Exosomes Derived from Mouse Breast Carcinoma Cells Facilitate Diabetic Wound Healing.

BACKGROUND: Exosomes derived from breast cancer have been reported to play a role in promoting cell proliferation, migration, and angiogenesis, which has the potential to accelerate the healing process of diabetic wounds. The aim of this investigation was to examine the function of exosomes originating from 4T1 mouse breast carcinoma cells (TEXs) in the process of diabetic wound healing. METHODS: The assessment of primary mouse skin fibroblasts cell proliferation and migration was conducted through the utilization of CCK-8 and wound healing assays, while the tube formation of HUVECs was evaluated by tube formation assay. High-throughput sequencing, RT-qPCR and cell experiments were used to detect the roles of miR-126a-3p in HUVECs functions in vitro. The in vivo study employed a model of full-thickness excisional wounds in diabetic subjects to explore the potential therapeutic benefits of TEXs. Immunohistochemical and immunofluorescent techniques were utilized to evaluate histological changes in skin tissues. RESULTS: The findings suggested that TEXs facilitate diabetic wound healing through the activation of cell migration, proliferation, and angiogenesis. An upregulation of miR-126a-3p has been observed in TEXs, and it has demonstrated efficient transferability from 4T1 cells to HUVEC cells. The activation of the PI3K/Akt pathway has been attributed to miR-126a-3p derived from TEXs. CONCLUSIONS: The promotion of chronic wound healing can be facilitated by TEXs through the activation of cellular migration, proliferation, and angiogenesis. The activation of the PI3K/Akt pathway by miR-126a-3p originating from TEXs has been discovered, indicating a potential avenue for enhancing the regenerative capabilities of wounds treated with TEXs.

Synergistic wound repair effects of a composite hydrogel for delivering tumor-derived vesicles and S-nitrosoglutathione.

Treating chronic wounds requires transition from proinflammatory M1 to anti-inflammatory M2 dominant macrophages. Based on the role of tumor extracellular vesicles (tEVs) in regulating the phenotypic switching from M1 to M2 macrophages, we propose that tEVs may have a beneficial impact on alleviating the overactive inflammatory microenvironment associated with refractory wounds. On the other hand, as a nitric oxide donor, S-nitrosoglutathione (GSNO) can regulate inflammation, promote angiogenesis, enhance matrix deposition, and facilitate wound healing. In this study, a guar gum-based hydrogel with tEVs and GSNO was designed for the treatment of diabetic refractory wounds. This hybrid hydrogel was formed through the phenyl borate bonds, which can automatically disintegrate in response to the high reactive oxygen species (ROS) level at the site of refractory diabetic wounds, releasing tEVs and GSNO. We conducted a comprehensive evaluation of this hydrogel in vitro, which demonstrated excellent performance. Meanwhile, using a full-thickness excision model in diabetic mice, the wounds exposed to the therapeutic hydrogel healed completely within 21 days. The increased closure rate was associated with macrophage polarization and collagen deposition, accelerated fibroblast proliferation, and increased angiogenesis in the regenerating tissues. Therefore, this multifunctional hybrid hydrogel appears to be promising for clinical applications.

An AIEgen-based "turn-on" probe for sensing cancer cells and tiny tumors with high furin expression.

Peptide-aggregation-induced emission (AIE) luminogen (AIEgen) conjugates are widely used in the bioimaging field for their good resistance to photobleaching, red and near-infrared light emission, good biocompatibility, etc. However, their peptides are mainly negatively charged and the positively charged peptide-AIEgen conjugates are rarely used in in vivo imaging due to their high non-specific interaction with protein to cause "false-positive" results and their potential risk of triggering hemolysis. Herein, we introduce a black hole quencher 3 (BHQ3) to RVRRGFF-AIE (FA) to build a "turn-on" probe, named BHQ3-RVRRGFF-AIE (BFA). Compared with FA, BFA has advantages in the anti-interference ability for different proteins and many solution environments. But, both BFA and FA have high risks of inducing hemolysis, which restricts their further application. Through co-assembly with poly-γ-glutamic acid (γ-PGA), molecular probes BFA and FA are formed into PGA-BFA and PGA-FA nanoparticles with high biocompatibility and suppressed phototoxicity. Cell studies show that PGA-BFA can discriminate cancer cells with high furin expression from low furin-expressed cancer cells and normal cells. In vivo studies show that PGA-BFA can light up tiny tumors in the abdominal cavity with a better tumor-to-intestine ratio (3.14) than that of PGA-FA (1.47), which is helpful for the accurate excision of tiny tumors. This study will advance the development of constructing good biosafety probes with a high signal-to-noise ratio for fluorescence image-guided cancer surgery.

