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1.
J Mater Chem B ; 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31475276

RESUMO

Combination therapy with multiple chemotherapeutic agents is the main approach for cancer treatment in the clinic. Polyphenol-based materials are found in our diet, demonstrate good biocompatibility, and prevent numerous diseases. In this study, we encapsulate two drugs in a single polyphenol-based polymer with Fe3+ or Mn2+ ions as the cross-linker for cancer therapy. The combination index of two drugs is an essential parameter to evaluate drug combinations. The amphiphilic polymer poly(ethylene glycol)-block-polydopamine (PEG-PDA) was prepared by RAFT polymerization. The nanoparticles were prepared via self-assembly with Fe3+ or Mn2+ ions. Both doxorubicin (DOX) and simvastatin (SV) were encapsulated in the core of the nanoparticles. The cell viability and combination index were evaluated in vitro. The tumor accumulation of the nanoparticles was investigated by positron-emission tomography (PET) and magnetic resonance (MR) imaging. The as-prepared nanoparticles exhibited high drug loading capacity. The drug loaded nanoparticles could kill cancer cells effectively with a combination index <1. Both PET and MRI revealed that the nanoparticles showed long blood circulation time and high tumor accumulation. The nanoparticles could inhibit tumor inhibition via intravenous injection of nanoparticles. The polyphenol-based nanoplatform may serve as a promising theranostic candidate for clinical application.

2.
Adv Mater ; : e1903443, 2019 Aug 05.
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.

3.
Eur J Nucl Med Mol Imaging ; 46(10): 2152-2162, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31270559

RESUMO

PURPOSE: Optic pathway glioma (OPG) is a rare neoplasm that arises predominantly during childhood. Its location in a sensitive region involving the optic pathways, onset in young patients and controversial therapy choice make the management of OPG a challenge in paediatric neuro-oncology. In this study we assessed gastrin-releasing peptide receptor (GRPR)-targeted positron emission tomography (PET) imaging in children with OPG, and the application of a PET/MRI imaging-guided surgery navigation platform. METHODS: Eight children (five boys, mean age 8.81 years, range 5-14 years) with suspicion of optic pathway glioma on MRI were recruited. Written informed consent was obtained from all patients and legal guardians. Brain PET/CT or PET/MRI acquisitions were performed 30 min after intravenous injection of 1.85 MBq/kg body weight of 68Ga-NOTA-Aca-BBN(7-14). Four patients also underwent 18F-FDG brain PET/CT for comparison. All patients underwent surgical resection within 1 week. RESULTS: All 11 lesions (100%) in the eight patients showed prominent 68Ga-NOTA-Aca-BBN(7-14) uptake with excellent contrast in relation to surrounding normal brain tissue. Tumour-to-background ratios (SUVmax and SUVmean) were significantly higher for 68Ga-NOTA-Aca-BBN(7-14) than for 18F-FDG (28.4 ± 5.59 vs. 0.47 ± 0.11 and 18.3 ± 4.99 vs. 0.35 ± 0.07, respectively). Fusion images for tumour delineation were obtained in all patients using the PET/MRI navigation platform. All lesions were pathologically confirmed as OPGs with positive GRPR expression, and 75% were pilocytic astrocytoma WHO grade I and 25% were diffuse astrocytoma WHO grade II. There was a positive correlation between the SUV of 68Ga-NOTA-Aca-BBN(7-14) and the expression level of GRPR (r2 = 0.56, P < 0.01, for SUVmax; r2 = 0.47, P < 0.05, for SUVmean). CONCLUSION: This prospective study showed the feasibility of 68Ga-NOTA-Aca-BBN(7-14) PET in children with OPG for tumour detection and localization. 68Ga-NOTA-Aca-BBN(7-14) PET/MRI may be helpful for assisting surgery planning in OPG patients with severe symptoms, GRPR-targeted PET has the potential to provide imaging guidance for further GRPR-targeted therapy in patients with OPG.

4.
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.

5.
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.

