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1.
Theranostics ; 9(24): 7200-7209, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695762

RESUMO

Reactive oxygen species (ROS)-generating anticancer agents can act through two different mechanisms: (i) elevation of endogenous ROS production in mitochondria, or (ii) formation/delivery of exogenous ROS within cells. However, there is a lack of research on the development of ROS-generating nanosystems that combine endogenous and exogenous ROS to enhance oxidative stress-mediated cancer cell death. Methods: A ROS-generating agent based on polymer-modified zinc peroxide nanoparticles (ZnO2 NPs) was presented, which simultaneously delivered exogenous H2O2 and Zn2+ capable of amplifying endogenous ROS production for synergistic cancer therapy. Results: After internalization into tumor cells, ZnO2 NPs underwent decomposition in response to mild acidic pH, resulting in controlled release of H2O2 and Zn2+. Intriguingly, Zn2+ could increase the production of mitochondrial O2·- and H2O2 by inhibiting the electron transport chain, and thus exerted anticancer effect in a synergistic manner with the exogenously released H2O2 to promote cancer cell killing. Furthermore, ZnO2 NPs were doped with manganese via cation exchange, making them an activatable magnetic resonance imaging contrast agent. Conclusion: This study establishes a ZnO2-based theranostic nanoplatform which achieves enhanced oxidative damage to cancer cells by a two-pronged approach of combining endogenous and exogenous ROS.

2.
Zhongguo Zhong Yao Za Zhi ; 44(14): 3049-3054, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31602852

RESUMO

The contents of terrestrosin D and hecogenin from Tribuli Fructus were determined before and after stir-frying. The results showed that the content of terrestrosin D was decreased significantly,and the content of hecogenin was increased significantly after such processing. In order to verify the inference that terrestrosin D was converted to hecogenin by stir-frying,the quantitative variation rules of terrestrosin D and hecogenin were studied by simulated processing technology,and the simulated processing product of terrestrosin D was qualitatively characterized by ultra performance liquid chromatography/time of flight mass spectrometry( UPLC-TOF/MS) to clarify its transformation process during stir-frying. The results showed that the content of terrestrosin D was decreased significantly at first and then a platform stage appeared with the prolongation of processing time at a certain temperature. Raising the stir-frying temperature could further decrease the content of terrestrosin D and delay the time that the platform stage appeared. When the processing was simulated at higher temperatures( 220 ℃ and 240 ℃),the content of hecogenin was increased gradually with the increase of processing temperature and the prolongation of processing time. In the process of stir-frying,the deglycosylation reaction of terrestrosin D to hecogenin was not completed in one step. The deglycosylation reaction occurred first at the end of the sugar chain,and then other glycosyl units in the sugar chain were sequentially removed from the outside to the inside to finally form the hecogenin. This study provides a basis for further revealing the detoxification mechanism of stir-fried Tribuli Fructus.


Assuntos
Frutas/química , Sapogeninas/análise , Zygophyllaceae/química , Cromatografia Líquida , Temperatura Alta , Compostos Fitoquímicos/análise , Espectrometria de Massas em Tandem
3.
Biomaterials ; 223: 119460, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31513993

RESUMO

This article describes a nanoplatform based on matrix metalloproteinase (MMP)-responsive gold nanoparticles (AuNPs) for tumor-targeted photoacoustic (PA) imaging-guided photothermal therapy and drug delivery. AuNPs were grafted with complementary DNA strands, tethered with doxorubicin and coated with poly(ethylene glycol) via a thermal-labile linker and a MMP-cleavable peptide, respectively. The nanoprobes remained well-isolated in healthy tissues, but formed aggregates rapidly under MMP-abundant conditions. The DNA hybridization-induced assembly of the nanoprobes led to prolonged tumor retention and strong near-infrared (NIR) absorption, which is beneficial to deep-tissue imaging and therapy. Compared with MMP-inert nanoprobes, our platform demonstrated significantly enhanced efficiency in PA imaging and photothermal conversion upon NIR irradiation. Meanwhile, doxorubicin could be released rapidly in response to the localized elevation of temperature, leading to synergistic chemo-photothermal therapy. The unique nanoplatform may find applications in effective disease control by delivering imaging and therapy to tumors with high specificity, safety, and universality.

