Photocurable biodegradable hyperelastic coating for fully covered tracheal stents enables synergistic thermochemotherapy of airway tumors.

Open AccessCCS ChemistryRESEARCH ARTICLE29 Mar 2022Temperature and Tumor Microenvironment Dual Responsive Mesoporous Magnetic Nanospheres for Magnetothermal Effect-Induced Cancer Theranostics Zhiyi Wang†, Shuren Wang†, Xiaoguang Zhang, Ziyuan Li, Zeeshan Ali, Donghai Yu, Hongtao Zhang, Fugeng Sheng, Song Gao and Yanglong Hou Zhiyi Wang† Beijing Key Laboratory for Magnetoelectric Materials and Devices, School of Materials Science and Engineering, Peking University, Beijing 100871 Institute of Spin-X Science and Technology, South China University of Technology, Guangzhou 510641 , Shuren Wang† Beijing Key Laboratory for Magnetoelectric Materials and Devices, School of Materials Science and Engineering, Peking University, Beijing 100871 , Xiaoguang Zhang Beijing Key Laboratory for Magnetoelectric Materials and Devices, School of Materials Science and Engineering, Peking University, Beijing 100871 , Ziyuan Li Beijing Key Laboratory for Magnetoelectric Materials and Devices, School of Materials Science and Engineering, Peking University, Beijing 100871 , Zeeshan Ali School of Chemical and Materials Engineering, National University of Sciences & Technology, Islamabad 44000 , Donghai Yu Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 , Hongtao Zhang Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071 , Fugeng Sheng Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071 , Song Gao Institute of Spin-X Science and Technology, South China University of Technology, Guangzhou 510641 and Yanglong Hou *Corresponding author: E-mail Address: [email protected] Beijing Key Laboratory for Magnetoelectric Materials and Devices, School of Materials Science and Engineering, Peking University, Beijing 100871 https://doi.org/10.31635/ccschem.022.202201805 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail The development of smart drug delivery systems (SDDSs) based on engineered nanomaterials is important for clinical applications. Nevertheless, controllable administration of chemotherapeutic drugs for deep tumors and the avoidance of side effects caused by off-targeting during delivery remain a great challenge. Herein, a stimulus-responsive system of mesoporous nanospheres (composed of [email protected]2[email protected]2) with good magnetothermal effect is introduced into the tumor microenvironment. This system plays an important role in image-guided controllable targeted drug delivery that is independent of tumor depth. Aggregation-induced emission luminogen-based fluorescence imaging and magnetic resonance imaging were utilized since these techniques visualize the delivery process in real time. In addition, the degraded nanocarriers showed high catalytic activity for Fenton and Fenton-like reactions, upregulating the level of hydroxyl radicals (•OH) in cancer cells to realize chemodynamic therapy. The induced •OH led to the overexpression of pho-STAT3, activating the STAT3 signaling pathway, eventually inducing cancer cell apoptosis. Through metabolic monitoring, this SDDS is removed from the body after its degradation in vivo. The synergistically enhanced therapeutic effect was obtained in the chemo-chemodynamic therapy of 4T1 tumor-bearing mice, offering a platform for efficient cancer therapy with a personalized theranostic strategy. Download figure Download PowerPoint Introduction Pharmacokinetic obstacles have been a major underlying reason for the failure to treat solid tumors, according to cumulative scientific evidence in recent decades.1 It has been generally accepted that pharmacokinetic disorders can be divided into three sublevels: (1) systemic pharmacokinetic disorders, (2) intratumoral pharmacokinetic disorders, and (3) cellular pharmacokinetic disorders. As the intratumoral pharmacokinetics disorders represent a core obstacle for drug delivery,2 to achieve the optimal anticancer effect, anticancer drugs need to be delivered not only to every single micromilieu of solid tumor microregions, but also at cytotoxic concentrations. Tumor cells placed in anticancer drugs with subcytotoxic concentrations of anticancer drug have met with tumor resistance, not just treatment failure.3,4 In other words, the challenge of drug delivery within the solid tumor micromilieu is mainly attributed to the complicated biology of the intratumoral microenvironment.5 Hence, to resolve this issue, a series of stimulus-responsive nanocarrier-mediated drug delivery systems (DDSs), including endogenous stimuli-responsive nanomaterials (NMs) (such as pH, enzyme, and redox),6 exogenous stimuli-responsive NMs,7–10 and multistimuli -esponsive NMs (such as temperature, light, ultrasound, and magnetic field),11,12 have been developed over the past few decades. These