Hollow and porous structured GdVO4:Dy3+ spheres were fabricated via a facile self-sacrificing templated method. The large cavity allows them to be used as potential hosts for therapeutic drugs, and ...the porous feature of the shell allows guest molecules to easily pass through the void space and surrounding environment. The samples show strong yellow-green emission of Dy3+ (485 nm, 4F9/2 → 6H15/2; 575 nm, 4F9/2 → 6H13/2) under UV excitation. The emission intensity of GdVO4:Dy3+ was weakened after encapsulation of anticancer drug (doxorubicin hydrochloride, DOX) and gradually restored with the cumulative released time of DOX. These hollow spheres were nontoxic to HeLa cells, while DOX-loaded samples led to apparent cytotoxicity as a result of the sustained release of DOX. ICP measurement indicates that free toxic Gd ions can hardly dissolate from the matrix. The endocytosis process of DOX-loaded hollow spheres is observed using confocal laser scanning microscopy (CLSM). Furthermore, GdVO4:Dy3+ hollow spheres can be used for T 1-weighted magnetic resonance (MR) imaging. These results implicate that the luminescent GdVO4:Dy3+ spheres with hollow and porous structure are promising platforms for drug storage/release and MR imaging.
The quantity of programmed cell death-ligand 1 (PD-L1) is regarded as a predicting factor of clinical response to anti-PD-1 axis immunotherapy. However, the expression of PD-L1 and its prognostic ...value in hepatocellular carcinoma (HCC) patients remain debated. Meanwhile, the molecular features of PD-1's other ligand, namely PD-L2, as well as its correlation with clinicopathological parameters and HCC tumor microenvironment (TME), are still poorly understood. In this study, immunohistochemistry (IHC) data from 304 HCC patients were used to determine the clinicopathological features of PD-L1 and PD-L2 and their correlation with CD8
+
T cells in HCC. Moreover, fresh clinical HCC samples were used to identify the immune cell subtypes expressing PD-L1 and PD-L2. By using The Cancer Genome Atlas (TCGA) dataset, we further assessed the correlation between mutation signature, copy number variation (CNV), number of neoepitopes, immune gene expression, immune/stromal cell infiltration to the expression of PD-L1 and PD-L2. While membrane expression of PD-L2 was observed in 19.1% of tumor samples, no obvious expression of PD-L1 was detected on tumor cell membranes. High expression of PD-L2 on tumor membranes and PD-L1 in immune stroma were both significantly associated with poorer overall survival (OS) and disease-free survival (DFS) outcomes. Flow cytometry analysis and immunofluorescence showed that macrophages were the main immune cell subtype expressing both PD-L1 and PD-L2. Moreover, positive expression of PD-Ls was correlated with higher CD8
+
T cells infiltration in immune stroma. CNV analysis showed a similarity between PD-L1 and PD-L2 in affecting gene expression. In addition, higher levels of PD-Ls correlated with higher expression of immune related genes, enhanced cytolytic activity, and larger proportions of immune/stromal cell infiltration. Collectively, our study reveals the impact of both PD-L1 and PD-L2 on the HCC tumor microenvironment for the first time, providing insight for new therapeutic options.
Tumor-targeted delivery of nanomedicine is of great importance to improve therapeutic efficacy of cancer and minimize systemic side effects. Unfortunately, nowadays the targeting efficiency of ...nanomedicine toward tumor is still quite limited and far from clinical requirements. In this work, we develop an innovative peptide-based nanoparticle to realize light-triggered nitric oxide (NO) release and structural transformation for enhanced intratumoral retention and simultaneously sensitizing photodynamic therapy (PDT). The designed nanoparticle is self-assembled from a chimeric peptide monomer, TPP-RRRKLVFFK-Ce6, which contains a photosensitive moiety (chlorin e6, Ce6), a β-sheet-forming peptide domain (Lys-Leu-Val-Phe-Phe, KLVFF), an oligoarginine domain (RRR) as NO donor and a triphenylphosphonium (TPP) moiety for targeting mitochondria. When irradiated by light, the constructed nanoparticles undergo rapid structural transformation from nanosphere to nanorod, enabling to achieve a significantly higher intratumoral accumulation by 3.26 times compared to that without light irradiation. More importantly, the conversion of generated NO and reactive oxygen species (ROS) in a light-responsive way to peroxynitrite anions (ONOO−) with higher cytotoxicity enables NO to sensitize PDT in cancer treatment. Both in vitro and in vivo studies demonstrate that NO sensitized PDT based on the well-designed transformable nanoparticles enables to eradicate tumors efficiently. The light-triggered transformable nanoplatform developed in this work provides a new strategy for enhanced intratumoral retention and improved therapeutic outcome.