4.
Adv Mater ; 31(37): e1903443, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31379091

RESUMO

The targeted and sustained drug release from stimuli-responsive nanodelivery systems is limited by the irreversible and uncontrolled disruption of the currently used nanostructures. Bionic nanocapsules are designed by cross-linking polythymine and photoisomerized polyazobenzene (PETAzo) with adenine-modified ZnS (ZnS-A) nanoparticles (NPs) via nucleobase pairing. The ZnS-A NPs convert X-rays into UV radiation that isomerizes the azobenzene groups, which allows controlled diffusion of the active payloads across the bilayer membranes. In addition, the nucleobase pairing interactions between PETAzo and ZnS-A prevent drug leakage during their in vivo circulation, which not only enhances tumor accumulation but also maintains stability. These nanocapsules with tunable permeability show prolonged retention, remotely controlled drug release, enhanced targeted accumulation, and effective antitumor effects, indicating their potential as an anticancer drug delivery system.

5.
ACS Nano ; 13(8): 8903-8916, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31374171

RESUMO

A major concern about glucose oxidase (GOx)-mediated cancer starvation therapy is its ability to induce serious oxidative damage to normal tissues through the massive production of H2O2 byproducts in the oxygen-involved glucose decomposition reaction, which may be addressed by using a H2O2 scavenger, known as an antioxidation agent. Surprisingly, H2O2 removal accelerates the aerobic glycometabolism of tumors by activating the H2O2-dependent "redox signaling" pathway of cancer cells. Simultaneous oxygen depletion further aggravates tumor hypoxia to increase the toxicity of a bioreductive prodrug, such as tirapazamine (TPZ), thereby improving the effectiveness of cancer starvation therapy and bioreductive chemotherapy. Herein, a "nitrogen-protected silica template" method is proposed to design a nanoantioxidant called an organosilica-based hollow mesoporous bilirubin nanoparticle (HMBRN), which can act as an excellent nanocarrier to codeliver GOx and TPZ. In addition to efficient removal of H2O2 for self-protection of normal tissues via antioxidation, GOx/TPZ-coloaded HMBRN can also rapidly deplete intratumoral glucose/oxygen to promote a synergistic starvation-enhanced bioreductive chemotherapeutic effect for the substantial suppression of solid tumor growth. Distinct from the simple combination of two treatments, this study introduces antioxidation-activated self-protection nanotechnology for the significant improvement of tumor-specific deoxygenation-driven synergistic treatment efficacy without additional external energy input, thus realizing the renaissance of precise endogenous cancer therapy with negligible side effects.

6.
Small ; 15(41): e1903422, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31448577

RESUMO

Gd chelates have occupied most of the market of magnetic resonance imaging (MRI) contrast agents for decades. However, there have been some problems (nephrotoxicity, non-specificity, and low r1 ) that limit their applications. Herein, a wet-chemical method is proposed for facile synthesis of poly(acrylic acid) (PAA) stabilized exceedingly small gadolinium oxide nanoparticles (ES-GON-PAA) with an excellent water dispersibility and a size smaller than 2.0 nm, which is a powerful T1 -weighted MRI contrast agent for diagnosis of diseases due to its remarkable relaxivities (r1 = 70.2 ± 1.8 mM-1 s-1 , and r2 /r1 = 1.02 ± 0.03, at 1.5 T). The r1 is much higher and the r2 /r1 is lower than that of the commercial Gd chelates and reported gadolinium oxide nanoparticles (GONs). Further ES-GON-PAA is developed with conjugation of RGD2 (RGD dimer) (i.e., ES-GON-PAA@RGD2) for T1 -weighted MRI of tumors that overexpress RGD receptors (i.e., integrin αv ß3 ). The maximum signal enhancement (ΔSNR) for T1 -weighted MRI of tumors reaches up to 372 ± 56% at 2 h post-injection of ES-GON-PAA@RGD2, which is much higher than commercial Gd-chelates (<80%). Due to the high biocompatibility and high tumor accumulation, ES-GON-PAA@RGD2 with remarkable relaxivities is a promising and powerful T1 -weighted MRI contrast agent.

