AX formation), steady-state concentrations of PR-104H/M and formation of reduced drug-DNA adducts but not DNA adducts retaining the dinitro groups of PR-104A. The fold-change in the sum of PR-104H and PR-104M correlated with the fold-change in reduced crosslinks or monoadducts (R2 = 0.87 for both), demonstrating their potential for assessing the capacity of cancer cells to bioactivate PR-104A.

Fabrication of Conjugated Amphiphilic Triblock Copolymer for Drug Delivery and Fluorescence Cell Imaging.

An elegant integration of light-emitting segments into the structure of polymeric delivery systems endows the resulting self-assembled nanovehicles with the diagnostic ability toward an enhanced therapeutic efficiency. A variety of polyfluorene (PF)-based binary delivery systems were designed and developed successfully, but PF-based ternary formulations remain rarely explored, likely due to the synthetic challenge. To develop a universal synthesis strategy toward linear conjugated amphiphilic triblock copolymer for cancer theranostics, herein we focused on the functionalization of the PF terminus for further chain extension and prepared well-defined PF-based amphiphilic triblock copolymers, PF-b-poly(ε-caprolactone)-b-poly(oligo(ethylene glycol) monomethyl ether methacrylate) (PF-b-PCL-b-POEGMA), by integrated state-of-the-art polymer chemistry techniques, including Suzuki reaction, ring-opening polymerization, atom transfer radical polymerization, and click coupling. The resulting conjugated amphiphilic triblock copolymers can self-assembe into core-shell-corona (CSC) micelles with PF block constructing the inner hydrophobic core for fluorescent tracking, PCL segment forming the hydrophobic middle shell for drug encapsulation, and POEGMA moiety building the hydrophilic outer corona for particulate stabilization. Interestingly, the CSC micelles with hydrophobic PCL middle layer show a greater drug loading capacity as well as a higher fluorescence quantum yield (Φ) relative to the core-shell micelles self-assembled from the control of PF-b-POEGMA diblock copolymers without PCL sequence due to having more hydrophobic spaces and better separation of PF sequence provided simultaneously by the PCL central block. The efficient cellular uptake of the anticancer drug doxorubicin-loaded CSC micelles together with the in vitro cytotoxicity against the HeLa cells makes the conjugated amphiphilic triblock copolymers developed herein a promising platform for simultaneous cell image and drug delivery, thus offering great potential for cancer theranostics.