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•An innovative mitochondria-targeting chimeric peptide composed of four discrete functional domains is designed and prepared.•The peptide can self-assemble into nanospheres and transform into nanorods via light-triggered ROS generation and NO release.•The sphere−to−rod structural transformation remarkably enhances the intratumoral retention and accumulation of nanomedicine.•The conversion of generated ROS and NO to RNS with higher cytotoxicity enables NO to sensitize PDT in cancer treatment.
Novel multifunctional poly(ε-caprolactone)-gelatin encapsulating upconversion core/shell silica nanoparticles (NPs) composite fibers as dual drugs delivery system (DDDS), with indomethacin (IMC) and ...doxorubicin (DOX) releasing in individual release properties, have been designed and fabricated via electrospinning process. Uniform and monodisperse upconversion (UC) luminescent NaYF4:Yb3+, Er3+ nanocrystals (UCNCs) were encapsulated with mesoporous silica shells, resulting in the formation of core/shell structured NaYF4:Yb3+, Er3+@mSiO2 (UCNCs@mSiO2) NPs, which can be performed as DOX delivery carriers. These UCNCs@mSiO2 NPs loading DOX then were dispersed into the mixture of poly(ε-caprolactone) (PCL) and gelatin-based electrospinning solution containing IMC, followed by the preparation of dual drug-loaded composite fibers (DDDS) via electrospinning method. The drugs release profiles of the DDDS were measured, and the results indicated that the IMC and DOX released from the electrospun composite fibers showed distinct properties. The IMC in the composite fibers presented a fast release manner, while DOX showed a sustained release behavior. Moreover, the UC luminescent intensity ratios of 2H11/2/4S3/2–4I15/2 to 4F9/2–4I15/2 from Er3+ vary with the amounts of DOX in the system, and thus drug release can be tracked and monitored by the luminescence resonance energy transfer (LRET) mechanism.
Malignant melanoma cell-intrinsic PD-1:PD-L1 interaction thrusts tumorigenesis, angiogenesis, and radioresistance via mTOR hyperactivation to aggravate circumjacent aggression. Interdicting melanoma ...intrinsic growth signals, including the blockade of PD-L1 and mTOR signaling concurrently, cooperative with radiotherapy may provide a vigorous repertoire to alleviate the tumor encumbrance. Thence, we design a three-pronged platinum@polymer-catechol nanobraker to deliver mTOR inhibitor TAK228 and anti-PD-L1 antibody (aPD-L1) for impeding the melanoma-PD-1-driven aggression and maximizing the melanoma eradication. The aPD-L1 collaborated with TAK228 restrains melanoma cell-intrinsic PD-1: PD-L1 tumorigenic interaction via blocking melanoma-PD-L1 ligand and the melanoma-PD-1 receptor-driven mTOR signaling; corresponding downregulation of mTOR downstream protumorigenic cellular MYC and proangiogenic hypoxia-inducible factor 1-alpha is conducive to preventing tumorigenesis and angiogenesis, respectively. Further, high-Z metal platinum sensitizing TAK228-enhanced radiotherapy confers the nanobraker on remarkable tumoricidal efficacy. Hereto, the customized three-pronged nanobrakers efficiently suppress melanoma tumorigenesis and angiogenesis concomitant with the amplification of radiotherapeutic efficacy. Such an ingenious tactic may provide substantial benefits to clinical melanoma patients.
