Improved Cooling Performance of Hydrogel Wound Dressings via Integrating Thermal Conductivity and Heat Storage Capacity for Burn Therapy.

Burn injury has become a crucial public health issue worldwide. It is necessary to explore new methods to reduce heat damage and improve healing efficiency during burn injury treatment. In this study, a kind of hydrogel combining heat storage capacity and thermal conductivity was fabricated via a one-pot method for burn therapy. The novel hydrogel was easily prepared by in situ cross-linking polymerization, using poly(ethylene glycol) (PEG) derivatives, oligo(ethylene glycol) methacrylate and 2-(2-methoxyethoxy) ethyl methacrylate, as thermally responsive base materials and hydroxylated multiwall carbon nanotubes (CNT-OH) as thermally conductive fillers. By dispersing CNT-OH, a thermally conductive network was formed in the hydrogel, leading to an increase in the thermal conductivity. The cooling performance, thermal conductivity, heat storage property, swelling performance, rheological and mechanical properties, biocompatibility, in vivo cooling effect, and wound healing properties of the prepared hydrogel were systematically investigated. The hydrogel consisted of thermally responsive PEG derivatives, and CNT-OH performed a function of rapid heat absorption, further reduced thermal damage, and promoted wound healing. The improved cooling performance of the hydrogel was ascribed to the improved thermal conductivity, enhanced heat storage capacity, and good adhesive ability. Thus, the hydrogel has great potential to be practically applied in burn therapy, laser treatment, cooling fabrics, heat-protective clothing, and other emergency scenarios.

NIR Photothermal-Responsive Shape Memory Polyurethane with Protein-Inspired Aggregated Chymotrypsin-Sensitive Degradable Domains.

Biodegradable shape memory polymers are promising biomaterials for stents used in minimally invasive surgical procedures such as intestinal stents. Herein, a series of biodegradable shape memory polyurethanes (SMPUs) containing a novel phenylalanine-derived chain extender (PHP) are synthesized. Inspired by the fact that the function of biomacromolecules such as proteins is rich and varied because of the multiple combinations of the amino acid in highly evolved biosystems, this study finds that the sequence distribution of PHP in SMPU will also have a great influence on the phase structure and degradation behavior, especially the difference of surface morphology caused by degradation. Considering that the transition temperature (Ttrans ) of SMPU obtained is higher than physiological temperature, oxidized carbon black (OCB) with the ability of photothermal conversion is introduced into SMPU, which can not only endow SMPU with near-infrared response shape recovery characteristics, but also enhance phase separation degree and mechanical properties of them. SMPU/OCB composites show excellent shape memory effect and rapid photothermal response, and they can be degraded by chymotrypsin with an adjustable degradation rate. These SMPU/OCB composites show broad potential for application as intestinal stents.

Multifunctional Mixed Micelles Cross-Assembled from Various Polyurethanes for Tumor Therapy.

A challenge in the development of multifunctional drug delivery systems is to establish a reasonable and effective synthetic route for multifunctional polymer preparation. Herein, we propose a unique protocol to prepare multifunctional micelles by a cross-assembly process using three different functional polyurethanes incorporating acidic sensitive hydrazone, folic acid for active targeting, and gemini quaternary ammonium (GQA) as efficient cell uptake ligands, respectively. These multifunctional mixed micelles (GFHPMs) have been endowed tunable particle sizes and zeta potential and a unique three-order-layer cross-assemble structure. Their drug-loading contents have been significantly improved, and drug release profiles displayed controlled release of their payloads under acid condition. The folate and GQA ligands showed a synergistic effect to enhance the cell uptake. Biodistribution and antitumor effect of these micelles were systematically investigated in vivo, the mixed micelles could penetrate into the depths of tumors, and drug concentrations in tumors reached the maximum of 6.5% ID/g at 24 h, resulting in an excellent therapeutic effect that the volumes of tumors treated with GFHPM are five times smaller than those treated with blank micelles. Our present work provides an effective approach to the design of multifunctional nanocarriers for tumor-targeted and programmed intracellular drug delivery.

Construction of targeting-clickable and tumor-cleavable polyurethane nanomicelles for multifunctional intracellular drug delivery.

New strategies for the construction of versatile nanovehicles to overcome the multiple challenges of targeted delivery are urgently needed for cancer therapy. To address these needs, we developed a novel targeting-clickable and tumor-cleavable polyurethane nanomicelle for multifunctional delivery of antitumor drugs. The polyurethane was synthesized from biodegradable poly(ε-caprolactone) (PCL) and L-lysine ethyl ester diisocyanate (LDI), further extended by a new designed L-cystine-derivatized chain extender bearing a redox-responsive disulfide bond and clickable alkynyl groups (Cys-PA), and finally terminated by a detachable methoxyl-poly(ethylene glycol) with a highly pH-sensitive benzoic-imine linkage (BPEG). The obtained polymers show attractive self-assembly characteristics and stimuli-responsiveness, good cytocompatibility, and high loading capacity for doxorubicin (DOX). Furthermore, folic acid (FA) as a model targeting ligand was conjugated to the polyurethane micelles via an efficient click reaction. The decoration of FA results in an enhanced cellular uptake and improved drug efficacy toward FA-receptor positive HeLa cancer cells in vitro. As a proof-of-concept, this work provides a facile approach to the design of extracellularly activatable nanocarriers for tumor-targeted and programmed intracellular drug delivery.