nanocarrier-mediated SDDSs have shown several obvious advantages, including greater accumulation of drugs at the diseased or pathological sites, enhanced cellular uptake, prolonged circulation time, high systemic stability, and reduction of toxic effects of the encapsulated compounds on healthy tissues.13–15 All these aspects of DDSs greatly promote the controllability and efficiency of drug delivery for cancer therapy. Nevertheless, the development of DDSs is still restricted by the problems with controllable drug delivery in the deepest tissues and off-targeting in the process of drug delivery. In addition to the drug delivery efficiency mentioned above, the pharmacological effect of drugs will also affect the therapeutic effect in the treatment of major diseases. Hence, some catalytic reactions such as Fenton and Fenton-like reactions have been employed to improve that efficacy. This strategy is considered as the classical chemical reaction in the field of environmental science,16 while the core reaction is to employ Fe2+, Cu+, and other variable valence transition metal ions to catalyze hydrogen peroxide (H2O2) to produce hydroxyl radical (•OH) with strong oxidation under the acidic conditions of the tumor microenvironment (TME).17,18 This strategy, defined as chemodynamic therapy (CDT), is a new treatment strategy with great potential for clinical transformation and development.17 At present, CDT has become a leading subject of cutting-edge research for the interdisciplinary scientific community while the distinctive characteristics of Fenton-like chemistry are the core in the field of chemical biology.19 Considering the fact that the catalyst plays a decisive role in kinetics and efficiency of Fenton and Fenton-like reactions, the selective design of CDT nanocatalysts will prove to be of great significance in improving its therapeutic effect on cancer, and will be given priority to combine with other treatments to achieve a synergistic enhancement effect. As a proof of concept, we designed a special kind of SDDS with degradable mesoporous magnetic nanospheres (NSs) for personalized imaging-guided cancer therapy (Figure 1). Primarily, [email protected]2[email protected]2 NSs with rich mesoporous structures were designed and synthesized as nanocarriers. Then the doxorubicin (DOX) and synthesized aggregation-induced emission luminogen (AIEgen) of TPE-based schiff base (TPE-SB) were filled into the mesopores of the [email protected]2[email protected]2 NSs and encapsulated by phase-change materials (PCMs) (i.e., lauric acid/stearic acid (LA/SA)) to avoid off-targeting during delivery. The combination of TPE-SB-based fluorescence imaging and magnetic resonance imaging (MRI) was used to visualizethe delivery process of SDDSs. Afterward, nucleolin-specific aptamer AS1411 was used to improve the targeting of 4T1 cancer through acylation reaction on the surface of SDDSs as depicted in Figure 1a. These SDDSs showed high catalytic activity for Fenton and Fenton-like reactions, which could upregulate the level of •OH in 4T1 cells, and led to the controlled overexpression of pho-STAT3 to activate the STAT3 signaling pathway so as to induce apoptosis of cancer cells. Hence, such nanocarriers are strongly reccomneded for use in CDT (Figure 1b). Controlled release of DOX was achieved for the SDDSs in mild alternating magnetic fields (AMF). In addition, synergistic enhancement of the cancer therapeutic effect was finally achieved by chemo-chemodynamic therapy in 4T1 tumor-bearing mice. In summary, our study provides a platform for personalized therapy of cancer with smartly engineered design, high-efficiency, targeted and controlled drug delivery, and enhanced therapeutic effect. Figure 1 | (a) Fabrication of [email protected]2[email protected]2-LA/SA/DOX/TPE-SB-AS1411. (b) Schematic representation of magnetothermal effect-induced smart drug delivery system for precision tumor theranostics. Download figure Download PowerPoint Experimental Methods Synthesis of TPE-SB TPE-SB was synthesized by the aldimine condensation between 1,2,4,5-Benzenetetramine and 4-(1,2,2-triphenylvinyl)benzaldehyde (TPE-CHO). First, the hydrochloric acid in amine hydrochloride (1,2,4,5-Benzenetetramine tetrahydrochloride) was removed by extraction operation under alkaline condition; then, the above obtained 1,2,4,5-Benzenetetramine and TPE-CHO were mixed in chloroform solvent for 12 h. Finally the reaction product TPE-SB was isolated and purified by recrystallization. Synthesis of [email protected]2C nanoparticles [email protected]2C nanoparticles (NPs) were synthesized by a thermal decomposition method in oil phase. Typically, copper(II) acetylacetonate (1 mmol), 1-octadecene (ODE) (15 mL), OAm (5 mL) and NH4Br (0.1 mmol) were mixed under a gentle N2 flow for 10 min in a four-necked flask. Then the solution was heated to 120 °C