Qianhua Feng

Tumor-targeted and multi-stimuli responsive drug delivery system for near-infrared light induced chemo-phototherapy and photoacoustic tomography

UNLABELLED In this work, a tumor-targeted and multi-stimuli responsive drug delivery system has been developed for combining photoacoustic tomography imaging with chemo-phototherapy. We utilized a kind of near infrared (NIR) resonant material-hollow mesoporous copper sulfide nanoparticles (HMCuS NPs) to encapsulate doxorubicin (DOX). After that, the outer surface of HMCuS NPs was capped with multifunctional hyaluronic acid (HA) simultaneously as smart gatekeeper as well as tumor targeting moiety. Herein, HMCuS-HA could serve as a powerful contrast agent for photoacoustic tomography (PAT) to guide chemo-phototherapy by providing the identification of cancerous lesions. In vitro and in vivo studies, the nanoplatform (DOX/HMCuS-HA) pinpointed MCF-7 cells via CD44 receptor-mediated endocytosis pathway. Subsequently, intracellular enzyme-responsive controlled drug release would take place in lysosome after the HA degradation by hyaluronidase. Under near infrared (NIR) light irradiation, HMCuS NPs could not only effectively convert NIR light into heat for photothermal therapy, but also generate high levels of reactive oxygen species (ROS) for photodynamic therapy. In addition, NIR light and low pH environment could facilitate intracellular tunable drug release with spatial/temporal resolution, and thus synergistic combination of chemo-phototherapy should be simultaneously driven by an 808nm laser irradiation, which brought out an outstanding therapeutic effect. In vivo optical imaging demonstrated that HMCuS-HA significantly enhanced targeting and accumulation capacity in tumor site. Furthermore, tumor-bearing mice treated with DOX/HMCuS-HA under NIR irradiation (808nm, 2W/cm(2), 0.5min) in vivo displayed the highest inhibition ratio of about 88.9%. Taken together, our present study of the tumor-targeted and multi-stimuli responsive drug delivery system provides new insights into multimodality theranostic applications in cancer treatment. STATEMENT OF SIGNIFICANCE Until now, chemotherapy is still the major therapeutic approach applied in oncology. Despite their pharmacologically efficacy in cancer treatments, most chemotherapeutic agents without tumor-specific targeting ability have brought out serious toxicities to normal tissues. This study provides a promising near infrared (NIR) resonant material-hollow mesoporous copper sulfide nanoparticles (HMCuS NPs) with capping of multifunctional hyaluronic acid (HA) simultaneously as smart gatekeeper as well as tumor targeting moiety to address the above problem. After the nanoplatform (DOX/HMCuS-HA) pinpointed breast cancer cells via CD44 receptor-mediated endocytosis pathway, intracellular multi-stimuli responsive controlled drug release would take place with remarkable spatial/temporal resolution. Then photoacoustic tomography (PAT) and synergistic combination of chemo-phototherapy would be simultaneously driven by the same NIR irradiation in a coordinated way, which brought out an outstanding theranostic effect. This work can arouse broad interests among researchers in the fields of nanomedicine, nanotechnology, and drug delivery system.

A novel redox-sensitive system based on single-walled carbon nanotubes for chemo-photothermal therapy and magnetic resonance imaging

Recently, nanomaterials with multiple functions, such as drug carrier, magnetic resonance imaging (MRI) and optical imaging, and photothermal therapy, have become more and more popular in cancer research. In this work, a novel redox-sensitive system constructed from hyaluronic acid (HA), single-walled carbon nanotubes (SWCNTs), doxorubicin (DOX), and gadolinium (Gd) was successfully developed. Herein, HA-modified SWCNTs (SWCNTs-HA) was first synthesized, and then DOX was conjugated with HA by disulfide bond (SWCNTs-HA-ss-DOX). Finally, MRI contrast agents, Gd3+-ion loading occurred through the sidewall defects of SWCNTs, whose cytotoxicity could be sequestered within the SWCNTs. In vitro release of DOX showed that this system accomplished much faster drug release under reducing condition. Confocal microscopy analysis confirmed that Gd/SWCNTs-HA-ss-DOX were capable of simultaneously delivering DOX and SWCNTs into Michigan Cancer Foundation-7 cells via HA receptor-mediated endocytosis followed by rapid transport of cargoes into the cytosol. Enhanced cytotoxicity of Gd/SWCNTs-HA-ss-DOX further proved that the sensitive system was more potent for intracellular drug delivery as compared with the insensitive control. Meanwhile, tumor cell killing potency was improved when Gd/SWCNTs-HA-ss-DOX were combined with near-infrared irradiation, with IC50 of 0.61 µg/mL at 48 hours. In vivo investigation demonstrated that Gd/SWCNTs-HA-ss-DOX could effectively accumulate in tumor sites and possessed the greatest synergistic antitumor efficacy, especially under the 808 nm laser irradiation. More importantly, this system could be used as a contrast agent for MRI to identify the location and extent of tumor tissues. These results suggested that Gd/SWCNTs-HA-ss-DOX might be a promising system for targeting chemo-photothermal therapy and MRI diagnosis in future clinical anticancer applications.