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•The pH-responsive platinum-polyphenol networks were fabricated via a one-step self-assembly method.•The melanoma cell-intrinsic PD-1:PD-L1 protumorigenic signaling were synergistically subdued by APTP NPs.•High-Z platinum cooperates with mTOR inhibitor (TAK228) to expedite tumor eradication via sensitizing radiotherapy.•APTP NPs exhibit anti-angiogenesis performance to aid the anti-tumor effect.
The bottom-up self-assembly of protein subunits into supramolecular nanoarchitectures is ubiquitously exploited to recapitulate and expand the features of natural proteins to advance nanoscience in ...medicine. Various chemical and biological re-engineering approaches are available to render diverse functions in the given proteins. They are, unfortunately, capable of compromising protein integrity and stability after extensive modifications. In this study, we introduce a new protein re-engineering method, metal ion assisted interface re-engineering (MAIR), to serve as a robust and universal strategy to extend the functions of self-assembly proteins by boosting structural features to advance their diverse biomedical applications. In particular, the MAIR strategy was applied to a widely used natural protein, ferritin, as a model protein to coordinate with copper ions in its mutagenic artificial metal binding domain. Structure directed rational protein mutagenesis was carried out at the C2 interface amino acid residues of the ferritin subunit for metal ion coordination site optimization. Copper binding at the artificial binding pocket was highly specific over the other divalent ions present in physiological fluids, and the structurally embedded copper ion in turn strengthened the overall protein integrity and stability. In the presence of isotopic copper-64, the interface re-engineered ferritin worked as a chelator-free molecular nanoprobe with an extraordinarily high specific activity to allow PET imaging of tumors in live animals. We also found that the re-engineered ferritin coordinating with copper ions demonstrates high drug loading capacity of a widely used anti-cancer agent, doxorubicin (DOX), to achieve significant drug retention at the tumor site and enhance tumor regression for improved anti-cancer effects. The MAIR approach, thus, exploited the copper ion to facilitate efficient one-step labeling of mutant ferritin derivatives for simultaneous molecular imaging and drug delivery. The reported interface re-engineering strategy provides an unparalleled opportunity to expand protein biofunctions to serve as a new theranostic agent in cancer research.
Ordered arrays of luminescent YVO4:Eu3+ films with square (side length 19.17 ± 2.05 μm) and dot (diameter 11.20 ± 1.82 μm) patterns were fabricated by two kinds of soft lithography processes, namely, ...microtransfer molding (μTM) and microcontact printing (μCP), respectively. Both soft‐lithography processes utilize a PDMS elastomeric mold as the stamp combined with a Pechini‐type sol‐gel process to produce luminescent patterns on quartz plates, in which a YVO4:Eu3+ precursor solution was employed as ink. The ordered luminescent YVO4:Eu3+ patterns are revealed by optical microscopy and their microstructure, consisting of nanometer‐scale particles, is unveiled by scanning electronic microscopy (SEM) observations. Additionally, photoluminescence (PL) and cathodoluminescence (CL) were carried out to characterize the patterned YVO4:Eu3+ samples. A strong red emission as a result of 5D0–7F2 transition of Eu3+ was observed under UV‐light or electron‐beam excitation, which implies that combining soft lithography with a Pechini‐type sol‐gel route has potential for fabricating rare‐earth luminescent pixels for next‐generation field‐emission display devices.
Ordered, uniform square (see figure) and circle arrays of luminescent YVO4:Eu3+ patterns are fabricated by microtransfer molding and microcontact printing processes, respectively. No deformation nor swelling can be seen in the resulting luminescent patterns. Upon UV irradiation and electron‐beam excitation, both types of patterns emit strong red light because of the presence of Eu3+ (5D0–7F2) in the YVO4 host.
