The complex tumor microenvironment (TME) and nonspecific drug targeting limit the clinical efficacy of photodynamic therapy in combination with chemotherapy. Herein, a metal–organic framework (MOF) ...assisted strategy is reported that modulates TME by reducing tumor hypoxia and intracellular glutathione (GSH) and offers targeted delivery and controlled release of the trapped chemodrug. Platinum(IV)‐diazido complex (Pt(IV)) is loaded inside a Cu(II) carboxylate‐based MOF, MOF‐199, and an aggregation‐induced‐emission photosensitizer, TBD, is conjugated to polyethylene glycol for encapsulating Pt(IV)‐loaded MOF‐199. Once the fabricated TBD‐Pt(IV)@MOF‐199 nanoparticles are internalized by cancer cells, MOF‐199 consumes intracellular GSH and decomposes to fragments to release Pt(IV). Upon light irradiation, the released Pt(IV) generates O2 that relieves hypoxia and produces Pt(II)‐based chemodrug inside cancer cells. Concomitantly, efficient reactive oxygen species generation and bright emission are afforded by TBD, resulting in synergistic image‐guided photo‐chemo therapy with enhanced efficacies and mitigated side effects.
Tumor microenvironment (TME) modulated image‐guided photo‐chemo therapy is realized by constructing a MOF‐199‐assisted nanoplatform. In this nanosystem, MOF‐199 greatly scavenges glutathione and collapses to selectively release the O2‐evolving Pt(IV) prodrug inside cancer cells. The Pt(IV) prodrug generates O2 and cytotoxic Pt(II) to relieve tumor hypoxia and ablate cancer cells; the PSs can thus efficiently sensitize singlet oxygen for image‐guided therapy.
► Orthogonal matrix design was used to optimize the submerged culture conditions to simultaneously produce the mycelial biomass and betulin by I. obliquus. ► The morphology of I. obliquus was ...characterized and the favorable mycelial form for betulin production was determined during the fermentation period. ► Antioxidant capacity of betulin was also investigated in vitro.
This paper is concerned with optimization of submerged culture conditions for the mycelial growth and betulin production by Inonotus obliquus by one-factor-at-a-time and orthogonal experiment design. Among the variables of medium components, glucose, yeast extract, and MgSO4 were identified to be the most suitable carbon, nitrogen, and mineral sources, respectively. The optimal temperature and initial pH for mycelial growth and betulin production were found to be 25°C and 6.0, respectively. Subsequently, the concentration of glucose, yeast extract, and MgSO4 were optimized using the orthogonal experiment design. The optimal concentration for the enhanced production are determined as 30g/L glucose, 3g/L yeast extract, 5mmol/L MgSO4·7H2O for mycelial yield, and 30g/L glucose, 3.5g/L yeast extract, 5mmol/L MgSO4·7H2O for betulin production, respectively. The subsequent verification experiments confirmed the validity of the models. Under optimal culture conditions, the maximum betulin concentration in a 5-L stirred-tank bioreactor reached to 69.37mg/L. Furthermore, the morphological parameters of the pellets were characterized by their mean diameter, circularity, roughness and compactness. It was proved that mycelial growth and pellet morphology (i.e. compactness, mean diameter and roughness) may be the critical parameters affecting betulin production. In addition, betulin showed the potential antioxidant capacities on scavenging DPPH radical and hydroxyl radical.
The major nutrients, pH and temperature were evaluated for the exopolysaccharide (EPS) production by
Daedalea dickinsii
in submerged culture to derive an optimal medium composition and conditions as ...follows: 50 g/L maltose, 5 g/L soy peptone, 5 mM CaCl
2
, at pH 6.0 and 28 °C. A purified EPS fraction was attained from gel filtration chromatography and its major molecular characteristics were determined. FT-IR spectral analysis revealed the prominent characteristic groups of polyhydric alcohols. GC analysis and NMR spectrum showed its major molecular composition of glucose and galactose. Furthermore, thermogravimetric analysis indicated its degradation temperature (
T
d
) of 189 °C. The antioxidant activity of the EPS fraction showed a correlation with the molecular properties. It might be attributed to the functional groups in the EPS fraction, which can donate electrons to reduce the radicals to a more stable form or react with the free radicals to terminate the radical chain reaction.
There has been a surging interest in the synthesis of activatable photosensitizers (PSs) as they can be selectively activated with minimum nonspecific phototoxic damages for photodynamic therapy ...(PDT). Conventional strategies to realize activatable PSs are only applicable to a limited number of molecules. Herein, a simple and general strategy to yield activatable PSs by coupling MIL‐100 (Fe) (MIL: Materials Institute Lavoisier) with different kinds of PSs is presented. Specifically, when PSs are encapsulated into MIL‐100 (Fe), the photosensitization capability is suppressed due to their isolation from O2. After the reaction between iron(III) in MIL‐100 (Fe) and H2O2 occurs, the framework of MIL‐100 (Fe) collapses and the encapsulated PSs regain contact with O2, leading to activation of photosensitization. In addition, the decomposition of H2O2 can generate O2 to relieve tumor hypoxia and enhance PDT effect. As O2 is an indispensable factor for PDT, the activation strategy should be generally applicable to different PSs for activatable PDT.
A simple and general strategy to realize activatable photodynamic therapy is achieved by encapsulating photosensitizers (PSs) into MIL‐100 (Fe). The initial photosensitizing capabilities are blocked due to isolation of PSs from oxygen, which can be activated by tumor‐secreted H2O2 as a result of dissociation of MIL‐100 (Fe) and regained contact between PSs and oxygen.