for 30 min to remove the organic impurities. Fe(CO)5 (5 mmol) was injected into the reaction system when the temperature reached 180 °C for 10 min, and the system was raised up to 265 °C for another 30 min. After the system cooled down to room temperature, 27 mL of acetone was added to the system. After centrifugation, the product was washed by ethanol and hexane. Finally, the [email protected]2C NPs were dispersed in hexane. Synthesis of [email protected]2[email protected]2 NSs [email protected]2[email protected]2 NSs were synthesized by coating mesoporous silicon on the surface of [email protected]2C NPs. Typically, [email protected]2C NPs (20 mg NPs in 1 mL hexane) and triethylamine (2 mmol) were dissolved in a mixed solution of cetyltrimethylammonium chloride (CTAC) solution (25 wt %, 24 mL) and deionized water (36 mL). Then the resulting solution was heated to 60 °C for 4 h to remove the hexane. After 4 h, tetraethoxysilane (TEOS) (1 mL, dispersed in 20 mL hexane) was added dropwise into the above mixed solution and continued to react for 48 h. After the reaction, when the system reached room temperature, 50 mL of absolute ethanol was added to the mixture and then centrifuged and collected. The collected product was washed with absolute ethanol three times, and the product was finally dispersed in deionized water for storage. Synthesis of [email protected]2[email protected]2-LA/SA/DOX/TPE-SB-AS1411 [email protected]2[email protected]2-LA/SA/DOX/TPE-SB-AS1411 was synthesized by the amidation between [email protected]2[email protected]2-LA/SA/DOX/TPE-SB and AS1411. Typically, [email protected]2[email protected]2-LA/SA/DOX/TPE-SB (50.0 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (0.12 mmol), and N-hydroxysuccinimide (NHS) (0.15 mmol) were dissolved in 10 mL of N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) (HEPES) buffer (pH 7.2) with stirring at room temperature. After 4 h, AS1411 (5 OD) was added in the above mixture, and it continued to react for 24 h. Finally, the reaction product was isolated and purified by dialysis. In addition, the synthesis of [email protected]2[email protected]2-LA/SA/TPE-SB-AS1411 was consistent with the above synthesis process. Degradation experiment in vitro Degradation of [email protected]2[email protected]2-LA/SA/DOX/TPE-SB in vitro was directly observed in the time-dependent structural evolution of [email protected]2[email protected]2-LA/SA/DOX/TPE-SB in different pH conditions by transmission electron microscope (TEM) during the degradation evaluation. Typically, [email protected]2[email protected]2-LA/SA/DOX/TPE-SB was added into phosphate-buffered saline (PBS) buffer. To investigate the pH influence on biodegradation, the PBS buffer solution with different pH conditions was adopted (pH 7.4, 6.5, and 5.4). All the evaluations were based on the concentration of 10 mg mL−1 [email protected]2[email protected]2-LA/SA/DOX/TPE-SB. The testing solution was put into a water bath (at 37 °C) under slow magnetic stirring (i.e., at 300 rpm) for 9 days. Samples were taken at different time points (0, 1, 2, 3, 4, and 9 days), and the morphological changes of the samples were observed by TEM. Magnetothermal effect of [email protected]2[email protected]2-LA/SA/DOX 1.5 mL of [email protected]2[email protected]2-LA/SA/DOX dispersions with different concentrations (of 0, 20, 40, 60, 80, and 100 mg L−1) were tested by AMF (heating current: 9A, oscillation frequency: 45–50 kHz) for 5 min, and their temperature in solution was recorded by an online-type thermocouple thermometer. Cell culture NIH3T3 and 4T1 cell lines were obtained from the Cancer Institute and Hospital of the Chinese Academy of Medical Science. All cell-culture-related reagents were purchased from Invitrogen. RPMI-1640 culture medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin was used to culture cells at 37 °C under 5% CO2 with 100% humidity. Colocalization of lysosomes and NSs assay The as-prepared sample of [email protected]2[email protected]2 NSs was conjugated with. 4T1 cells (5 × 104 cells per well) which was then seeded into a glass-bottom cell culture dish (20 mm). When the cell density reached 80–90%, the cells were then incubated with [email protected]2[email protected]2 NSs for 6 h. Subsequently, 4T1 cells were counterstained with Lyso-Tracker Green (L7526, Life TechnologiesTM, United States) and 4′,6-diamidino-2-phenylindole (DAPI) (C0060, Solaribio, Beijing, China) for 15 min. Finally, the cells were washed with PBS three times for NIR-II fluorescence imaging observation through multidimensional confocal microfluorescence imaging system (FLIM+confocal+AFM, Q2, ISS-USA). Double staining of living/dead cells assay Double staining of the living/dead cells assay was measured by Calcein-AM/PI Double Stain Kit (40747ES76, Yeasen, Shanghai, China). 