Dual-encapsulated biodegradable 3D scaffold from liposome and waterborne polyurethane for local drug control release in breast cancer therapy.

Compared with the traditional chemotherapy by injection, local release of drugs in the lesion area is a more efficient and less harmful treatment for solid tumors. However, the selection of appropriate drug carrier and controlled release of chemotherapy drugs are still great challenges. Herein, a kind of dual-encapsulated three-dimensional (3D) scaffold is designed for local drug release via blending the paclitaxel (PTX) loaded phospholipid liposomes with waterborne polyurethane (PU) by freeze-drying. The controlled release of paclitaxel is carried out through two simultaneous procedures. First, liposomes encapsulated in polyurethane scaffold can slowly release by water absorption and degradation of polyurethane. Then paclitaxel encapsulated in liposomes can also be released into water. Compared with the polyurethane scaffold which directly encapsulated paclitaxel, dual-encapsulated scaffold has slower initial release amount and maintain higher concentration of paclitaxel in later stage. Moreover, the protection of the phospholipid layer can prevent paclitaxel from being quickly decomposed and cleared, which could greatly improve the bioavailability and therapeutic effect of paclitaxel. Cell experiment results can be seen that dual-encapsulated scaffold not only has higher inhibition rate to the breast cancer MCF7 cells, but also has less damage to normal tissue cells. It provides a more effective platform for the local drug therapy in the treatment of tumors.[Formula: see text].

Stable, Bioresponsive, and Macrophage-Evading Polyurethane Micelles Containing an Anionic Tripeptide Chain Extender.

Polymeric nanocarriers have been extensively used in medicinal applications for drug delivery. However, intravenous nanocarriers circulating in the blood will be rapidly cleared from the mononuclear macrophage system. The surface physicochemical characterizations of nanocarriers are the primary factors to determine their fate in vivo, such as evading the reticuloendothelial system, exhibiting long blood circulation times, and accumulating in the targeted site. In this work, we develop a series of polyurethane micelles containing segments of an anionic tripeptide, hydrophilic mPEG, and disulfide bonds. It is found that the long hydrophilic mPEG can shield the micellar surface and have a synergistic effect with the negatively charged tripeptide to minimize macrophage phagocytosis. Meanwhile, the disulfide bond can rapidly respond to the intracellular reduction environment, leading to the acceleration of drug release and improvement of the therapeutic effect. Our results verify that these anionic polyurethane micelles hold great potential in the development of the stealth immune system and controllable intracellular drug transporters.

Albumin-Modified Cationic Nanocarriers To Potentially Create a New Platform for Drug Delivery Systems.

Cationic nanocarriers have emerged as promising nanoparticle systems for the effective delivery of nucleic acid and anticancer drugs to cancer cells. A positive charge is desirable for promoting cell internalization, whereas it also causes some adverse effects, such as toxicity and rapid clearance by mononuclear phagocytic systems. Herein, a new strategy of modifying cationic polymer micelles with albumin forming a protein corona to improve the surface physiochemical properties is reported. The corona with a monolayer or a multilayer was constructed depending on the albumin concentration, and the proteins would denature in different degrees due to the interaction with the surface of cationic micelles. It is demonstrated that multilayer albumin corona is beneficial to prevent macrophage uptake, increase accumulation in tumor tissues, and reduce toxic side effects to normal tissues. Our work provides a promising method to modify the cationic nanoplatform by optimizing the biosecurity and bioavailability for potential application in drug delivery.

Understanding the effect of alkyl chains of gemini cations on the physicochemical and cellular properties of polyurethane micelles.

Cationic gemini quaternary ammonium (GQA) has been used as a cell internalization promoter to improve the permeability of the cell membrane and enhance the cellular uptake. However, the effect of the alkyl chain length on the cellular properties of nanocarriers has not been elucidated yet. In this study, we developed a series of polyurethane micelles containing GQAs with various alkyl chain lengths. The alteration of the gemini alkyl chain length was found to change the distribution of GQA surfactants in the micellar structure and affect the surface charge exposure, stability, and the protein absorption properties of nanocarriers. Moreover, we also clarified the role of the alkyl chain length in tumor cell internalization and macrophage uptake of polyurethane micelles. This work provides a new understanding on the effect of the GQA alkyl chain length on the physicochemical and biological properties of nanomedicines, and offers guidance on the rational design of effective drug delivery systems where the issue of functional group exposure at the micellar surface should be considered.

Surface Distribution and Biophysicochemical Properties of Polymeric Micelles Bearing Gemini Cationic and Hydrophilic Groups.