6.
Ultrasound Med Biol ; 45(8): 2118-2132, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31151732

RESUMO

This study investigated and compared the time and frequency characteristics of cavitation activity between phase-shift nanodroplets (NDs) and lipid-shelled microbubbles (MBs) exposed to focused ultrasound (FUS) under physiologically relevant flow conditions. Root-mean-square (RMS) of broadband noise, spectrograms of the passive cavitation detection signals and inertial cavitation doses (ICDs) were calculated during FUS at varying mean flow velocities and two different peak-rarefactional pressures. At a lower pressure of 0.94 MPa, the mean values of the RMS amplitudes versus time for the NDs showed an upward trend but slowed down as the mean flow velocity increased. For flowing NDs, the rate of growth in RMS amplitudes within 2-5 MHz decreased more obviously than those within 5-8 MHz. At a higher pressure of 1.07 MPa, the increase in RMS amplitudes was accelerated as the mean flow velocity increased from 0 to 10 cm/s and slowed down as the mean flow velocity reached 15 cm/s. The general downward trends of RMS amplitudes for the MBs were retarded as the mean flow velocity increased at both acoustic pressures of 0.94 MPa and 1.07 MPa. At 0.94 MPa, the mean ICD value for the NDs decreased from 57 to 36 as the mean flow velocity increased from 0 to 20 cm/s. At 1.07 MPa, the mean ICD value initially increased from 45 to 57 as the mean flow velocity increased from 0 to 10 cm/s and subsequently decreased to 43 as the mean flow velocity reached 20 cm/s. For the MBs, the mean ICD value increased with increasing mean flow velocity at both acoustic pressures. These results could aid in future investigations of cavitation-enhanced FUS with the flowing phase-shift NDs and encapsulated, gas-filled MBs for various applications.

7.
Bioconjug Chem ; 30(6): 1745-1753, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31181890

RESUMO

As highly expressed in insulinomas, the glucagon-like peptide-1 receptor (GLP-1R) is believed to be an attractive target for diagnosis, localization, and treatment with radiolabeled exendin 4. However, the high and persistent radioactivity accumulation of exendin 4 in the kidneys limits accurate diagnosis and safe, as well as effective, radiotherapy in insulinomas. In this study, we intend to reduce the renal accumulation of radiolabeled exendin 4 through degradation mediated by brush border membrane enzymes. A new exendin 4 ligand NOTA-MVK-Cys40-Leu14-Exendin 4 containing Met-Val-Lys (MVK) linker between the peptide and 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator was synthesized and labeled with 68Ga. The in vitro mouse serum stability and cell binding affinity of the tracer were evaluated. Initial in vitro cleavage of the linker was determined by incubation of a model compound Boc-MVK-Dde with brush border membrane vesicles (BBMVs) with and without the inhibitor of neutral endopeptidase (NEP). Further cleavage studies were performed with the full structure of NOTA-MVK-Cys40-Leu14-Exendin 4. Kidney and urine samples were collected in the in vivo metabolism study after intravenous injection of 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4. The microPET images were acquired in INS-1 tumor model at different time points; the radioactivity uptake of 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4 in tumor and kidneys were determined and compared with the control radiotracer without MVK linker. 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4 was stable in mouse serum. The MVK modification did not affect the affinity of NOTA-MVK-Cys40-Leu14-Exendin 4 toward GLP-1R. The in vitro cleavage study and in vivo metabolism study confirmed that the MVK sequence can be recognized by BBM enzymes and cleaved at the amide bond between Met and Val, thus releasing the small fragment containing Met. MicroPET images showed that the tumor uptake of 68Ga-NOTA-MVK-Cys40-Leu14-Exendin 4 was comparable to that of the control, while the kidney uptake was significantly reduced. As a result, more favorable tumor to kidney ratios were achieved. In this study, a novel exendin 4 analogue, NOTA-MVK-Cys40-Leu14-Exendin 4, was successfully synthesized and labeled with 68Ga. With the cleavable MVK sequence, this ligand could be cleaved by the enzymes on kidneys, and releasing the fragment of 68Ga-NOTA-Met-OH, which will rapidly excrete from urine. As the high and consistent renal radioactivity accumulation could be significantly reduced, NOTA-MVK-Cys40-Leu14-Exendin 4 shows great potential in the diagnosis and radiotherapy for insulinoma.

8.
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.