7.
ACS Appl Mater Interfaces ; 11(31): 27558-27567, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31317730

RESUMO

Glutathione (GSH), one of the most significant reducing species in vivo, plays important roles in a variety of diseases and cellular functions. Precise quantification of GSH via advanced noninvasive photoacoustic imaging (PAI) is of vital significance for the early diagnosis and prompt treatment of GSH-related deep-seated diseases, which stresses the need for custom-design of GSH-sensitive PAI probes with changeable near-infrared spectroscopy (NIR) absorption. In this work, a novel intelligent tumor microenvironment-activated ratiometric PAI nanoprobe is first developed with the intention of specific ultrasensitive detection of intratumoral GSH by overcoming the limitations of previously reported fluorescent or PA imaging sensors. This special ratiometric PAI nanoprobe (CR-POM) is synthesized through the self-assembly of croconaine (CR) dye and molybdenum-based polyoxometalate (POM) clusters with opposite NIR absorbance change in response to GSH. The resulting amplified ratiometric absorbance (Ab866/Ab700), the relatively low limit of detection value (0.51 mM), and the unique acidity-activated self-aggregation contribute to the prolonged intratumoral retention and enhanced tumor accumulation of CR-POM for accurate quantification of intratumoral GSH (0.5-10 mM). Featuring the additional merit of 64Cu radiolabeling for whole-body positron-emission tomography imaging, the smartly designed CR-POM nanoprobe will open new horizons for real-time noninvasive monitoring of biodistribution and simultaneous accurate quantification of GSH levels, especially in tumor and other GSH-related pathophysiological processes.

8.
Biomaterials ; 218: 119365, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31344642

RESUMO

Metal-organic framework (MOF) nanoparticles have shown great potential as carrier platforms in theranostic applications. However, their poor physiological stability in phosphate-based media has limited their biological applications. Here, we studied the dissociation of MOF nanoparticles under physiological conditions, both in vitro and in vivo, and developed an in situ polymerization strategy on MOF nanoparticles for enhanced stability under physiological conditions and stimulus-responsive intracellular drug release. With polymer wrapped on the surface serving as a shield, the nanoscale MOFs were protected from decomposition by phosphate ions or acid and prevented the loaded cargos from leaking. An in vivo positron emission tomography (PET) study of 64Cu-labelled porphyrinic MOF indicated prolonged circulation time of the in situ polymerized MOF nanoparticles and greater tumor accumulation than unmodified MOF nanoparticles. With enhanced stability, cargos loaded into MOF nanoparticles or prodrugs conjugated on the surface can be efficiently delivered and released upon stimulus-responsive cleavage.

9.
Theranostics ; 9(10): 2791-2799, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31244923

RESUMO

The design of hybrid metal-organic framework (MOF) nanomaterials by integrating inorganic nanoparticle into MOF (NP@MOF) has demonstrated outstanding potential for obtaining enhanced, collective, and extended novel physiochemical properties. However, the reverse structure of MOF-integrated inorganic nanoparticle (MOF@NP) with multifunction has rarely been reported. Methods: We developed a facile in-situ growth method to integrate MOF nanoparticle into inorganic nanomaterial and designed a fluorescence switch to trigger enhanced photodynamic therapy. The influence of "switch" on the photodynamic activity was studied in vitro. The in vivo mice with tumor model was applied to evaluate the "switch"-triggered enhanced photodynamic therapy efficacy. Results: A core-satellites structure with fluorescence off and on function was obtained when growing MnO2 on the surface of fluorescent zeolitic imidazolate framework (ZIF-8) nanoparticles. Furthermore, A core-shell structure with photodynamic activity off and on function was achieved by growing MnO2 on the surface of porphyrinic ZrMOF nanoparticles (ZrMOF@MnO2). Both the fluorescence and photodynamic activities can be turned off by MnO2 and turned on by GSH. The GSH-responsive activation of photodynamic activity of ZrMOF@MnO2 significantly depleted the intracellular GSH via a MnO2 reduction reaction, thus triggering an enhanced photodynamic therapy efficacy. Finally, the GSH-reduced Mn2+ provided a platform for magnetic resonance imaging-guided tumor therapy. Conclusion: This work highlights the impact of inorganic nanomaterial on the MOF properties and provides insight to the rational design of multifunctional MOF-inorganic nanomaterial complexes.