Liposomes have been used as popular drug delivery systems for cancer therapy. However, it is difficult to track traditional liposome delivery systems in an efficient and stable fashion to assess ...their delivery efficacy and biodistribution after administration. Meanwhile, conventional fluorescent liposomes containing optical tracers face the challenge of aggregation‐caused quenching. Herein, we report a strategy for the integration of an aggregation‐induced emission fluorogen with a liposome to yield an AIEgen–lipid conjugate, termed “AIEsome”. The AIEsome exhibits bright red fluorescence along with great photostability and biocompatibility, and can be used for in vitro cancer cell labeling and in vivo tumor targeting. Meanwhile, benefiting from the excellent photosensitizing ability of the AIEgen and its good oxygen exposure in aqueous media, the AIEsome also performs well in efficient photodynamic therapy (PDT) for both in vitro cancer cell ablation and in vivo antitumor therapy after white light illumination.
Teamwork: An aggregation‐induced emission fluorogen was combined with a liposome to yield an AIEgen–lipid conjugate (“AIEsome”). The AIEsome exhibits bright red fluorescence and strong photosensitization along with great photostability and biocompatibility, and can be used for image‐guided photodynamic therapy for in vitro cancer cell ablation and in vivo antitumor therapy. PDT=photodynamic therapy, ROS=reactive oxygen species.
► R. mucilaginosa could transform betulin to betulone. ► The biotransformation was optimized and 52.65% betulin was converted. ► Betulone was proved to have higher potential antioxidant capacity.
In ...this study, betulin was biotransformed to betulone by a strain of yeast. A primary screening was carried out using 47 microbial strains isolated from soil, that was able to grow in the presence of betulin as sole carbon source. The strain of yeast was identified as Rhodotorula mucilaginosa by Bruker MALDI Biotyper and 26S rDNA analysis. Under the optimum conditions, this yeast converted 52.65% of the added 4mg/ml betulin to two products. One was betulone detected by high performance liquid chromatography (HPLC), isolated by preparative HPLC and characterized by high resolution mass spectrum (HRMS), 13C NMR and 1H NMR spectra. The other was a semi-volatile aromatic compound identified as 11,14-Octadecadienoic acid methyl ester by GC–MS. In the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging system, the activity of betulone was about 2 times higher than that of betulin.
Pyrroloquinoline quinone (PQQ) is an important biofactor which can be synthesized by several bacteria. To determine the level of PQQ in a fermentation broth, a rapid and reliable UPLC-DAD-MS/MS ...method was developed. In this method, solid phase extraction allowed for excellent recoveries (>90 %) and eliminated interference at the same time. The pretreated sample was separated on a Waters Acquity BEH C₁₈ column (2.1 × 100 mm, 1.7 μm) and detected using an ESI tandem mass spectrometer operated in negative-ion mode at a m/z range between 90.0 and 1000.0 and a DAD detector in the range from 200 to 400 nm. PQQ was observed to separate absolutely from the other components using gradient elution with water and acetonitrile. This separation also reduced the matrix effects. The assay range is 200–500 µg/mL and proved to be linear (R ² > 0.996), accurate (≤10 % deviation), and precise (CV < 15 %). The retention time for PQQ in the column was almost 1 min due to the high column efficiency on the UPLC system. Therefore, this work provides a rapid and reliable method to quantitate the PQQ level in a fermentation broth.
CAR-T-cell therapies must be expanded to obtain a large number of effector cells quickly, and the current technology cannot address this challenge. A longer operational time would lose or alter the ...function and phenotype of CAR-T cells in response to therapy, and it also causes a loss in the optimal treatment time for patients. At present, lower survival time and homing efficiency reduce the antitumor effect of CAR-T in vivo. But nobody has solved these two issues in one system, which has a similar microenvironment of lymphoid organs to activate/expand cell delivery for immunotherapy. Here, we generated artificial, customized immune cell matrix scaffolds based on a self-assembling peptide to preserve and augment the cell phenotype in light of the characteristics of CAR-T. The all-in-one nanoscale matrix scaffolds reduced the processing time of CAR-T to 3 days and resulted in over a 10-fold increase compared with the traditional protocol. The cells were combined to modulate mechanotransduction and chemical signals, and the mimic matrix scaffolds showed optimal stiffness and adhesive ligand density, thereby accelerating CAR-T-cell proliferation. Meanwhile, engineering CAR-T-secreted intrinsic PD-1 blocking single-chain variable fragments (scFv) further increased cell proliferation and cytotoxicity by resisting the self and tumor microenvironment in a paracrine and autocrine manner. Local delivery of CAR-T cells from the scaffolds significantly enabled long-term retention, suppressed tumor growth, and increased infiltration of effector T cells compared with traditional CAR-T treatment. The application of bioengineering and genetic engineering approaches has led to the development of rapid culture environments that can control matrix scaffold properties for CAR-T-cell and cancer immunotherapies.
Metabolic glycoengineering of unnatural glycans with bio-orthogonal chemical groups and a subsequent click reaction with fluorescent probes have been widely used in monitoring various bioprocesses. ...Herein, we developed a dual-responsive metabolic precursor that could specifically generate unnatural glycans with azide groups on the membrane of targeted cancer cells with high selectivity. Moreover, a water-soluble fluorescent light-up probe with aggregation-induced emission (AIE) was synthesized, which turned its fluorescence on upon a click reaction with azide groups on the cancer cell surface, enabling special cancer cell imaging with low background signal. Furthermore, the probe can generate 1O2 upon light irradiation, fulfilling its dual role as an imaging and therapeutic agent for cancer cells. Therefore, the concepts of the cancer-cell-specific metabolic precursor cRGD–S-Ac3ManNAz and the AIE light-up probe are promising in bio-orthogonal labeling and cancer-specific imaging and therapy.
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