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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 Mn 2+ 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 Mn 2+ 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. [ABSTRACT FROM AUTHOR]

Co-delivery of photosensitizers and synergistic agents by one single nanoplatform is interesting for enhancing photodynamic therapy (PDT) of cancer. Here, a multifunctional nanoplatform for enhanced photodynamic therapy and magnetic resonance imaging of cancer was constructed. The poly (lactide- co -glycolide) (PLGA) nanoparticles (NPs) loaded with hematoporphyrin monomethyl ether (HMME) were coated with multifunctional manganese dioxide (MnO 2 ) shells, which were designed as PLGA/HMME@MnO 2 NPs. Once the NPs were effectively taken up by tumor cells, the intracellular H 2 O 2 was catalysed by the MnO 2 shells to generate O 2 . Meanwhile, the higher glutathione (GSH) promoted the degradation of MnO 2 into Mn 2+ ions with the ability of magnetic resonance (MR) imaging. After the degradation of outer layer, the release of photosensitizer was promoted. Under irradiation, the released HMME produced cytotoxic reactive oxygen species (ROS) to damage the tumor cells when the O 2 was generated in the hypoxic tumor site. Furthermore, the decreased GSH level further inhibited the consumption of the produced ROS, which greatly enhanced the PDT efficacy. Therefore, this study suggested that this multifunctional system has the potential for enhanced photodynamic therapy and magnetic resonance imaging. [ABSTRACT FROM AUTHOR]

Context: Functionalized single-walled carbon nanotubes (SWNT) with 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) were used as novel and more convenient carriers of small interfering RNA (siRNA). Objective: To utilize the unique capability of SWNT to be easily modified by functional groups and readily internalized by mammalian cells to bind, condense, stabilize siRNA and enhance its transfection efficiency. Methods: After SWNT were non-covalently functionalized by cationic DOTAP (SWNT–DOTAP), siRNA interacted with SWNT–DOTAP via static electricity (SWNT–DOTAP/siRNA). Subsequently, the size, zeta potential and morphology of SWNT–DOTAP/siRNA were analyzed. The optimal compression ratio and stability of siRNA were assessed by agarose gel electrophoresis. Furthermore, in prostate carcinoma PC-3 cells, RT-PCR, flow cytometry and sulforhodamine B assays were used to evaluate the silencing activity, transfection efficiency and cell proliferation, respectively. Results and discussion: The characteristics of SWNT–DOTAP, i.e. an average size of 194.49 nm, a zeta potential of 45.16 mV and lower cytotoxicity than Lipofectamine 2000, indicated that this vector was suitable for siRNA delivery. Moreover, after interaction with SWNT–DOTAP, siRNA of human telomerase reverse transcriptase was bound, condensed and stabilized. In PC-3 cells, SWNT–DOTAP/siRNA exhibited 82.6% silencing activity and 92% transfection efficiency. Furthermore, the complexes inhibited cell proliferation by 42.1%. Conclusion: SWNT–DOTAP may be a promising siRNA delivery vector for gene-based therapeutic applications in cancer. [ABSTRACT FROM AUTHOR]

Gold nanomaterials possess unique physical and chemical properties, which attracted much attention in recent years. As a new type of gold nanomaterials, gold nanostars (GNSTs) have been prepared and characterized in this study. GNSTs under near-infrared (NIR) light irradiation can exert not only cancer photothermal therapy via heat production but also photodynamic therapy via generation of reactive oxygen species. GNSTs were able to enter the cytoplasm as well as nuclei of human breast michigan cancer foundation-7 (MCF-7) cells. Under NIR light irradiation, GNSTs caused more severe DNA damage, arrest the cell cycle in G0/G1 phase, and reduce more cellular glutathione level, causing more severe apoptosis and cell death in vitro. Intratumoral injection of GNSTs with NIR light irradiation significantly inhibited tumor growth in vivo. In addition, GNSTs were demonstrated to be a contrast agent for X-ray imaging. All the in vitro and in vivo results showed that GNSTs can be used for the potential diagnosis and medical treatment of cancer. [ABSTRACT FROM AUTHOR]

Abstract Combination therapy with multiple drugs or/and multiple assistant treatments has become a hot spot in cancer therapy. In this study, a new type of core-shell structured dual-drug delivery system based on poly (lactic- co -glycolic acid) (PLGA, inner cores) and hyaluronic acid (HA, outer shells) was constructed. Firstly, HA was conjugated to PLGA for preparation of HA-PLGA block copolymer. Secondly, 5-amino levulinic acid (ALA) was connected to PLGA through a pH-sensitive hydrazone bond for synthesization of PLGA-HBA-ALA. Finally, the core-shell structured nanoparticles (HA-PLGA@ART/ALA NPs) were constructed by self-assembled method for artemisinin (ART) loading in PLGA cores. In this co-delivery system, ALA and ART can be released in a manner of procedural controlled release. ALA was released from the NPs at first though the pH sensitive hydrazone bond cleavage in order to generate protoporphyrin IX (PpIX) for heme formation. And the increase of heme can effectively improve the curative effect of the subsequent released ART. Furthermore, this system has also shown obvious sonodynaimc activity which can be used for cancer sonodynamic combination therapy. The in vitro and in vivo anticancer results demonstrate that HA-PLGA@ART/ALA delivery system could provide a prospective comprehensive treatment strategy for cancer therapy. Graphical abstract A tumor-targeting drug delivery system based on the PLGA nanoparticles for ART and ALA dual-drug delivery and sonodynamic combination cancer therapy. Unlabelled Image Highlights • The dual drug delivery system has drug procedural controlled release function. • 5-amino levulinic acid can generate protoporphyrin IX for heme formation. • The increase of heme can effectively improve the curative effect of artemisinin. • The delivery system can be used for cancer sonodynamic combination therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]