10.
J Am Chem Soc ; 141(25): 9937-9945, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31199131

RESUMO

Chemodynamic therapy (CDT) employs Fenton catalysts to kill cancer cells by converting intracellular H2O2 into hydroxyl radical (•OH), but endogenous H2O2 is insufficient to achieve satisfactory anticancer efficacy. Despite tremendous efforts, engineering CDT agents with specific and efficient H2O2 self-supplying ability remains a great challenge. Here, we report the fabrication of copper peroxide (CP) nanodot, which is the first example of a Fenton-type metal peroxide nanomaterial, and its use as an activatable agent for enhanced CDT by self-supplying H2O2. The CP nanodots were prepared through coordination of H2O2 to Cu2+ with the aid of hydroxide ion, which could be reversed by acid treatment. After endocytosis into tumor cells, acidic environment of endo/lysosomes accelerated the dissociation of CP nanodots, allowing simultaneous release of Fenton catalytic Cu2+ and H2O2 accompanied by a Fenton-type reaction between them. The resulting •OH induced lysosomal membrane permeabilization through lipid peroxidation and thus caused cell death via a lysosome-associated pathway. In addition to pH-dependent •OH generation property, CP nanodots with small particle size showed high tumor accumulation after intravenous administration, which enabled effective tumor growth inhibition with minimal side effects in vivo. Our work not only provides the first paradigm for fabricating Fenton-type metal peroxide nanomaterials, but also presents a new strategy to improve CDT efficacy.

11.
Angew Chem Int Ed Engl ; 58(26): 8752-8756, 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31046176

RESUMO

Tumor hypoxia, the "Achilles' heel" of current cancer therapies, is indispensable to drug resistance and poor therapeutic outcomes especially for radiotherapy. Here we propose an in situ catalytic oxygenation strategy in tumor using porphyrinic metal-organic framework (MOF)-gold nanoparticles (AuNPs) nanohybrid as a therapeutic platform to achieve O2 -evolving chemoradiotherapy. The AuNPs decorated on the surface of MOF effectively stabilize the nanocomposite and serve as radiosensitizers, whereas the MOF scaffold acts as a container to encapsulate chemotherapeutic drug doxorubicin. In vitro and in vivo studies verify that the catalase-like nanohybrid significantly enhances the radiotherapy effect, alleviating tumor hypoxia and achieving synergistic anticancer efficacy. This hybrid nanomaterial remarkably suppresses the tumor growth with minimized systemic toxicity, opening new horizons for the next generation of theranostic nanomedicines.

13.
Nat Biomed Eng ; 3(4): 257-258, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952986
14.
Small ; 15(16): e1900691, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30913380

RESUMO

Activatable imaging probes are promising to achieve increased signal-to-noise ratio for accurate tumor diagnosis and treatment monitoring. Magnetic resonance imaging (MRI) is a noninvasive imaging technique with excellent anatomic spatial resolution and unlimited tissue penetration depth. However, most of the activatable MRI contrast agents suffer from metal ion-associated potential long-term toxicity, which may limit their bioapplications and clinical translation. Herein, an activatable MRI agent with efficient MRI performance and high safety is developed for drug (doxorubicin) loading and tumor signal amplification. The agent is based on pH-responsive polymer and gadolinium metallofullerene (GMF). This GMF-based contrast agent shows high relaxivity and low risk of gadolinium ion release. At physiological pH, both GMF and drug molecules are encapsulated into the hydrophobic core of nanoparticles formed by the pH-responsive polymer and shielded from the aqueous environment, resulting in relatively low longitudinal relativity and slow drug release. However, in acidic tumor microenvironment, the hydrophobic-to-hydrophilic conversion of the pH-responsive polymer leads to amplified MR signal and rapid drug release simultaneously. These results suggest that the prepared activatable MRI contrast agent holds great promise for tumor detection and monitoring of drug release.

15.
Adv Mater ; 31(19): e1900401, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30920710

RESUMO

2D nanomaterials have attracted broad interest in the field of biomedicine owing to their large surface area, high drug-loading capacity, and excellent photothermal conversion. However, few studies report their "enzyme-like" catalytic performance because it is difficult to prepare enzymatic nanosheets with small size and ultrathin thickness by current synthetic protocols. Herein, a novel one-step wet-chemical method is first proposed for protein-directed synthesis of 2D MnO2 nanosheets (M-NSs), in which the size and thickness can be easily adjusted by the protein dosage. Then, a unique sono-chemical approach is introduced for surface functionalization of the M-NSs with high dispersity/stability as well as metal-cation-chelating capacity, which can not only chelate 64 Cu radionuclides for positron emission tomography (PET) imaging, but also capture the potentially released Mn2+ for enhanced biosafety. Interestingly, the resulting M-NS exhibits excellent enzyme-like activity to catalyze the oxidation of glucose, which represents an alternative paradigm of acute glucose oxidase for starving cancer cells and sensitizing them to thermal ablation. Featured with outstanding phototheranostic performance, the well-designed M-NS can achieve effective photoacoustic-imaging-guided synergistic starvation-enhanced photothermal therapy. This study is expected to establish a new enzymatic phototheranostic paradigm based on small-sized and ultrathin M-NSs, which will broaden the application of 2D nanomaterials.