Photodynamic therapy (PDT) is a novel technique that has been extensively employed in cancer treatment; it utilizes reactive oxygen species to kill malignant cells. However, poor performance of the ...photosensitizer itself, limited penetration depth and the overexpression of glutathione (GSH) in cancer cells are the major obstacles facing the actual clinical application of PDT. Inspired by the challenges mentioned above, here we propose multifunctional nanoparticles utilizing mesoporous manganese silicate (MnSiO3)-coated upconversion nanoparticles (UCNPs) as nanocarriers for loading highly fluorescent graphitic-phase carbon nitride quantum dots (g-C3N4 QDs) to simultaneously act as a photosensitive drug and imaging agent. Surface modification of the nanoparticles with polyethylene glycol (PEG) endows the samples (denoted as UMCNs-PEG) with excellent biocompatibility and long-term in vivo circulation. Taking advantage of the inherent performance of the as-synthesized nanoparticles, multimodality imaging, including upconversion luminescence (UCL), computed tomography (CT) and magnetic resonance imaging (MRI), has been achieved; this is conducive to providing effective treatment information by real-time monitoring. In vivo photodynamic therapy to achieve effective tumor inhibition was then realized without inducing significant toxicity to treated mice. As a result, this work provides a novel paradigm with highly integrated functionalities which not only exhibits excellent prospects for imaging-guided photodynamic anticancer therapy but also encourages further exploration of new types of multifunctional nanoparticles for biomedical applications.
To overcome the problems of commercial magnetic resonance imaging (MRI) contrast agents (CAs) (i.e., small molecule Gd chelates), we have proposed a new concept of Gd macrochelates based on the ...coordination of Gd.sup.3+ and macromolecules, e.g., poly(acrylic acid) (PAA). To further decrease the r.sub.2/r.sub.1 ratio of the reported Gd macrochelates that is an important factor for T.sub.1 imaging, in this study, a superior macromolecule hydrolyzed polymaleic anhydride (HPMA) was found to coordinate Gd.sup.3+. The synthesis conditions were optimized and the generated Gd-HPMA macrochelate was systematically characterized. The obtained Gd-HPMA29 synthesized in a 100 L of reactor has a r.sub.1 value of 16.35 mM.sup.-1 s.sup.-1 and r.sub.2/r.sub.1 ratio of 2.05 at 7.0 T, a high Gd yield of 92.7% and a high product weight (1074 g), which demonstrates the feasibility of kilogram scale facile synthesis. After optimization of excipients and sterilization at a high temperature, the obtained Gd-HPMA30 formulation has a pH value of 7.97, osmolality of 691 mOsmol/kg water, density of 1.145 g/mL, and viscosity of 2.2 cP at 20 â or 1.8 cP at 37 â, which meet all specifications and physicochemical criteria for clinical injections indicating the immense potential for clinical applications.
Intratumoral CD8+ T cells are crucial for effective cancer immunotherapy, but an immunosuppressive tumor microenvironment (TME) contributes to dysfunction and insufficient infiltration. Drug ...repurposing has successfully led to new discoveries among existing clinical drugs for use as immune modulators to ameliorate immunosuppression in TME and reactivate T‐cell‐mediated antitumor immunity. However, due to suboptimal tumor bioavailability, the full potential of immunomodulatory effects of these old drugs has not been realized. The self‐degradable PMI nanogels carrying two repurposed immune modulators, imiquimod (Imi) and metformin (Met), are reported for TME‐responsive drug release. It remodels the TME through the following aspects: 1) promoting dendritic cells maturation, 2) repolarizing M2‐like tumor‐associated macrophages, and 3) downregulating PD‐L1 expression. Ultimately, PMI nanogels reshaped the immunosuppressive TME and efficiently promote CD8+ T cell infiltration and activation. These results support that PMI nanogels can potentially be an effective combination drug for enhancing the antitumor immune response of anti‐PD‐1 antibodies.
Self‐degradable nanogels with tumor microenvironment (TME)‐responsiveness exhibit unique properties of targeted and rapid drug release, which can revert the immunosuppressive TME to the anti‐tumor state. And the improved immunosuppressive TME can reactivate T‐cell‐mediated antitumor immunity by promoting CD8+ T cell infiltration and activation, which enhances the anticancer activity of current cancer immunotherapy.
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