Naturally biocompatible melanin based iron-complex nanoparticles for pH-responsive magnetic resonance imaging.

The sensitivity and diagnostic accuracy of magnetic resonance imaging (MRI) mainly depend on the relaxation capacity of contrast agents (CAs) and their accumulated amount at the pathological region. Due to the better biocompatibility and high-spin capacity, Fe-complexes have been studied widely as an alternative to replace popular Gd-based CAs associated with potential biotoxicity. Compared with a variety of Fe complex-based CAs, such as small molecular, macrocyclic, multinuclear complexes, the form of nanoparticle exhibits outstanding longitudinal relaxation, but the clinical transformation was still limited by the inconspicuous difference of contrast between tumor and normal tissue. The enhanced effect of contrast is a positive relation as relaxation of CAs and their concentration in desired region. To specifically improve the amount of CAs accumulated in the tumor, pH-responsive polymer poly(2-ethyl-2-oxazoline) (PEOz) was modified on melanin, a ubiquitous natural pigment providing much active sites for chelating with Fe(III). The Fe(III)-Mel-PEOz we prepared could raise the tumor cell endocytosis efficiency via switching surface charge from anion to cation with the stimuli of the decreasing pH of tumor microenvironment. The change of pH has negligible effect on the r1 of Fe(III)-Mel-PEOz, which is always maintained at around 1.0 mM-1s-1 at 0.5 T. Moreover, Fe(III)-Mel-PEOz exhibited low cytotoxicity, and satisfactory enhancement of positive contrast effect in vivo. The excellent biocompatibility and stable relaxation demonstrate the high potential of Fe(III)-Mel-PEOz in the diagnosis of tumor. .

GelMA-catechol coated FeHAp nanorods functionalized nanofibrous reinforced bio-instructive and mechanically robust composite hydrogel scaffold for bone tissue engineering.

Critical bone defects complicate tissue graft-based surgeries, raising healthcare expenditures and underscoring scaffold-based tissue-engineering strategies to support bone reconstruction. Our study highlighted that the phase-compatible combination of inorganic nanorods, nanofibers, and hydrogels is promising for developing biomimetic and cell-instructive scaffolds since the bone matrix is a porous organic/inorganic composite. In brief, methacrylated gelatin (GelMA) was reacted with dopamine to form catechol-modified GeLMA (GelMA-C). The GelMA-C was nanocoated onto an iron-doped hydroxyapatite (FeHAp) nanorod via metal-catechol network coordination. The modified nanorod (FeHAp@GelMA-C) was loaded onto GelMA-based nanofibers. The nanorods loaded pre-fibers were electrospun onto GelMA solution and photochemically crosslinked to fabricate a fiber-reinforced hydrogel. The structural, mechanical, physicochemical, biocompatibility, swelling properties, osteogenic potential, and bone remodelling potential (using rat femoral defect model) of modified nanorods, simple hydrogel, and nanorod-loaded fiber-reinforced hydrogel were studied. The results supported that the interface interaction between GelMA-C/nanorods, nanorods/nanofibers, nanorods/hydrogels, and nanofiber/hydrogels significantly improved the microstructural and mechanical properties of the scaffold. Compared to pristine hydrogel, the nanorod-loaded fiber-reinforced scaffold better supported cellular responses, osteogenic differentiation, matrix mineralization, and accelerated bone regeneration. The nanorod-loaded fiber-reinforced hydrogel proved more biomimetic and cell-instructive for guided bone reconstruction.

Donor-Acceptor Engineering for Tailoring Highly Efficient Photosensitizers for Image-Guided Antitumor Photodynamic Therapy.

Photosensitizers (PSs) have greatly flourished as a promising tool for photodynamic therapy owing to their integration of both in situ diagnosis and treatment in a single nanoplatform. However, there is still a need to explore synthesis pathways that can result in high-performance PSs with good reproducibility, high yield, less dark toxicity, and an attractive therapeutic index. Therefore, by exploiting the precise molecular engineering guideline, this work unveils a straightforward protocol to fabricate three homologous PSs (TPA-T-RS, TPA-Ts-RS, and TPA-Ts-RCN) with aggregation-induced emission (AIE) characteristics. Through slight structural tuning, the PSs are capable of anchoring to the cell membrane, mitochondria, and lysosome, and effectively generating reactive oxygen species (ROS). More importantly, TPA-Ts-RCN proved an intuitively appealing imaging-guided photodynamic therapy (PDT) effect. This work is expected to add a promising dimension to the field of architecting AIE PSs for image-guided photodynamic therapy.

Hypoxia-Responsive T2-to-T1 Dynamically Switchable Extremely Small Iron Oxide Nanoparticles for Sensitive Tumor Imaging In Vivo.