16.
Biomed Pharmacother ; 111: 1429-1437, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841458

RESUMO

OBJECTIVE: To examine the effect of connective tissue growth factor (CTGF)-mediated ERK signaling pathway on the inflammatory response and intestinal flora in ulcerative colitis (UC). METHODS: CTGF expression was determined through immunohistochemistry in UC and colon polyp patients. Dextran sulfate sodium (DSS) was used to construct UC models. Wild-type (WT) and CTGF-deficient (CTGF-/-) mice were randomly divided into WT/CTGF-/- + saline, WT/CTGF-/- + DSS, and WT/CTGF-/- + DSS + U0126 (ERK pathway inhibitor) groups. HE staining was conducted to observe the pathological changes in intestinal mucosa. The quantity of intestinal flora was tested in the feces. ELISA, qRT-PCR, and Western blotting were used to detect related-molecules expressions. RESULTS: CTGF was up-regulated in the intestinal mucosa of UC patients in relation to the severity and grade. Moreover, UC patients showed enhanced the expressions of p-ERK/ERK and pro-inflammatory factors (IL-1ß, IL-6, TNF-α, MPO), increased the quantity of Bacteriodes fragilis (B. fragilis) and Escherichia coli (E. coli), and decreased Bifidobacterium and Lactobacillus. CTGF and pERK/ERK expressions were increased in DSS-induced WT mice, but the pERK expression was lower in CTGF-/- + DSS group than that in the WT + DSS group. U0126 decreased the expressions of pro-inflammatory factors and improved the intestinal flora in WT mice induced with DSS. No significant differences were found in the above indexes between CTGF-/- + DSS group and WT + DSS + U0126 group. CONCLUSION: Inhibiting CTGF could improve inflammatory response and intestinal flora to partially reverse DSS-induced UC via blocking ERK signaling pathway.


Assuntos
Colite Ulcerativa/metabolismo , Colite Ulcerativa/microbiologia , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Microbioma Gastrointestinal/fisiologia , Mediadores da Inflamação/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Transdução de Sinais/fisiologia , Adolescente , Adulto , Animais , Estudos de Casos e Controles , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/metabolismo , Inflamação/microbiologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Regulação para Cima/fisiologia , Adulto Jovem
17.
Nanotechnology ; 30(28): 284004, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30925490

RESUMO

Atomically thin transition metal dichalcogenides (TMDs) are ideal candidates for ultrathin optoelectronics that are flexible and semitransparent. Photodetectors based on TMDs show remarkable performance, with responsivity and detectivity higher than 103 AW-1 and 1012 Jones, respectively, but they are plagued by response times as slow as several tens of seconds. Although it is well established that gas adsorbates such as water and oxygen create charge traps and significantly increase both the responsivity and the response time, the underlying mechanism is still unclear. Here we study the influence of adsorbates on MoS2 photodetectors under ambient conditions, vacuum and illumination at different wavelengths. We show that, for wavelengths sufficiently short to excite electron-hole pairs in the MoS2, light illumination causes desorption of water and oxygen molecules. The change in the molecular gating provided by the physisorbed molecules is the dominant contribution to the device photoresponse in ambient conditions.

18.
Nat Commun ; 10(1): 1241, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30886142

RESUMO

The success of radiotherapy relies on tumor-specific delivery of radiosensitizers to attenuate hypoxia resistance. Here we report an ammonia-assisted hot water etching strategy for the generic synthesis of a library of small-sized (sub-50 nm) hollow mesoporous organosilica nanoparticles (HMONs) with mono, double, triple, and even quadruple framework hybridization of diverse organic moieties by changing only the introduced bissilylated organosilica precursors. The biodegradable thioether-hybridized HMONs are chosen for efficient co-delivery of tert-butyl hydroperoxide (TBHP) and iron pentacarbonyl (Fe(CO)5). Distinct from conventional RT, radiodynamic therapy (RDT) is developed by taking advantage of X-ray-activated peroxy bond cleavage within TBHP to generate •OH, which can further attack Fe(CO)5 to release CO molecules for gas therapy. Detailed in vitro and in vivo studies reveal the X-ray-activated cascaded release of •OH and CO molecules from TBHP/Fe(CO)5 co-loaded PEGylated HMONs without reliance on oxygen, which brings about remarkable destructive effects against both normoxic and hypoxic cancers.