Polymeric micelles containing cationic gemini quaternary ammonium (GQA) groups have shown enhanced cellular uptake and efficient drug delivery, while the incorporation of poly(ethylene glycol) (PEG) corona can potentially reduce the absorption of cationic carriers by opsonic proteins and subsequent uptake by mononuclear phagocytic system (MPS). To understand the interactions of GQA and PEG groups and their effects on the biophysicochemical characteristics of nanocarriers, a series of polyurethane micelles containing GQA and different molecular weights of PEG were prepared and carefully characterized. It was found that the GQA and PEG groups are unevenly distributed on the micellar surface to form two kinds of hydrophilic domains. As a result, the particle surface with some defects cannot be completely shielded by the PEG corona. Despite this, the longer PEG chains with a brush conformation provide superior stabilization and steric repulsion against the absorption of proteins and, thus, can reduce the cytotoxicity, protein absorption, and MPS uptake of micelles to some extent. This study provides a new understanding on the interactions between PEG chains and cationic groups and a guideline for the design and fabrication of safe and effective drug delivery systems.

The preliminary study of immune superparamagnetic iron oxide nanoparticles for the detection of lung cancer in magnetic resonance imaging.

To improve the sensitive and specific detection of metastasis of lung cancer, this study fabricated immune superparamagnetic iron oxide nanoparticles (SPIONs) used in magnetic resonance (MR) immumoimaging. These SPIONs were coated with oleic acid and carboxymethyl dextran, and then conjugated to mouse anti-CD44v6 monoclonal antibody. The physicochemical properties of magnetic nanoparticles without monoclonal antibody were characterized by X-ray powder diffraction (XRD), thermogravimetric analysis (TGA), and Fourier transform infrared spectroscopy (FTIR). The sizes of the nanoparticles were determined by dynamic light scattering measurements (DLS) and transmission electron microscope (TEM). Coated nanoparticles could well disperse in water with low dosage of CMD as the Fe/CMD ratio is 1/1 and 2/1 (w/w). Importantly, these SPIONs have relatively high saturation magnetization, as measured by vibrating sample magnetometer (VSM). They could efficiently become the transversal relaxation times (T2) contrast agent to improve detection limit through measured in vitro magnetic resonance imaging (MRI) and actively target human lung adenocarcinoma (A549) cells in vitro cell culture. Thus, these immune SPIONs are potentially useful for lung tumor-targeting diagnosis.

Inspired by nonenveloped viruses escaping from endo-lysosomes: a pH-sensitive polyurethane micelle for effective intracellular trafficking.

A multifunctional drug delivery system (DDS) for cancer therapy still faces great challenges due to multiple physiological barriers encountered in vivo. To increase the efficacy of current cancer treatment a new anticancer DDS mimicking the response of nonenveloped viruses, triggered by acidic pH to escape endo-lysosomes, is developed. Such a smart DDS is self-assembled from biodegradable pH-sensitive polyurethane containing hydrazone bonds in the backbone, named pHPM. The pHPM exhibits excellent micellization characteristics and high loading capacity for hydrophobic chemotherapeutic drugs. The responses of the pHPM in acidic media, undergoing charge conversion and hydrophobic core exposure, resulting from the detachment of the hydrophilic polyethylene glycol (PEG) shell, are similar to the behavior of a nonenveloped virus when trapped in acidic endo-lysosomes. Moreover, the degradation mechanism was verified by gel permeation chromatography (GPC). The endo-lysosomal membrane rupture induced by these transformed micelles is clearly observed by transmission electron microscopy. Consequently, excellent antitumor activity is confirmed both in vitro and in vivo. The results verify that the pHPM could be a promising new drug delivery tool for the treatment of cancer and other diseases.

Toward the next-generation nanomedicines: design of multifunctional multiblock polyurethanes for effective cancer treatment.

Specific accumulation of therapeutics at tumor sites to improve in vivo biodistribution and therapeutic efficacy of anticancer drugs is a major challenge for cancer therapy. Herein, we demonstrate a new generation of intelligent nanosystem integrating multiple functionalities in a single carrier based on multifunctional multiblock polyurethane (MMPU). The smart nanocarriers equipped with stealth, active targeting, and internalizable properties can ferry paclitaxel selectively into tumor tissue, rapidly enter cancer cells, and controllably release their payload in response to an intracellular acidic environment, thus resulting in an improved biodistribution and excellent antitumor activity in vivo. Our work provides a facile and versatile approach for the design and fabrication of smart intracellular targeted nanovehicles for effective cancer treatment, and opens a new era in the development of biodegradable polyurethanes for next-generation nanodelivery systems.

Molecular engineered super-nanodevices: smart and safe delivery of potent drugs into tumors.

A super-nanodevice engineered at molecular level integrates various desired properties in a smart and coordinated way, and can "switch on" or "turn off" certain functionalities as required. Importantly, it can break through complex physiological barriers, and then precisely ferry potent toxic triptolide into tumor cells in vivo, thus significantly maximizing the therapeutic efficacy and reducing the drug toxicity.