Targeting and hyperthermia of doxorubicin by the delivery of single-walled carbon nanotubes to EC-109 cells

A targeting and photothermal drug delivery system of doxorubicin (DOX) was successfully developed based on the AS1411 aptamer modified single wall carbon nanotubes (SWNTs). In this study, DOX was efficiently loaded onto SWNTs (DOX-AS1411-SWNTs) with drug loading of 121% and released from DOX-AS1411-SWNTs in a pH-dependent manner. Internalization analysis demonstrated that the tertiary complex (DOX-AS1411-SWNTs) could transfer into the cell through the AS1411-mediated endocytosis in 2 h. Moreover, the cytotoxicity test of DOX-AS1411-SWNTs showed higher inhibition effect on EC-109 cells compared to DOX control group. Meanwhile, 808 nm near-infrared laser was used here for photothermal treatment, and AS1411-SWNTs were proved to have a strong efficacy on tumor hyperthermia. Furthermore, with a focus on the G2-M phase, we found DOX-AS1411-SWNTs capable of altering G2-M cell-cycle phase, owing to the hyperthermia and synergistic effect.

Copper sulfide nanoparticle-based localized drug delivery system as an effective cancer synergistic treatment and theranostic platform

Localized cancer treatment with combination therapy has attracted increasing attention for effective inhibition of tumor growth. In this work, we introduced diffusion molecular retention (DMR) tumor targeting effect, a new strategy that employed transferrin (Tf) modified hollow mesoporous CuS nanoparticles (HMCuS NPs) to undergo extensive diffuse through the interstitium and tumor retention after a peritumoral (PT) injection. Herein, HMCuS NPs with strong near-infrared (NIR) absorption and photothermal conversion efficiency could serve as not only a drug carrier but also a powerful contrast agent for photoacoustic imaging to guide chemo-phototherapy. The iron-dependent artesunate (AS), which possessed profound cytotoxicity against tumor cell, was used as model drug. As a result, this AS loaded Tf-HMCuS NPs (AS/Tf-HMCuS NPs) system could specially target to tumor cells and synchronously deliver AS as well as irons into tumor to achieve enhanced antitumor activity. It was found that AS/Tf-HMCuS NPs was taken up by MCF-7 cells via Tf-mediated endocytosis, and could effectively convert NIR light into heat for photothermal therapy as well as generated high levels of reactive oxygen species (ROS) for photodynamic therapy. In addition, in vivo antitumor efficacy studies showed that tumor-bearing mice treated with AS/Tf-HMCuS NPs through peritumoral (PT) injection under NIR laser irradiation displayed the strongest inhibition rate of about 74.8%, even with the reduced frequency of administration. Furthermore, to demonstrate DMR, the optical imaging, photoacoustic tomography and immunofluorescence after PT injection were adopted to track the behavior of AS/Tf-HMCuS NPs in vivo. The results exhibited that Tf-HMCuS NPs prolonged the local accumulation and retention together with slow vascular uptake and extensive interstitial diffusion, which was consistent with the biodistribution studies of AS/Tf-HMCuS NPs. Therefore, the approach of localized delivery through DMR combined with multi-mechanism therapy may be a promising method for cancer treatment. STATEMENT OF SIGNIFICANCE In recent years, localized cancer treatment using different biomaterials has attracted increasing attention for effective inhibition of tumor growth. However, it is still challenging for this kind of system to achieve a high drug loading, overcome biological barriers from the site of injection to the site of action, and combine synergetic therapy with diagnosis without adversely affecting the formation process. This study provides a localized diffusion molecular retention (DMR) tumor targeting drug delivery system based on hollow mesoporous copper sulfide nanoparticles (HMCuS NPs) entrapment of anticancer drug for the first time, which can achieve high drug loading, improve local drug accumulation and retention, accomplish synergistic combination of chemo-phototherapy, and finally enhance antitumor effect. In addition, HMCuS NPs also possesses the property suitable for photoacoustic imaging, which could offer us a theranostic platform.