9.
Biotechnol Bioeng ; 116(10): 2652-2661, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31180145

RESUMO

A pyrogen test is crucial for evaluating the safety of drugs and medical equipment, especially those involved in injections. As existing pyrogen tests, including the rabbit pyrogen test, the limulus amoebocyte lysate (LAL) test and the monocyte activation test have limitations, development of new models for pyrogen testing is necessary. Here we develop a sensitive cell model for pyrogen test based on the lipopolysaccharides (LPS) signal pathway. TLR4, MD2, and CD14 play key roles in the LPS-mediated pyrogen reaction. We established a new TLR4/MD2/CD14-specific overexpressing knock-in cell model using the CRISPR/CAS9 technology and homologous recombination to detect LPS. Stimulation of our TLR4/CD14/MD2 knock-in cell line model with LPS leads to the release of the cytokines IL-6 and TNF-alpha, with a detection limit of 0.005 EU/ml, which is greatly lower than the lower limit of 0.015 EU/ml detected by the Tachypleus amebocyte lysate (TAL) assay.

10.
Acad Radiol ; 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31151900

RESUMO

OBJECTIVE: To investigate the correlation between dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) parameters and angiogenesis and to explore prospectively the feasibility of using DSC-MRI to differentiate malignant from benign soft tissue tumors (STTs) in limbs. METHODS: This prospective study included 33 patients with STTs in limbs who underwent DSC-MRI after bolus Gd-DTPA infusion. All STTs were confirmed by pathological examination after surgery and microvessel density (MVD), vascular endothelial growth factor (VEGF) expression, were evaluated by immune-histochemical analysis. Semiquantitative DSC-MRI parameters, including negative enhancement integral (NEI), maximum slopes of decrease (MSD) and increase (MSI), and mean time to enhancement were calculated by postprocessing in workstation. The correlation was analyzed between DSC-MRI parameters and angiogenesis factors. Then, the DSC-MRI parameters were compared between benign and malignant STTs and evaluated for diagnostic efficiency by receiver operating characteristic. RESULTS: The 33 evaluated tumors were consisted of 13 benign and 20 malignant STTs in limbs. Significant positive correlations were observed between NEI, MSD, MSI and MVD, VEGF (p < 0.05). However, mean time to enhancement had no correlation with MVD and VEGF. The benign and malignant STTs differed significantly in terms of NEI, MSD, and MSI (p < 0.05). The areas under the curve (AUC) of NEI, MSD, and MSI were 0.915, 0.862, and 0.815 for discriminating between benign and malignant STTs, respectively. CONCLUSION: DSC-MRI parameters are positively correlated with MVD and VEGF, which can evaluate angiogenesis indirectly. Furthermore, DSC-MRI can be considered as one of assistant noninvasive MR imaging technique in differentiation between benign and malignant STTs in limbs.

11.
Bioconjug Chem ; 30(6): 1711-1723, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31082207

RESUMO

The effectiveness of numerous molecular drugs is hampered by their poor pharmacokinetics. Different from previous approaches with limited effectiveness, most recently, emerging high-affinity albumin binding moieties (ABMs) for in vivo hitchhiking of endogenous albumin opens up an avenue to chaperone small molecules for long-acting therapeutics. Although several FDA-approved fatty acids have shown prolonged residence and therapeutic effect, an easily synthesized, water-soluble, and high-efficiency ABM with versatile drug loading ability is urgently needed to improve the therapeutic efficacy of short-lived constructs. We herein identified an ideal bivalent Evans blue derivative, denoted as N(tEB)2, as a smart ABM-delivery platform to chaperone short-lived molecules, through both computational modeling screening and efficient synthetic schemes. The optimal N(tEB)2 could reversibly link two molecules of albumin through its two binding heads with a preferable spacer, resulting in significantly extended circulation half-life of a preloaded cargo and water-soluble. Notably, this in situ dimerization of albumin was able to sandwich peptide therapeutics to protect them from proteolysis. As an application, we conjugated N(tEB)2 with exendin-4 for long-acting glucose control in a diabetic mouse model, and it was superior to both previously tested NtEB-exendin-4 (Abextide) and the newly FDA-approved semaglutide, which has been arguably the best commercial weekly formula so far. Hence, this novel albumin binder has excellent clinical potential for next-generation biomimetic drug delivery systems.