Facile fabrication of a biodegradable multi-hollow iron phosphate nanoplatform for tumor-specific nanocatalytic therapy and chemotherapy.

In this study, a type of biodegradable multi-hollow iron phosphate (FeP) with excellent Fenton reaction ability and doxorubicin (DOX) loading capacity is synthesized in one-pot. This hollow FeP with complex interior not only affords high drug loading efficiency, but also obviates DOX leakage in normal tissues. In order to inhibit the formation of inert Fe(OH)x and endow the nanoplatform with a highly hydrophilic surface, PEG was anchored to it with a dopamine linkage, which formed an Fe chelating complex. DOX-loaded FeP modified with PEG could be disintegrated when responding to the lysosomal acid environment, releasing both ferric and ferrous ions as well as DOX. Therefore, apart from chemotherapy with DOX, the continuously generated iron ions catalyze a fast Fenton reaction with the innate H2O2 in tumor cells and produce abundant highly toxic hydroxyl radicals for nanocatalytic tumor therapy. Taken together, we believe that this nanoplatform will significantly advance the fields of both Fe-based nanomaterials and nanocatalytic tumor therapy.

The facile preparation of solid-state fluorescent carbon dots with a high fluorescence quantum yield and their application in rapid latent fingerprint detection.

Because of direct π-π interactions and excessive energy resonance transfer, it is very challenging to prepare carbon dots (CDs) with a high fluorescence quantum yield (QY) in the solid state. In this study, novel CDs which gave solid-state fluorescence (SSF) with high brightness were successfully prepared via a simple microwave-assisted method. The prepared ScCDs can emit strong blue fluorescence in the solid state, and the absolute QY of this ScCDs powder reaches 51.7%. Such a high QY means that the ScCDs powder could be successfully applied in rapid latent fingerprint (LFP) detection. The LFP detection performance of this ScCDs powder was studied in detail, and the results show that the LFPs developed using the ScCDs powder can be visualized with high definition and contrast under different conditions. This research not only developed a new type of SSF-emitting CDs, but it also proved that the developed CDs have great potential for applications in LFP detection, and this research may also provide inspiration and ideas for the design of new SSF-emitting CDs.

Cascade catalytic nanoplatform based on ions interference strategy for calcium overload therapy and ferroptosis.

Intracellular ions played prominent part in cell function and behavior. Disrupting intracellular ions homeostasis might switch ions signal from "regulating" to "destroying". Inspired by this, we introduced the ions interference strategy for tumor therapy. Herein, curcumin (CUR) and transferrin (Tf) co-loaded calcium peroxide nanoparticles (CaO2 NPs) were formulated. With tumor targeting ability, CaO2/Tf/CUR pinpointed tumor cells and then instantaneously decomposed in acidic lysosomes, concurrently accompanying with the release of Ca2+ and CUR, as well as the production of H2O2. Then H2O2 not only damaged structure of Tf to release Fe3+, but also was converted to hydroxyl radicals via ferric ions mediated Fenton reaction for ferroptosis. In addition, the released Ca2+ and CUR induced Ca2+ overload via exogenous and endogenous calcium ions accumulation, respectively, further activating mitochondria apoptosis signaling pathway for cell injury. Therefore, based on calcium and ferric ions interference strategy, the cascade catalytic CaO2/Tf/CUR offered synergistic combination of ferroptosis, Ca2+ overload therapy and chemotherapy, which held a great promise in cancer treatment.

Pressure-driven accumulation of Mn-doped mesoporous silica nanoparticles containing 5-aza-2-deoxycytidine and docetaxel at tumours with a dry cupping device.