Assuntos
Antineoplásicos/administração & dosagem , Quimiorradioterapia/métodos , Portadores de Fármacos/síntese química , Liberação Controlada de Fármacos/efeitos da radiação , Neoplasias/terapia , Animais , Monóxido de Carbono/química , Feminino , Células Hep G2 , Humanos , Radical Hidroxila/química , Radical Hidroxila/efeitos da radiação , Compostos de Ferro/administração & dosagem , Camundongos , Camundongos Nus , Nanopartículas/química , Compostos de Organossilício/síntese química , Tamanho da Partícula , Polietilenoglicóis/química , Porosidade , Células RAW 264.7 , Resultado do Tratamento , Raios X , Ensaios Antitumorais Modelo de Xenoenxerto , terc-Butil Hidroperóxido/administração & dosagem , terc-Butil Hidroperóxido/efeitos da radiação
19.
ACS Nano ; 13(3): 3083-3094, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30835435

RESUMO

A cancer vaccine is an important form of immunotherapy. Given their effectiveness for antigen processing and presentation, dendritic cells (DCs) have been exploited in the development of a therapeutic vaccine. Herein, a versatile polymersomal nanoformulation that enables generation of tumor-associated antigens (TAAs) and simultaneously serves as adjuvant for an in situ DC vaccine is reported. The chimeric cross-linked polymersome (CCPS) is acquired from self-assembly of a triblock copolymer, polyethylene glycol-poly(methyl methyacrylate- co-2-amino ethyl methacrylate (thiol/amine))-poly 2-(dimethylamino)ethyl methacrylate (PEG-P(MMA- co-AEMA (SH/NH2)-PDMA). CCPS can encapsulate low-dose doxorubicin hydrochloride (DOX) to induce immunogenic cell death (ICD) and 2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH), a photosensitizer to facilitate photodynamic therapy (PDT) for reactive oxygen species (ROS) generation. This combination is able to enhance the population of TAAs and DC recruitment, eliciting an immune response cascade. In addition, CCPS with primary and tertiary amines act as adjuvant, both of which can stimulate DCs recruited to form an in situ DC vaccine after combination with TAAs for MC38 colorectal cancer treatment. In vivo results indicate that the all-in-one polymersomal nanoformulation (CCPS/HPPH/DOX) increases mature DCs in tumor-draining lymph nodes (tdLNs) and CD8+ T cells in tumor tissues to inhibit primary and distant MC38 tumor growth following a single intravenous injection with a low dose of DOX and HPPH.

20.
Theranostics ; 9(2): 526-536, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30809290

RESUMO

Molecular photoacoustic imaging (PA) is a promising technology to understand tumor pathology and guide precision therapeutics. Despite the capability of activatable PA probes to image tumor-specific biomarkers, limitations in their molecular structure hamper them from effective drug delivery and the drug release monitoring. Herein, we developed a perylene diimide (PDI) based theranostic platform that provides noninvasive PA imaging signals to monitor tumor-specific pH-responsive drug release. Methods: we first designed and synthesized an acid-responsive amine-substituted PDI derivative. The pH sensitive properties of the PDI was demonstrated by density functional theory (DFT) calculations, UV-vis experiments and PA studies. The theranostic platform (THPDINs) was fabricated by self-assembly of the acid-responsive PDI, a pH irrelevant IR825 dye, and anti-cancer drug doxorubicin (DOX). The PA properties in various pH environment, drug delivery, cytotoxicity, cell uptake, ratiometric PA imaging and anti-tumor efficacy of the THPDINs were investigated in vitro and in vivo by using U87MG glioma cell line and U87MG tumor model. Results: We found that our designed PDI was sensitive to the tumor specific pH environment, reflected by absorbance shift, PA intensity and aggregation morphology changes in aqueous solution. The as-synthesized pH sensitive PDI acted as a molecular switch in the THPDINs, in which the switch can be triggered in the mild acidic tumor microenvironment to accelerate DOX release. Meanwhile, the DOX release could be monitored by ratiometric PA imaging. Conclusions: We developed a multifunctional PDI based theranostic platform for noninvasive real-time ratiometric PA imaging of tumor acidic pH and monitoring of drug release in living mice simultaneously. This strategy will shed light on the development of smart activatable theranostic nanoplatforms and will significantly advance the application of PA theranostics in biology and medicine.

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