12.
Bioconjug Chem ; 30(6): 1821-1829, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31117347

RESUMO

Magnetic resonance imaging (MRI) diagnosis is better assisted by contrast agents that can augment the signal contrast in the imaging appearance. However, this technique is still limited by the inherently low sensitivity on the recorded signal changes in conventional T1 or T2 MRI in a qualitative manner. Here, we provide a new paradigm of MRI diagnosis using T1- T2 dual-modal MRI contrast agents for contrast-enhanced postimaging computations on T1 and T2 relaxation changes. An albumin-binding molecule (i.e., truncated Evans blue) chelated with paramagnetic manganese ion was developed as a novel T1- T2 dual-modal MRI contrast agent at high magnetic field (7 T). Furthermore, the postimaging computations on T1- T2 dual-modal MRI led to greatly enhanced signal-to-noise ratios (SNR) and contrast-to-noise ratios (CNR) in both subcutaneous and orthotopic brain tumor models compared with traditional MRI methods. The T1- T2 dual-modal MRI computations have great potential to eliminate suspicious artifacts and false-positive signals in mouse brain imaging. This study may open new avenues for contrast-enhanced MRI diagnosis and holds great promise for precision medicine.

14.
Adv Mater ; 31(21): e1901187, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30957918

RESUMO

The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) genome-editing system has shown great potential in biomedical applications. Although physical approaches, viruses, and some nonviral vectors have been employed for CRISPR/Cas9 delivery and induce some promising genome-editing efficacy, precise genome editing remains challenging and has not been reported yet. Herein, second near-infrared window (NIR-II) imaging-guided NIR-light-triggered remote control of the CRISPR/Cas9 genome-editing strategy is reported based on a rationally designed semiconducting polymer brush (SPPF). SPPF can not only be a vector to deliver CRISPR/Cas9 cassettes but also controls the endolysosomal escape and payloads release through photothermal conversion under laser irradiation. Upon laser exposure, the nanocomplex of SPPF and CRISPR/Cas9 cassettes induces effective site-specific precise genome editing both in vitro and in vivo with minimal toxicity. Besides, NIR-II imaging based on SPPF can also be applied to monitor the in vivo distribution of the genome-editing system and guide laser irradiation in real time. Thus, this study offers a typical paradigm for NIR-II imaging-guided NIR-light-triggered remote control of the CRISPR/Cas9 system for precise genome editing. This strategy may open an avenue for CRISPR/Cas9 genome-editing-based precise gene therapy in the near future.


Assuntos
Sistemas CRISPR-Cas , Polietilenoglicóis/química , Polietilenoimina/química , Animais , Edição de Genes , Vetores Genéticos , Células HCT116 , Humanos , Raios Infravermelhos , Lasers , Camundongos Nus , Semicondutores
15.
Clin Nucl Med ; 44(6): 431-438, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30985422

RESUMO

AIM: Combined Ga-PSMA-617 PET imaging and Lu-PSMA-617 therapy is a precise targeted theranostic approach for patients with metastatic castration-resistant prostate cancer (mCRPC). The purpose of this study was to determine whether pretherapeutic standard uptake value (SUV) in Ga-PSMA-617 PET could indicate the effective dose in the main organs and absorbed dose in tumor lesions. METHODS: After institutional review board approval and informed consent, 9 patients with mCRPC were recruited and underwent Ga-PSMA-617 PET/CT scans. Five patients received Lu-PSMA-617 (1.30-1.42 GBq, 35-38.4 mCi) and then underwent serial whole-body planar imaging and SPECT/CT imaging of both thoracic and abdominal regions at 0.5-, 2-, 24-, 48-, and 72-hour time points. The other 4 patients received Lu-EB-PSMA-617 (0.80-1.1 GBq, 21.5-30 mCi) and then underwent the same imaging procedures at 2-, 24-, 72-, 120-, and 168-hour time points. The effective dose in the main organs and the absorbed dose in tumor lesions were calculated. Detailed correlations between the pretherapeutic SUV in Ga-PSMA-617 PET and effective dose in the main organs as well as absorbed dose in the tumor lesions were analyzed. RESULTS: SUV of Ga-PSMA-617 PET was moderately correlated with effective dose in main organs (r = 0.610 for Lu-PSMA-617, r = 0.743 for Lu-EB-PSMA-617, both P < 0.001). SUV of tumor lesions in Ga-PSMA-617 PET had high correlation with those in Lu-PSMA-617 (r = 0.915, P < 0.001) and moderate correlation with those in Lu-EB-PSMA-617 (r = 0.611, P = 0.002). CONCLUSIONS: Pretherapeutic Ga-PSMA-617 PET may indicate the dosimetry of Lu-PSMA-617 and Lu-EB-PSMA-617. Both the effective dose in main organs and absorbed dose in tumor lesions correlate with SUV of Ga-PSMA-617 PET. This relationship may help select appropriate candidates for peptide receptor radionuclide therapy. Further investigations of larger cohorts are needed to confirm these initial findings.