To realize the accurate diagnosis of tumors by magnetic resonance imaging (MRI), switchable magnetic resonance contrast agents (CAs) between T1 and T2 contrast enhancement that are constructed based on extremely small iron oxide nanoparticles (ESIONPs) have been developed in recent years. We herein report, for the first time, a novel ESIONP-based nanocluster (named EAmP), which exhibited hypoxia responsiveness to the tumor microenvironment and offered a T2-to-T1-switchable contrast enhancement function, effectively distinguishing between the normal tissue and tumor tissue. In detail, active perfluorophenyl ester-modified ESIONPs with a diameter of approximately 3.6 nm were initially synthesized, and then 4,4'-azodianiline was used as a cross-linker to facilitate the formation of nanoclusters from ESIONPs through the reaction between the active ester and amine. Finally, poly(ethylene glycol) was further modified onto nanoclusters by utilizing the remaining active ester residues. The resulting EAmP demonstrated satisfactory colloidal stability and favorable biosafety and exhibited a desired T2-to-T1-switchable function, as evidenced by conversion from nanocluster to the dispersed state and a significant decrease in the r2/r1 ratio from 14.86 to 1.61 when exposed to a mimical hypoxic environment in the solution. Moreover, EAmP could decompose into dispersed ESIONPs at the tumor region, resulting in a switch from T2 to T1 contrast enhancement. This T2-to-T1-switchable contrast agent offers high sensitivity and signal-to-noise ratio to realize the accurate diagnosis of tumors. In conclusion, hypoxia-responsive EAmP is a potential MRI nanoprobe for improving the diagnostic accuracy of solid tumors.

Perovskite-Type Manganese Vanadate Sonosensitizers with Biodegradability for Enhanced Sonodynamic Therapy of Cancer.

Sonodynamic therapy (SDT) has attracted intensive attention, but is still hindered by low sonosensitization and non-biodegradability of the traditional sonosensitizers. Herein, perovskite-type manganese vanadate (MnVO3 ) sonosensitizers integrating high reactive oxide species (ROS) production efficiency and appropriate bio-degradability are developed for enhanced SDT. Taking advantage of the intrinsic properties of perovskites such as narrow bandgap and substantial oxygen vacancies, MnVO3 shows a facile ultrasound (US)-triggered electrons-holes separation and restrained recombination, thus enhancing the ROS quantum yield in SDT. Furthermore, MnVO3 exhibits a considerable chemodynamic therapy (CDT) effect under the acidic condition probably owing to the presence of manganese and vanadium ions. Due to the presence of high-valent vanadium, MnVO3 can also eliminate glutathione (GSH) within the tumor microenvironment, which synergistically amplifies the efficacy of SDT and CDT. Importantly, the perovskite structure bestows MnVO3 with superior biodegradability, which alleviates the long-term presence of residues in metabolic organs after therapeutic actions. Based on these characteristics, US-assisted MnVO3 achieves an excellent antitumor outcome along with low systemic toxicity. Overall, perovskite-type MnVO3 may be promising sonosensitizers for highly efficient and safe treatment of cancer. The work attempts to explore the potential utility of perovskites in the design of degradable sonosensitizers.

A tumor-targeting and ROS-responsive iron-based T1 magnetic resonance imaging contrast agent for highly specific tumor imaging.

T1 contrast agents (CAs) exhibit outstanding capacity in enhancing the magnetic resonance imaging (MRI) contrast between tumor tissues and normal tissues for generating bright images. However, the clinical application of representative gadolinium(III) chelate-based T1 CAs is limited due to their potential toxicity and low specificity for pathological tissues. To obtain MRI CAs with a combination of low toxicity and high tumor specificity, herein, we report a reactive oxygen species (ROS)-responsive T1 CA (GA-Fe(II)-PEG-FA), which was constructed by chelating Fe(II) with gallic acid (GA), and modified with tumor-targeted folic acid (FA). The resultant CA could accumulate in tumor tissues via the affinity between FA and their receptors on the tumor cell membrane. It realized the switch from Fe(II) to Fe(III), and further enhancing the longitudinal relaxation rate (r1) under the stimuli of ROS in the tumor microenvironment. The r1 of GA-Fe(II)-PEG-FA on a 0.5 T nuclear magnetic resonance analyzer increased to 2.20 mM-1 s-1 under ROS stimuli and was 5 times greater than the r1 (0.42 mM-1 s-1) before oxidation. The cell and in vivo experiments demonstrated that GA-Fe(II)-PEG-FA exhibited good biocompatibility and significant targeting specificity to tumor cells and tumor tissues. Furthermore, in vivo MRI studies demonstrated that the enhanced T1 contrast effect against tumors could be achieved after injecting the CA for 3 h, indicating that GA-Fe(II)-PEG-FA has the potential as an ideal tumor MRI CA to increase the contrast and improve the diagnostic precision.

Effective design of organic luminogens for near-infrared-II fluorescence imaging and photo-mediated therapy.