4T1 cells were seeded into a 24-well culture plate (2 × 104 cells per well). When the cell density reached 70%, the cells were then incubated with [email protected]2[email protected]2 NSs for 24 h. After washing out the free NPs with PBS, fresh culture medium was added. AMF (oscillation frequency: 45–50 kHz, heating current: 9 A) was then used to cover the cells for 5 min. The staining was carried out as per given instructions. The cells were finally visualized using an inverted microscope (Olympus IX71). Fluorescence imaging of reactive oxygen species generation in 4T1 cells The reactive oxygen species (ROS)-generating capabilities of control group (saline) and [email protected]2[email protected]2 NSs were assessed by dihydrorhodamine 123 (DHR123) respectively. DHR123 staining was carried out as follows: cells were incubated with saline or [email protected]2[email protected]2 NSs (60 mg L−1) for 24 h. Then, 1 μg of DHR123 was added to cell media under laser irradiation (808 nm, 0.3 W cm−2) for 1 min. Confocal laser scanning microscopy and flow cytometry were used to observe the fluorescence intensity of DHR123 (λex/em = 488 nm/520 nm, n = 3). Intracellular ROS assay Intracellular ROS assay was measured by ROS Assay Kit (S0033, Beyotime, China). 4T1 cells were seeded into a 24-well culture plate (2 × 104 cells per well). When the cell density reached 70%, the cells were then incubated with [email protected]2[email protected]2 NSs for 24 h. After washing out the free NPs with PBS, fresh culture medium was added. AMF (oscillation frequency: 45–50 kHz, heating current: 9 A) was then used to cover the cells for 5 min. The staining was carried out as per given instructions. The cells were finally visualized using an inverted microscope (Olympus IX71) or detected through flow cytometry using BD Fortessa flow cytometer (BD Biosciences). Animals and tumor model Balb/c mice four to five weeks old with an average weight of 20 g were purchased from Vital River Laboratory Animal Technology Co. Ltd. (Beijing, China). An specific pathogen-free (SPF) animal house was provided to mice under a 12 h light and 12 h darkness cycle, and they were fed a standard laboratory diet and tap water ad libitum. For the subcutaneous tumor model, 4T1 cells (2 × 106 cells in 0.1 mL of saline) were injected subcutaneously into these mice. Fluorescence imaging in vivo The 4T1 triple-negative breast cancer (TNBC)-bearing mice were intravenously injected with [email protected]2[email protected]2-LA/SA/TPE-SB and [email protected]2[email protected]2-LA/SA/TPE-SB-AS1411 (20 mg kg−1, 200 μL) for fluorescence imaging in vivo. The fluorescence signal was recorded by the CRi Maestro ex in vivo imaging system (United States) at 0, 3, 6, 12, 24, and 48 h after the injection. To confirm the in vivo distribution of [email protected]2[email protected]2-LA/SA/TPE-SB and [email protected]2[email protected]2-LA/SA/TPE-SB-AS1411, mice were sacrificed 48 h post-injection. The main organs (liver, heart, lung, spleen, tumor, and kidneys) were collected for imaging and semiquantitative biodistribution analysis (n = 6). MRI in vivo The 4T1 TNBC-bearing mice were intravenously injected with [email protected]2[email protected]2-LA/SA/TPE-SB and [email protected]2[email protected]2-LA/SA/TPE-SB-AS1411 (20 mg kg−1, 200 μL) for MRI in vivo. After the injection, T2 images were obtained at 0, 6, 12, 24, and 48 h by a clinical 3.0 T MRI scanner (Philips, TR = 1200 ms, TE = 30.2 ms, slice thickness = 2.5 mm). The intensity of the MRI signal before injection was used as the control (n = 6). In vivo antitumor efficiency evaluation Mice bearing 200 mm3 4T1 TNBC were randomly divided into six groups: (1) control (only saline); (2) AMF; (3) [email protected]2[email protected]2-LA/SA/TPE-SB; (4) [email protected]2[email protected]2-LA/SA/DOX/TPE-SB; (5) [email protected]2[email protected]2-LA/SA/DOX/TPE-SB-AS1411; and (6) [email protected]2[email protected]2-LA/SA/DOX/TPE-SB-AS1411+AMF. Each group contained six mice. After 200 mL of saline or NPs (20 mg kg−1) were intravenously injected into 4T1 tumor-bearing mice for 1, 4, and 7 days, the mice were exposed to AMF (heating current: 9 A, oscillation frequency: 45–50 kHz) for 5 min three times. The changes in body weight and tumor volume during the 20 days of the treatment period were recorded. Histological evaluation Mice from each group were euthanized, and major organs and tumors were recovered, followed by fixing them with 10% neutral buffered formalin after 18 days of treatment. The organs were embedded in paraffin and sectioned at 5 mm. Hematoxylin and eosin (H&E) or Prussian blue staining was performed for histological examination. The slides were observed under an optical microscope (n = 6). Statistical analysis Statistical analysis was carried out by Tukey's post-hoc test with statistical significance assigned at **P < 0.01 (moderately significant), ***P < 0.001 (highly significant), and ****P < 0.0001 (highly significant). Results and Discussion Characterization of [email protected]2[email protected]2-LA/SA/DOX/TPE-SB-AS1411 The procedure for the synthesis of [email protected]2[email protected]2-LA/SA/DOX/TPE-SB-AS1411 is presented in Figure 1a while Figure 1b shows the tumor theranostic precision mechanism of [email protected]2[email protected]2-LA/SA/DOX/TPE-SB-AS1411. Initially, monodispersed core-shell structure [email protected]2C NPs were synthesized by the thermal decomposition method in the oil phase. TEM images clearly show that Cu cores are surrounded by the Fe2C domains with a thickness of nearly 3 nm (Figure 2a). The high-resolution TEM (HRTEM) analysis presented in Figure 2b evidences the lattice of spacing 2.08 Å between two (111) adjacent planes in the Cu region while the lattice spacing is 2.09Å in the Fe2C region, corresponding to the (101) planes of the hexagonal phase. Furthermore, energy dispersive X-ray (EDX) mapping of [email protected]2C NPs (presented in Supporting Information Figure S1), has also confirmed the composition and core-shell structure of [email protected]2C NPs. Subsequently, TEM and scanning electron microscopy (SEM) images [email protected]2[email protected]2 NSs after mSiO2 coating are presented in Figure 2c and Supporting Information Figure S2a. From these images, the estimated total size of [email protected]2[email protected]2 NSs is ∼65 nm. TEM images depicted in Supporting Information Figures S2b and S2c show characteristic lattice spacing of [email protected]2C NPs, which again reassures us that the NPs coated with mSiO2 are [email protected] NPs. EDX mapping and energy dispersive spectroscopy (EDS) line scan of [email protected]2[email protected]2 NSs are shown in Figures 2d and 2e, respectively, which has confirmed the composition and core-shell structure of [email protected]2[email protected]2 It is important to that the X-ray presented in Figure are consistent with TEM The X-ray spectroscopy of Cu and and and Supporting Information Figures and has confirmed the of and in [email protected]2C NPs and [email protected]2[email protected]2 The specific surface of [email protected]2[email protected]2 NSs is Supporting Information Figure while the average size distribution of [email NSs is nm after and analysis Supporting Information Figure also synthesized the before the drug into the mesopores of [email protected]2[email protected]2 As shown in Supporting Information Figure when the of to the of the is which is for the controllable release of drugs in vivo by inducing the magnetothermal effect of through mild In addition, we with TPE-CHO by organic synthesis to TPE-SB Supporting Information Figure This organic product was and by Supporting Information Figure and Supporting Information Figures and and after the of the the of the in the of a high Supporting Information Figure This confirmed that the above were and the TPE-SB were an of TPE-SB and DOX were mixed at a high temperature °C) with and then filled into the mesopores the surface of [email protected]2[email protected]2 NSs by to [email protected]2[email protected]2-LA/SA/DOX/TPE-SB. In addition, we AS1411 on the surface of [email protected]2[email protected]2-LA/SA/DOX/TPE-SB through amidation reaction to realize the targeting of [email protected]2[email protected]2-LA/SA/DOX/TPE-SB-AS1411. It be that the AS1411 has been developed and for cell in as a drug it has been utilized in targeted cancer The of was by the high of the of the of in the Supporting Information Figure Figure | Characterization of [email protected]2[email protected]2 (a) TEM of [email protected]2C NPs. (b) of [email protected]2C NPs. TEM of [email protected]2[email of [email protected]2[email protected]2 line scan of [email protected]2[email protected]2 of [email protected]2C NPs and [email protected]2[email protected]2 of Cu for [email protected]2[email protected]2 of for [email protected]2[email protected]2 Download figure Download PowerPoint of [email protected]2[email in vitro The of [email protected]2[email was by (pH 7.4, 6.5, and TEM imaging after 9 days (Figure and Supporting Information Figure was degradation of [email protected]2[email under these conditions after days, with the prolonged of [email protected]2[email in the PBS buffer (pH obvious degradation was in the other two (pH and also measured the of [email protected]2[email under three of pH conditions for different times by light (Figure which was consistent with the above of TEM. These prove that [email protected]2[email can in a time under acidic The of [email protected]2[email was in 4T1 cells. After 48 h of [email protected]2[email was degraded into NPs in the lysosomes of 4T1 cells. These are shown in the images in Figure It is that the pH of the tumor microenvironment