Drug delivery with the help of nanoparticles could transport more payloads to tumour site. Owing to their limited accumulation and penetration in the tumour tissues, to increase delivery efficiency is currently still required for applying nanomedicine to treat tumour. Here, we initially report a pressure-driven accumulation of drug-loaded nanoparticles to tumours for efficient tumour therapy with a dry cupping device. The mesoporous Mn-doped silica based nanoparticles delivering 5-aza-2-deoxycytidine and docetaxel were prepared, characterised and used as a model nanomedicine to investigate the potential of dry cupping treatment. For this system, the Mn doping not only endowed the mesoporous silica nanoparticles biodegradability, but also made it much easier to bind a tumour targeting group, which is a G-quadruplex-forming aptamer AS1411. On tumour-bearing mice, the in vivo results demonstrated that the dry cupping treatment could substantially improve the distribution of nanomedicines at tumour site, resulting in enhanced treatment efficacy. Overall, this method enables the therapeutical nanoparticles accumulate to tumour through increasing the blood perfusion as well as altering the biological barrier, which opened up possibilities for the development of pressure-driven nanomedicine accumulation at tumour site.

Novel yellow solid-state fluorescent-emitting carbon dots with high quantum yield for white light-emitting diodes.

Fluorescence quenching of carbon dots (CDs) occurs in their aggregated state ascribed to direct π-π interactions or excessive resonance energy transfer (RET). Thus, CDs have been severely restricted for applications requiring phosphors that emit in the solid state, such as the fabrication of white light-emitting diodes (WLEDs). In this report, novel CDs with bright solid-state fluorescence (SSF) were synthesized by simple microwave-assisted synthesis method, using 1,4,7,10-tetraazacyclododecane (cyclen) and citric acid as precursors. Under 365 nm UV light, these CDs emit bright yellow SSF, indicating they successfully overcome the aggregation-induced fluorescence quenching (ACQ) effect. When the excitation wavelength (λex) is fixed at 450 nm, the emission peak of the CDs is centered at 546 nm with the Commission Internationale de l'Eclairage chromaticity (CIE) coordinates of (0.43, 0.55), which means that they can be combined with a blue-emitting chip in order to fabricate WLEDs. More importantly, the absolute quantum yield (QY) of these CDs powder reached 48% at λex of 450 nm, which was much higher than many previously reported SSF-emitting CDs and indicating their high light conversion ability in solid-state. Thanks to the excellent optical property of these CDs powder, they were successfully used in the preparation of high-performance WLEDs. This study not only enriches SSF-emitting CD-based nanomaterials with good prospects for application, but also provides valuable reference for subsequent research on the synthesis of solid-state fluorescent CDs.

Bafilomycin A1 Accelerates Chronic Refractory Wound Healing in db/db Mice.

Numerous studies have reported that autophagy plays an important role in chronic wound healing, and enhancement of autophagic activity impairs cutaneous wound healing. The autophagy inhibitor Bafilomycin A1 (Baf A1) inhibits autophagy by preventing the formation of autophagosomes. This study aimed at elucidating the effect of Bafilomycin A1 on chronic refractory wound healing in diabetic mice. A total of 40 diabetic (db/db) mice and 20 nondiabetic (db/m) mice were used in this study. Full-thickness skin defects were generated in the db/db mice models, which were then divided into the following two groups: the nontreated (db/db group) and Baf A1-treated groups (Baf A1 group). The same skin defects were generated in db/m mice (db/m group) to serve as a control. We demonstrated that Baf A1 treatment significantly accelerated wound healing in db/db mice and exerted good healing effects. Moreover, Baf A1 inhibited autophagy in the newly generated epidermis and had minor effects on metabolism in db/db mice. PCNA expression, as detected by immunohistochemistry, and collagen thickness, as detected by Masson's trichrome staining on the 14th day, were higher in the db/m and Baf A1 groups than in the db/db group. In addition, the expression of the proinflammatory cytokine TNF-α in the db/m and Baf A1 groups increased significantly on day 6, and the expression of the anti-inflammatory cytokine IL-10 also increased significantly on day 9. However, there were no significant changes in the expression levels of TNF-α and IL-10 in the db/db group. Therefore, Baf A1 may accelerate diabetic chronic refractory wound healing by promoting cell proliferation, collagen production, and regulating the inflammatory balance.