Due to their electron coupling capability, organic luminescent materials exhibit powerful optoelectronic features that are responsible for their light-harvesting and light-amplification properties. The extensive modification of conjugated systems has shown significant improvement in their photonic properties thus broadening their applicability in photo-mediated imaging and photo-based treatment. Organic luminogens with emission in the near-infrared second region are found attractive not only for their deeper penetrating power but also for accurate visual imaging superiority with higher temporal resolution and spatial resolution suitable for tumor precision treatment. In this review, we underscore the latest development in organic luminogens (conjugated polymers and small molecules), focusing on chemical design, molecular engineering, and their applications in the scope of bioimaging followed by photo-assisted treatment, including photodynamic therapy (PDT), photothermal therapy (PTT), and immunotherapy ablation. Organic luminogens integrated with an aggregation-induced emission feature significantly optimize their physicochemical properties to act as quintessential nanoplatforms for controllable image-guided therapy. In conclusion, we clarify the limitations and challenges and provide insights into how to design organic dyes with improved safety for potential clinical applications.

Aptamer-Targeted Photodynamic Platforms for Tumor Therapy.

Achieving controlled and accurate delivery of photosensitizers (PSs) into tumor sites is a major challenge in conventional photodynamic therapy (PDT). Aptamer is a short oligonucleotide sequence (DNA or RNA) with a folded three-dimensional structure, which can selectively bind to specific small molecules, proteins, or the whole cells. Aptamers could act as ligands and be modified onto PSs or nanocarriers, enabling specific recognition and binding to tumor cells or their membrane proteins. The resultant aptamer-modified PSs or PSs-containing nanocarriers generate amounts of reactive oxygen species with light irradiation and obtain superior photodynamic therapeutic efficiency in tumors. Herein, we overview the recent progress in the designs and applications of aptamer-targeted photodynamic platforms for tumor therapy. First, we focus on the progress on the rational selection of aptamers and summarize the applications of aptamers which have been applied for targeted tumor diagnosis and therapy. Then, aptamer-targeted photodynamic therapies including various aptamer-PSs, aptamer-nanocarriers containing PSs, and aptamer-nano-photosensitizers are highlighted. The aptamer-targeted synergistically therapeutic platforms including PDT, photothermal therapy, and chemotherapy, as well as the imaging-guided theranostics, are also discussed. Finally, we offer an insight into the development trends and future perspectives of aptamer-targeted photodynamic platforms for tumor therapy.

Tumor Microenvironment-Responsive and Catalytic Cascade-Enhanced Nanocomposite for Tumor Thermal Ablation Synergizing with Chemodynamic and Chemotherapy.

Chemodynamic therapy (CDT) is considered as a promising nanocatalytic therapeutic strategy for cancer because of its specific response toward the tumor microenvironment (TME). Improving the efficiency of this kind of reactive oxygen species (ROS)-mediated therapy is still a formidable challenge. Herein, we integrate CDT with other therapeutic methods together to enhance anticancer effects via overcoming robust ROS defensive mechanisms and hypoxia in cancer cells. The biocompatible and biodegraded nanoplatform (HMnO2-DOX-GOD-HA) has been constructed on the basis of hollow MnO2 nanoparticles loaded with chemotherapeutics doxorubicin (DOX) and glucose oxide (GOD) and further decorated with hyaluronic acid (HA) for targeting tumor cells. We demonstrated that HMnO2-DOX-GOD-HA is not only able to deplete glutathione (GSH) to disturb the redox balance but also release Mn2+ to initiate the magnetic resonance imaging signal and induce Fenton reaction happening. Meanwhile, GOD-induced glucose oxidation and HMnO2-catalyzed O2 generation facilitate hypoxia relief and enhance toxic hydroxyl radical (•OH) production for CDT efficiency promotion. Upon 808 nm laser irradiation, cancer-killing efficiency can be notably increased by photothermally enhanced ion and drug release and thermal ablation. This work offers a paradigm to design a TME-responsive and imaging-guided synergistic strategy for hypoxia tumors based on GSH depletion and catalytic cascade-enhanced CDT, thermal ablation, and chemotherapy.

Self-production of oxygen system CaO2 /MnO2 @PDA-MB for the photodynamic therapy research and switch-control tumor cell imaging.

Photodynamic therapy (PDT) holds promise in biochemical study and tumor treatment. A novel multifunctional nanosystem CaO2 /MnO2 @polydopamine (PDA)-methylene blue (MB) nanosheet (CMP-MB) was designed. CaO2 nanoparticles were encapsulated by MnO2 nanosheet, and then PDA was coated on the surface of CaO2 /MnO2 nanosheets, which could adsorb photosensitizer MB through hydrophobic interaction or π-π stacking. In this nanosystem, CaO2 /MnO2 had the ability of self-production of oxygen, which solved the problem of tumor hypoxia largely. Moreover, it is worth mentioning that the fluorescence of MB was suppressed by MnO2 , while its emission was triggered in the simulated tumor microenvironment. Therefore, CMP-MB nanosheet could be used to switch-control cell imaging potentially. 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide testing and Live/Dead assay confirmed CMP-MB nanosheet had fewer side effects without illumination while it destroyed Hela cell with the illumination of light. Vitro cell experiment demonstrated CMP-MB nanosheet could achieve tumor microenvironment responsive imaging and inhibit tumor cell growth under illumination effectively. Therefore, the system has great potential for PDT application and switch-control tumor cell imaging. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2544-2552, 2018.