is the and of tumor while pH of and The TEM and of size for [email protected]2[email evidence that the acidic of in mesoporous can finally be degraded into water and through The core [email protected]2C NPs also to a under acidic conditions to achieve In the of the [email protected]2[email has been through these on the above the degradation process of [email protected]2[email is in Figure First, the by the magnetothermal effect of the [email protected]2[email protected]2 NSs is used to the in the mesopores from the solid to the so as to from the Then the mesoporous of the NSs under the of Finally, the degraded NSs are in the of in the resulting in the release of and Figure 3 | evaluation of [email protected]2[email in (a) TEM of [email protected]2[email under three different pH conditions (pH 7.4, 6.5, and over 9 days. (b) of size for [email protected]2[email which measured by imaging of [email protected]2[email in 4T1 Degradation process of [email protected]2[email Download figure Download PowerPoint evaluation at cellular level The above degradation characteristics of the NSs under acid After the degradation of the valence Cu and including and in [email protected]2[email protected]2 NSs The reaction of corresponding Fenton and Fenton-like reaction can be 3 (1) Cu

Incorporation of doxorubicin and CoFe2O4 nanoparticles into the cellulose acetate phthalate / polyvinyl alcohol (core)/ polyurethane (shell) nanofibers against A549 human lung cancer during chemotherapy/hyperthermia combined method

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Herein, original magnetic drug delivery nanomaterials for cancer therapy are developed and compared, with the purpose to show active control over drug release by using an alternative magnetic field (AMF). The rationale is to combine polymers and superparamagnetic nanoparticles to trigger such drug release under AMF. Two magnetic nanosystems are thus presented: magnetic nanogels made of thermosensitive and biocompatible polymers and core-shell nanoparticles with a magnetic core and a molecularly imprinted polymer as shell. Both encapsulate doxorubicin (DOX) and the DOX controlled release was investigated in vitro and in cells under AMF excitation. It confirms that the local heat profile at the vicinity of the iron oxide core can be used for the DOX controlled release. It also shows that both nanosystems help delivering more DOX inside the cells compared to internalization of free DOX. Finally, the DOX intracellular release could be remotely triggered under AMF, in athermal conditions, thus enhancing DOX cytotoxicity.

An alternating magnetic field (AMF)-stimuli responsive nanodevice based on magnetic nanoparticles (MNP) functionalized with water-soluble carboxylate-substituted pillar[5]arene (CP[5]A), namely MNP-CP[5]A, as a multiplatform for cancer treatment has been designed. MNP-CP[5]A was loaded with doxorubicin (DOX), showing a loading capacity of 9.5 mg g-1. The nanodevice demonstrated good colloidal stability, superparamagnetic behavior, and was capable to generate detectable heat in solution induced by AMF application. DOX release, monitored by ultraviolet-visible (UV-Vis) spectroscopy, was investigated by varying the temperature (37 and 45 °C) without AMF and in the presence of AMF (frequency (f) = 307 kHz, field amplitude (H) = 200 Oe, 45 °C) at pH = 7.4. Thermo-induced DOX release without AMF was 1.9% (1.8 μg mL-1) and 2.3% (3.3 μg mL-1) at 37, and 45 °C within 50 min, respectively. In an AMF DOX release increased to 5.7% (8.2 μg mL-1) within 50 min. Therefore, MNP-CP[5]A-DOX works as a chemo-hyperthermia nanodevice.

Experiments were performed on the superplastic Zn-22% Al eutectoid alloy to determine the contribution of grain boundary sliding at both low (35%) and high (∼235%) elongations. The tests were conducted at two different strain rates in the superplastic Region II, and the results show that, within the accuracy of the measurements, there is a large sliding contribution at both elongations. By taking detailed measurements of both the magnitude of the sliding offset and the type of interface, it is shown that the average offsets are generally a maximum at the Zn-Zn boundaries, there is less sliding at the Zn-Al interfaces, and the offsets are a minimum at the Al-Al boundaries. In addition, the distributions of the magnitudes of the sliding offsets are similar at both the low and high elongations. It is concluded that grain boundary sliding is an important deformation process in the superplastic Region II and that it remains important even when the elongation is very high. The nature of the results indicates also that experimental observations of the deformation behaviour in superplastic materials at low elongations (up to 50%) provide meaningful information on the behaviour at much higher (superplastic) elongations.