Improved mechanical properties by modifying fibrin scaffold with PCL and its biocompatibility evaluation.

Previous studies have proved that fibrin is an excellent scaffold material for tissue engineered blood vessel. However, the mechanical properties of fibrin are not enough. One way to solve the problem is to combine polymer materials with fibrin to enhance its biomechanical properties. In this study, a novel polycaprolactone (PCL)/fibrin composite scaffold was prepared by electrospinning technology. The morphological, physicochemical analysis, blood compatibility, biomechanical properties, biocompatibility and biodegradability of this vascular scaffold were evaluated. The results showed that electrospun PCL/fibrin scaffold possessed smaller aperture and larger fiber diameter than that of fibrin scaffold. The swelling ratio of the vascular PCL/fibrin scaffold at (0:100), (10:90), (20:80) and (30:70) was 112 ± 5.3, 103 ± 6.9, 94 ± 5.9 and 89 ± 3.4%, respectively. Mechanical properties of fibrin scaffolds were enhanced significantly by the addition of PCL. Furthermore, the time of plasma re-calcification, activated partial thromboplastin time and thromboplastin time in four different proportions of PCL/fibrin scaffolds were similar to that of the control group. Degradation experiments in vitro demonstrated that the degradation rate of PCL/fibrin scaffold was closely related to the content of PCL. MTT assays and immunofluorescence staining indicated that the stem cells cocultured with the PCL/fibrin scaffold had good proliferation behavior. Live/dead assay confirmed that the number of MSCs in the PCL/fibrin (10:90) group was significantly increased as compared to other groups. The tests in vivo results showed PCL/fibrin scaffold could promote cell infiltration and tissue regeneration and its degradation in vivo was faster than that of PCL scaffold. In summary, PCL/fibrin (20:80) scaffold exhibited balanced mechanical properties and degradability, as well as good cell compatibility properties; therefore, it was a promising tissue engineering material for vascular graft.

A two-step precise targeting nanoplatform for tumor therapy via the alkyl radicals activated by the microenvironment of organelles.

With the in-depth research of organelles, the microenvironment characteristics of their own, such as the acid environment of lysosomes and the high temperature environment of mitochondria, could be used as a natural and powerful condition for tumor therapy. Based on this, we constructed a two-step precise targeting nanoplatform which can realize the drug release and drug action triggered by the microenvironment of lysosomes (endosomes) and mitochondria, respectively. To begin with, the mesoporous silica nanoparticles (MSNs) were modified with triphenylphosphonium (TPP) and loaded with 2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIPH). Then, folic acid (FA) targeted pH-sensitive liposomes containing docetaxel (Lipo/DTX-FA) were prepared by thin-film dispersion method, and the core-shell AIPH/MSN-TPP@Lipo/DTX-FA nanoparticles were constructed by self-assembly during the hydration of the liposomes. When this nanoplatform entered into the tumor cells through FA receptor-mediated endocytosis, the pH-sensitive liposomes were destabilized in the lysosomes, resulting in the release of DTX and AIPH/MSN-TPP nanoparticles. After that, AIPH was delivered to mitochondria by AIPH/MSN-TPP, and the alkyl radicals produced by AIPH under the high temperature environment can cause oxidative damage to mitochondria. Not only that, the DTX could enhance the anti-tumor effect of AIPH by downregulating the expression of anti-apoptotic Bcl-2 protein. The in vitro and in vivo results demonstrate that this delivery system could induce apoptosis based on organelles' s own microenvironment, which provides a new approach for tumor therapy.

Enhancement of curcumin antitumor efficacy and further photothermal ablation of tumor growth by single-walled carbon nanotubes delivery system in vivo.