Smart nanocomposite hydrogels based on azo crosslinked graphene oxide for oral colon-specific drug delivery

A safe and efficient nanocomposite hydrogel for colon cancer drug delivery was synthesized using pH-sensitive and biocompatible graphene oxide (GO) containing azoaromatic crosslinks as well as poly (vinyl alcohol) (PVA) (GO-N=N-GO/PVA composite hydrogels). Curcumin (CUR), an anti-cancer drug, was encapsulated successfully into the hydrogel through a freezing and thawing process. Fourier transform infrared spectroscopy, scanning electron microscopy and Raman spectroscopy were performed to confirm the formation and morphological properties of the nanocomposite hydrogel. The hydrogels exhibited good swelling properties in a pH-sensitive manner. Drug release studies under conditions mimicking stomach to colon transit have shown that the drug was protected from being released completely into the physiological environment of the stomach and small intestine. In vivo imaging analysis, pharmacokinetics and a distribution of the gastrointestinal tract experiment were systematically studied and evaluated as colon-specific drug delivery systems. All the results demonstrated that GO-N=N-GO/PVA composite hydrogels could protect CUR well while passing through the stomach and small intestine to the proximal colon, and enhance the colon-targeting ability and residence time in the colon site. Therefore, CUR loaded GO-N=N-GO/PVA composite hydrogels might potentially provide a theoretical basis for the treatment of colon cancer with high efficiency and low toxicity.

Hypoxia-specific therapeutic agents delivery nanotheranostics: A sequential strategy for ultrasound mediated on-demand tritherapies and imaging of cancer

&NA; The hypoxic microenvironment induced by sonodynamic therapy (SDT) via sonochemical oxygen consumption usually triggered tumor resistance to SDT, impeding therapeutic efficacy. In this sense, it was highly desired to tackle the hypoxia‐related negative issues. Here we provide the therapeutic agents delivery system, TPZ/HMTNPs‐SNO, which was constructed by loading tirapazamine (TPZ) into hollow mesoporous titanium dioxide nanoparticles (HMTNPs) with modification of S‐nitrosothiol (R‐SNO). Upon encountering ultrasound waves, the HMTNPs as sonosensitizers would generate reactive oxygen species (ROS) for SDT. In a sequential manner, the followed SDT‐induced hypoxia further activated the “hypoxic cytotoxin”, TPZ, for hypoxia‐specific killing effect. Meanwhile, the generated ROS could sensitize ‐SNO groups for on‐demand nitric oxide (NO) release in an “anticancer therapeutic window”, resulting in the NO sensitized SDT effect. This study confirmed that the TPZ/HMTNPs‐SNO with multi‐mechanisms exploited the merits of synergistic combination of the three therapeutic modes, consequently potentiating the anticancer efficacy of SDT. Moreover, the echogenic property of NO made the nanoplatform as an ultrasound contrast agent to enhance ultrasound imaging. In this sense, we developed a sequential strategy for ultrasound mediated all‐in‐one nanotheranostic platform of TPZ/HMTNPs‐SNO, which highlighted new possibilities of advancing cancer theranostics in biomedical fields.

Tumor acidity-activatable manganese phosphate nanoplatform for amplification of photodynamic cancer therapy and magnetic resonance imaging

Amorphous biodegradable metal phosphate nanomaterials are considered to possess great potential in cancer theranostic application due to their promise in providing ultra-sensitive pH-responsive therapeutic benefits and diagnostic functions simultaneously. Here we report the synthesis of photosensitising and acriflavine-carrying amorphous porous manganese phosphate (PMP) nanoparticles with ultra-sensitive pH-responsive degradability and their application for a photoactivable synergistic nanosystem that imparts reactive oxygen species (ROS) induced cytotoxicity in synchrony with hypoxia-inducible factor 1α/vascular endothelial growth factor (HIF1α/VEGF) inhibitor that suppresses tumor growth and treatment escape signalling pathway. Carboxymethyl dextran (CMD) is chemically anchored on the surface of porous manganese phosphate theranostic system through the pH-responsive boronate esters. Upon the stimulus of the tumor acid microenvironment, manganese phosphate disintegrates and releases Mn2+ ions rapidly, which are responsible for the magnetic resonance imaging (MRI) effect. Meanwhile, the released photosensitizer chlorin e6 (Ce6) produces ROS under irradiation while acriflavine (ACF) inhibits the HIF-1α/VEGF pathway during the burst release of VEGF in tumour induced by photodynamic therapy (PDT), resulting in increased therapeutic efficacy. Considering the strong pH responsivity, MRI signal amplification and drug release profile, the PMP nanoparticles offer new prospects for tumor acidity-activatable theranostic application by amplifying the PDT through inhibiting the HIF-1α /VEGF pathway timely while enhancing the MRI effect. STATEMENT OF SIGNIFICANCE In this study, we report the synthesis of the tumor acidity-activatable amorphous porous manganese phosphate nanoparticles and their application for a photoactivable synergistic nanosystem that imparts reactive oxygen species (ROS) induced cytotoxicity in synchrony with hypoxia-inducible factor 1α/vascular endothelial growth factor (HIF-1α/VEGF) inhibitor that suppresses tumor growth and treatment escape signalling pathway. Besides, upon the stimulus of the tumor acid microenvironment, the manganese phosphate nanoparticles finally disintegrate and release Mn2+ ions rapidly, which are responsible for the magnetic resonance imaging (MRI) effect. This nanoplatform is featured with distinctive advantages such as ultra pH-responsive drug release, MRI function and rational drug combination exploiting the blockage of the treatment escape signalling pathway.