Liver cancer is an aggressive malignancy associated with high levels of mortality and morbidity. Doxorubicin (Dox) is often used to slow down liver cancer progression; however its efficacy is limited, and its severe side effects prevent its routine use at therapeutic concentrations. We present a biomimetic peptide that coacervates into micro-droplets, within which both Dox and magnetic nanoparticles (MNPs) can be sequestered. These Dox-loaded Magnetic Coacervates (DMCs) can be used for thermo-chemotherapy, with the controlled release of Dox triggered by an external Alternating Magnetic Field (AMF). The DMCs are internalized by the cells via an energy-independent mechanism which is not based on endocytosis. Application of AMF generates a temperature of 45 °C within the DMCs, triggering their disassembly and the simultaneous release of Dox, thereby resulting in dual hyperthermia and chemotherapy for more efficient cancer therapy. In vitro studies conducted under AMF reveal that DMCs are cytocompatible and effective in inducing HepG2 liver cancer cell death. Thermo-chemotherapy treatment against HepG2 cells is also shown to be more effective compared to either hyperthermia or chemotherapy treatments alone. Thus, our novel peptide DMCs can open avenues in theranostic strategies against liver cancer through programmable, wireless, and remote control of Dox release.

RETRACTED: Synthesis of hollow maghemite (<gamma>-Fe2O3) particles for magnetic field and pH-responsive drug delivery and lung cancer treatment

Due to no penetration depth limitation, low cost, and easy control, magnetic nanoparticles mediated magnetic hyperthermia therapy (MHT) has shown great potential in experimental and clinal treatments of various diseases. However, the low heating conversion efficiencies and short circulation times are major drawback for most existing magnetic-thermal materials. Additionally, single MHT treatment always leads to resistance and recurrence. Herein, a highly efficient magnetic-thermal conversion, ferrimagnetic vortex nanoring Fe3O4 coated with hyaluronic acid (HA) nanoparticles (Fe3O4@HA, FVNH NPs) was firstly constructed. Additionally, the doxorubicin (DOX) was successfully enclosed inside the FVNH and released remotely for synergetic magnetic–thermal/chemo cancer therapy. Due to the ferrimagnetic vortex-domain state, the ring shape Fe3O4 displays a high specific absorption rate (SAR) under an external alternating magnetic field (AMF). Additionally, antitumor drug (DOX) can be encapsulated inside the single large hole of FVNH by the hyaluronic acid (HA) shell and quickly released in response the tumor acidic microenvironments and AMF. What’s more, the non-loaded FVNH NPs show good biocompatibility but high cytotoxicity after loading DOX under AMF. Furthermore, the synthesized FVNH can efficiently reduce the transverse relaxation time and enhance negative magnetic resonance imaging (MRI). The impressive in vivo systemic therapeutic efficacy of FVNH was also proved in this work. Taken together, the results of this study demonstrate that the synthesized FVNH NPs offer the promise of serving as multifunctional theranostic nanoplatforms for medical imaging-guided tumor therapies.

A series of ultraviolet (UV)-photocurable 3,3′4,4′-benzophenone tetracarboxylic dianhydride (BTDA)-based multiacrylate oligomers containing pendant glycidyl methacrylate (GMA) or glycidyl acrylate (GA) and caprolactone acrylate (Tone M-100) or caprolactone methacrylate (Tone M-201) were synthesized. The effects of the acrylic functional groups, the moles of GMA, and the molar ratio of Tone M-201 to Tone M-100 on their properties were investigated. The prepared photocurable oligomers were cured rapidly when exposed to UV or sunlight radiation without the addition of any extra photoinitiator or photosensitizer. The acrylate-type oligomer resulted in a lower thermal curing temperature and a fast curing rate. Increasing the moles of GMA or the molar ratio of Tone M-201/Tone M-100 on reaction led to a higher crosslinking density and resulted in film with higher Young's modulus, higher breaking strength, and lower elongation. The methacrylate type oligomer cured to a very hard but brittle film with higher Young's modulus and lower elongation. By contrast, the acrylate-type oligomer cured to a hard, tough film with lower Young's modulus and higher elongation. The film properties of the oligomers coated on steel plates were also investigated. © 1997 John Wiley & Sons, Inc. J Appl Polym Sci 64: 1625–1634, 1997

Catechol–metal coordination-mediated nanocomposite hydrogels for on-demand drug delivery and efficacious combination therapy

An innovative magnetic delivery nanomaterial for triggered cancer therapy showing active control over drug release by using an alternative magnetic field is proposed. In vitro and In vivo release of doxorubicin (DOX) were investigated and showed a massive DOX release under an alternative magnetic field without temperature elevation of the medium.