Curcumin, a commonly used natural product for antitumor therapy, is unable to achieve full potential due to poor bioavailability. Based on our previous report of a novel delivery system for curcumin using functionalized single-walled carbon nanotubes by phosphatidylcholine and polyvinylpyrrolidone (SWCNT-Cur), we further evaluated SWCNT-Cur's performance in vivo and characteristics in vitro. SWCNT-Cur significantly increased the blood concentration of curcumin, up to 18-fold, in mice. And in a murine S180 tumor model, SWCNT-Cur exhibited significantly higher inhibition efficacy on tumor growth and no obvious toxicity in main organs. Moreover, photothermal therapy induced by SWCNT under near-infrared radiation further facilitated SWCNT-Cur to inhibit the tumor growth in vivo. In addition, solvent residue is negligible in SWCNT-Cur formulation, and hydrogen bonding was formed between void carriers and curcumin, as demonstrated by GC chromatograph and IR spectra. Furthermore, experiments of confocal microscopy and spectrofluorometer showed that SWCNT-Cur gave a six-fold higher uptake for curcumin compared to native curcumin in human prostate cancer PC-3 cells. In conclusion, curcumin delivery with functionalized SWCNT is a promising strategy to enhance anticancer activity in vivo by enhancing cell uptake and blood concentration, changing physicochemical properties of curcumin and combining phototherapeutic with chemotherapeutic effects.

Tumor-targeting core-shell structured nanoparticles for drug procedural controlled release and cancer sonodynamic combined therapy.

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.

An intelligent dual stimuli-responsive photosensitizer delivery system with O2-supplying for efficient photodynamic therapy.

The effects of photodynamic therapy (PDT) are limited by the hypoxic tumor microenvironment (TME). In this paper, a new type of biocompatible multifunctional photosensitizer delivery system was fabricated to relieve tumor hypoxia and improve the efficacy of PDT. The photosensitizer hematoporphyrin monomethyl ether (HMME) and catalase (CAT) were encapsulated in the pores of mesoporous graphitic-phase carbon nitride nanosheets (mpg-C3N4). Next, hyaluronic (HA) was coated on the surface of the mpg-C3N4 via an amide linkage to construct the tumor-targeting HAase/CAT dual activatable and mpg-C3N4/HMME response photosensitizer delivery system (HA@mpg-C3N4-HMME/CAT). Upon intravenous injection, HA@mpg-C3N4-HMME/CAT shows high tumor accumulation owing to the tumor-targeting HA coating. Meanwhile, CAT within mpg-C3N4 could trigger decomposition of endogenic TME H2O2 to increase oxygen supply in-situ to relieve tumor hypoxia. This effect together with mpg-C3N4/HMME dual response is able to dramatically improve PDT efficiency. The hypoxia status of tumors was evaluated in vivo to demonstrate the success of the O2-supplying. And the in vitro and in vivo results showed the excellent therapeutic effect of the HA@mpg-C3N4-HMME/CAT photosensitizer delivery system. O2-supplying PDT may enable the enhancement of traditional PDT and future PDT design.

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

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.

pH/Ultrasound Dual-Responsive Gas Generator for Ultrasound Imaging-Guided Therapeutic Inertial Cavitation and Sonodynamic Therapy.

Herein, a pH/ultrasound dual-responsive gas generator is reported, which is based on mesoporous calcium carbonate (MCC) nanoparticles by loading sonosensitizer (hematoporphyrin monomethyl ether (HMME)) and modifying surface hyaluronic acid (HA). After pinpointing tumor regions with prominent targeting efficiency, HMME/MCC-HA decomposes instantaneously under the cotriggering of tumoral inherent acidic condition and ultrasound (US) irradiation, concurrently accompanying with CO2 generation and HMME release with spatial/temporal resolution. Afterward, the CO2 bubbling and bursting effect under US stimulus results in cavitation-mediated irreversible cell necrosis, as well as the blood vessel destruction to further occlude the blood supply, providing a "bystander effect." Meanwhile, reactive oxygen species generated from HMME can target the apoptotic pathways for effective sonodynamic therapy. Thus, the combination of apoptosis/necrosis with multimechanisms consequently results in a remarkable antitumor therapeutic efficacy, simultaneously minimizing the side effects on major organs. Moreover, the echogenic property of CO2 make the nanoplatform as a powerful ultrasound contrast agent to identify cancerous lesions. Based on the above findings, such all-in-one drug delivery platform of HMME/MCC-HA is utilized to provide the US imaging guidance for therapeutic inertial cavitation and sonodynamic therapy simultaneously, which highlights possibilities of advancing cancer theranostics in biomedical fields.