Assuntos
Dipeptídeos/administração & dosagem , Dipeptídeos/farmacocinética , Compostos Heterocíclicos com 1 Anel/administração & dosagem , Compostos Heterocíclicos com 1 Anel/farmacocinética , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Neoplasias de Próstata Resistentes à Castração/radioterapia , Compostos Radiofarmacêuticos/administração & dosagem , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Radiometria , Compostos Radiofarmacêuticos/farmacocinética , Dosagem Radioterapêutica , Estudos Retrospectivos , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único/métodos , Imagem Corporal Total
16.
Theranostics ; 9(5): 1358-1368, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30867836

RESUMO

It remains a major challenge to achieve precise on-demand drug release. Here, we developed a modular nanomedicine integrated with logic-gated system enabling programmable drug release for on-demand chemotherapy. Methods: We employed two different logical AND gates consisting of four interrelated moieties to construct the nanovesicles, denoted as v-A-CED2, containing oxidation-responsive nanovesicles (v), radical generators (A), and Edman linker conjugated prodrugs (CED2). The first AND logic gate is connected in parallel by mild hyperthermia ( I ) and acidic pH ( II ), which executes NIR laser triggered prodrug-to-drug transformation through Edman degradation. Meanwhile, the mild hyperthermia effect triggers alkyl radical generation ( III ) which contributes to internal oxidation and degradation of nanovesicles ( IV ). The second AND logic gate is therefore formed by the combination of I-IV to achieve programmable drug release by a single stimulus input NIR laser. The biodistribution of the nanovesicles was monitored by positron emission tomography (PET), photoacoustic, and fluorescence imaging. Results: The developed modular nanovesicles exhibited high tumor accumulation and effective anticancer effects both in vitro and in vivo. Conclusions: This study provides a novel paradigm of logic-gated programmable drug release system by a modular nanovesicle, which may shed light on innovation of anticancer agents and strategies.

17.
Future Oncol ; 15(14): 1565-1576, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30888194

RESUMO

Aim: Utilize breast cancer samples in the same patient to indicate breast cancer development. Patients & methods: We performed whole-exome analysis of spatially independent ductal carcinoma in situ (DCIS) and invasive ductal carcinoma samples from the same breast. Results: In VEGF pathway, we observed two genes disrupted in DCIS, while another four (including ACTN2) mutated in invasive ductal carcinoma. When looked up TCGA database, we identified seven breast cancer patients with ACTN2 somatic mutations and observed a dramatic decrease in the overall survival time in ACTN2 mutant patients (p = 0.0182). A further finding in the TCGA database shows that breast cancer patients with ≥2 mutated genes in VEGF pathways showed worse prognosis (p = 0.0013). Conclusion: TCGA database and special case could inform each other to reveal DCIS developmental rules.

18.
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.

19.
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.

20.
Biotechnol Bioeng ; 116(6): 1269-1279, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30684361

RESUMO

Pyrogens are components derived from microorganisms that induce complex inflammatory responses. Current approaches to detect pyrogens are complex and difficult to replicate, thus there is a need for new methods to detect pyrogens. We successfully constructed a pyrogen-sensitive cell model by overexpressing Toll-like receptor (TLR)2, TLR4, MD2, and CD14 in HEK293 cells. Since the cytokine IL-6 is specifically released upon stimulation of the TLR2 and TLR4 signaling pathways in response to pyrogen stimulation, we used it as a read out for our assay. Our results show that IL-6 is released in response to trace amounts of pyrogens in our cell model. Pyrogen incubation times and concentrations were explored to determine the sensitivity of our cell model, and was found to be sensitive to 0.05 EU/ml of LPS and 0.05 ug/ml of LTA after stimulation for 5 hr. Our TLR overexpressing cell model, with IL-6 as readout, could be a new method for in vitro testing of pyrogens and applicable for evaluating the safety of drugs.

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