BackgroundTo improve responses to tumor microenvironments for achieving a better therapeutic outcome in combination cancer therapy, poly(ε-caprolactone)-SS-poly(methacrylic acid) diblock copolymer (PCL-SS-PMAA) with a disulfide linkage between the hydrophobic and hydrophilic junctions was synthesized.Materials and MethodsRepeating units of PCL and PMAA in PCL-SS-PMAA were controlled and formulated into polymersomes (PSPps). Truncated octahedral Fe3O4 nanoparticles (IONPs) were synthesized and encapsulated to produce IONPs-PSPps NPs and doxorubicin (DOX) was further loaded to produce IONPs-PSPps@DOX NPs for theranostic applications.ResultsIONPs-PSPps NPs remained a superparamagnetic property with a saturation magnetization value of 85 emu⋅gFe3O4−1 and a relaxivity value of 180 mM−1⋅s−1. Upon exposure to an alternating magnetic field (AMF), IONPs-PSPps NPs increased temperature from 25°C to 54°C within 15 min. Among test groups, the cell apoptosis was greatest in the group exposed to IONPs-PSPps@DOX NPs with AMF and magnet assistance. In vivo T2-weighted magnetic resonance images of A549 tumor-bearing mice also showed highest contrast and greatest tumor suppression in the tumor with AMF and magnet assistance.ConclusionIONPs-PSPps@DOX NPs are a potential theranostic agent having multifaceted applications involving magnetic targeting, MRI diagnosis, hyperthermia and chemotherapy.

By using radio-labeled multifunctional superparamagnetic iron oxide nanoparticles (SPIONs) and an alternating magnetic field (AMF), we carried out targeted hyperthermia, drug delivery, radio-immunotherapy (RIT), and controlled chemotherapy of cancer tumors. We synthesized and characterized Indium-111-labeled, Trastuzumab and Doxorubicin (DOX)-conjugated APTES-PEG-coated SPIONs in our previous work. Then, we evaluated their capability in SPECT/MRI (single photon emission computed tomography/magnetic resonance imaging) dual modal molecular imaging, targeting, and controlled release. In this research, AMF was introduced to evaluate therapeutic effects of magnetic hyperthermia on radionuclide-chemo therapy of HER2+ cells and tumor (HER2+)-bearing mice. In vitro and in vivo experiments using synthesized complex were repeated under an AMF (f: 100 KHz, H: 280 Gs). Instead of an intra-tumor injection in most hyperthermia experiments, SPIONs were injected to the tail vein, based on our delivery strategies. For magnetic delivery, we held a permanent Nd-B-Fe magnet near the tumor region. The results showed that simultaneous magnetic hyperthermia enhanced SKBR3 cancer cells, killing by 24%, 28%, 33%, and 80% at 48 hours post-treatment for treated cells with (1) bare SPIONs; (2) antibody-conjugated, DOX-free, surface-modified SPIONs; (3) 111In-labeled, antibody-conjugated surface-modified SPIONs; and (4) 111In-labeled, antibody- and DOX-conjugated surface-modified SPIONs, respectively. Moreover, tumor volume inhibitory rate was 85% after a 28 day period of treatment. By using this method, multimodal imaging-guided, targeted hyperthermia, RIT, and controlled chemotherapy could be achievable in the near future.

A novel locally injectable, biodegradable, and thermo-sensitive hydrogel made from chitosan and β-glycerophosphate salt was prepared. It incorporated polyethylenimine (PEI)-modified super-paramagnetic graphene oxide (GO/IONP/PEI) as a form of minimally invasive treatment of cancer lesions by magnetically induced local hyperthermia. Doxorubicin (DOX) was mixed into the hydrogel which was pre-loaded on GO/IONP/PEI to create a drug delivery system DOX-GO/IONP/PEI-gel. In addition to the evaluation of in vitro and in vivo antitumor activities, the physicochemical properties, magnetic properties and DOX release profile of the DOX-GO/IONP/PEI-gel were determined. The aqueous solution of the hydrogel showed a sol-gel transition behavior depending on temperature changes. Magnetization loops indicated the super-paramagnetic properties of GO/IONP/PEI. Compared with free DOX, DOX-GO/IONP/PEI could efficiently pass through cell membranes, leading to more apoptosis and demonstrating higher antitumor efficacy on MCF-7 cells in vitro. Furthermore, DOX-GO/IONP/PEI-gel intratumorally injected (i.t.) showed high antitumor efficacy on tumor-bearing mice in vivo, with no obvious toxicity. The antitumor efficacy was higher when combined with an alternating magnetic field (AMF), showing that DOX-GO/IONP/PEI-gel under AMF has great potential for cancer magnetic hyperthermia therapy.