An intelligent NIR-responsive chelate copper-based anticancer nanoplatform for synergistic tumor targeted chemo-phototherapy.

The chelate copper-based anticancer drug bleomycin (BLM) is usually believed to bind metal ions especially Cu(ii) to generate the "activated BLM" for DNA cleavage. Herein, BLM and L-menthol (LM) co-loaded hollow mesoporous Cu2-xS nanoparticles (HMCu2-xS NPs) with surface folic acid (FA) modification were formulated to construct an intelligent NIR-responsive nanoplatform for synergistic tumor targeted chemo-phototherapy. With the tumor targeting ability of the folate receptor (FR)-positive, FA-HMCu2-xS/BLM/LM could pinpoint tumor cells efficiently. Under NIR irradiation, the versatile HMCu2-xS would be bound to exploit the merits of phototherapy (including PTT and PDT-like effects) for cancer treatment. Meanwhile, benefiting from the controllable "solid-liquid" (S-L) phase transition feature of LM as a gatekeeper, FA-HMCu2-xS/BLM/LM offered a platform for simultaneous NIR-mediated temperature-responsive BLM and copper ion release, which further initiated the generation of the "activated BLM". As a matter of course, the remarkable synergistic combination of Cu-dependent chemo-phototherapy in vitro and in vivo by such a smart all-in-one drug delivery nanoplatform developed here provided information for advancing nanotherapy 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.

Gold nanorod-based poly(lactic-co-glycolic acid) with manganese dioxide core-shell structured multifunctional nanoplatform for cancer theranostic applications.

Recently, photothermal therapy has become a promising strategy in tumor treatment. However, the therapeutic effect was seriously hampered by the low tissue penetration of laser. Therefore, in this study, radiofrequency (RF) with better tissue penetration was used for tumor hyperthermia. First, one type of gold nanorods (AuNRs) suitable for RF hyperthermia was selected. Then, poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with AuNRs and docetaxel (DTX) (PLGA/AuNR/DTX) NPs were constructed. Finally, manganese dioxide (MnO2) ultrathin nanofilms were coated on the surfaces of PLGA/AuNR/DTX NPs by the reduction of KMnO4 to construct the PLGA/AuNR/DTX@MnO2 drug delivery system. This drug delivery system can not only be used for the combined therapy of chemotherapy and RF hyperthermia but can also produce Mn2+ to enable magnetic resonance imaging. Furthermore, the RF hyperthermia and the degradation of MnO2 can significantly promote the controlled drug release in a tumor region. The in vitro and in vivo results suggested that the PLGA/AuNR/DTX@MnO2 multifunctional drug delivery system is a promising nanoplatform for effective cancer theranostic applications.

Covalent self-assembled nanoparticles with pH-dependent enhanced tumor retention and drug release for improving tumor therapeutic efficiency.

Developing a smart drug delivery system with enhanced tumor retention at the tumor site, and rapid intracellular drug release promises to improve the therapeutic index and mitigate side effects. To this end, covalent phenylboronic acid (PBA)-based self-assembly nanoparticles (BNPs) consisting of pH-responsive cores and detachable poloxamer 188 shells were constructed for loading doxorubicin (DOX) in a simple process. The poloxamer 188 coating could be easily detached when the breakage of the borate ester bonds in the external nanocores was initially triggered in the tumor extracellular weak acid environment. The concealed PBA was subsequently exposed and could react with sialic acids (SA), which are overexpressed on tumor cells, and this enhanced the tumor retention effect of the fresh nanoparticle as well as facilitating the cellular uptake after removing the protective layers. Furthermore, owing to the existence of pH-responsive esters, the uptaken fresh nanoparticles could rapidly release DOX in the acidic tumor environment, which resulted in an enhanced therapeutic efficiency in vitro and in vivo. In summary, this pH dependent behaviour of DOX/BNPs provided new insights for enhanced chemotherapeutic treatment in cancer.