Artificial intelligence for the diagnosis of clinically significant prostate cancer based on multimodal data: a multicenter study.

BACKGROUND: The introduction of multiparameter MRI and novel biomarkers has greatly improved the prediction of clinically significant prostate cancer (csPCa). However, decision-making regarding prostate biopsy and prebiopsy examinations is still difficult. We aimed to establish a quick and economic tool to improve the detection of csPCa based on routinely performed clinical examinations through an automated machine learning platform (AutoML). METHODS: This study included a multicenter retrospective cohort and two prospective cohorts with 4747 cases from 9 hospitals across China. The multimodal data, including demographics, clinical characteristics, laboratory tests, and ultrasound reports, of consecutive participants were retrieved using extract-transform-load tools. AutoML was applied to explore potential data processing patterns and the most suitable algorithm to build the Prostate Cancer Artificial Intelligence Diagnostic System (PCAIDS). The diagnostic performance was determined by the receiver operating characteristic curve (ROC) for discriminating csPCa from insignificant prostate cancer (PCa) and benign disease. The clinical utility was evaluated by decision curve analysis (DCA) and waterfall plots. RESULTS: The random forest algorithm was applied in the feature selection, and the AutoML algorithm was applied for model establishment. The area under the curve (AUC) value in identifying csPCa was 0.853 in the training cohort, 0.820 in the validation cohort, 0.807 in the Changhai prospective cohort, and 0.850 in the Zhongda prospective cohort. DCA showed that the PCAIDS was superior to PSA or fPSA/tPSA for diagnosing csPCa with a higher net benefit for all threshold probabilities in all cohorts. Setting a fixed sensitivity of 95%, a total of 32.2%, 17.6%, and 26.3% of unnecessary biopsies could be avoided with less than 5% of csPCa missed in the validation cohort, Changhai and Zhongda prospective cohorts, respectively. CONCLUSIONS: The PCAIDS was an effective tool to inform decision-making regarding the need for prostate biopsy and prebiopsy examinations such as mpMRI. Further prospective and international studies are warranted to validate the findings of this study. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100048428. Registered on 06 July 2021.

Cognitive profile in mild cognitive impairment with Lewy bodies.

Introduction: This study aimed to elucidate the cognitive profile of patients with mild cognitive impairment with Lewy bodies (MCI-LB) and to compare it to that of patients with mild cognitive impairment due to Alzheimer's disease (MCI-AD). Methods: Subjects older than 60 years with probable MCI-LB (n = 60) or MCI-AD (n = 60) were recruited. All patients were tested with Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) to assess their global cognitive profile. Results: The MCI-AD and MCI-LB patients did not differ in total MMSE and MoCA scores. However, some sub-items in MMSE and MoCA were shown to be screening markers for differentiating MCI-LB from MCI-AD. In the visuoconstructive test, the total score and hands subitem score in the clock-drawing test were significantly lower in MCI-LB than in MCI-AD. As for the executive function, the 'animal fluency test', 'repeat digits backward test' and 'take paper by your right hand' in MMSE all showed lower scores in MCI-LB compared with MCI-AD. As for memory, 'velvet' and 'church' in MoCA and 'ball' and 'national flag' in MMSE had lower scores in MCI-AD than in MCI-LB. Conclusion: This study presents the cognitive profile of patients with MCI-LB. In line with the literature on Dementia with Lewy bodies, our results showed lower performance on tests for visuoconstructive and executive function, whereas memory remained relatively spared in the early period.

Mitochondrial temperature-responsive drug delivery reverses drug resistance in lung cancer.

Reversal of cancer drug resistance remains a critical challenge in chemotherapy. Mitochondria-targeted drug delivery has been suggested to mitigate drug resistance in cancer. To overcome the intrinsic limitations in conventional mitochondrial targeting strategies, we develop mitochondrial temperature-responsive drug delivery to reverse doxorubicin (DOX) resistance in lung cancer. Results demonstrate that the thermoresponsive nanocarrier can prevent DOX efflux and facilitate DOX accumulation and mitochondrial targeting in DOX-resistant tumors. As a consequence, thermoresponsive nanocarrier enhances the cytotoxicity of DOX and reverses the drug resistance in tumor-bearing mice. This work represents the first example of mitochondrial temperature-responsive drug delivery for reversing cancer drug resistance.

A Reduction Active Theranostic Nanoparticle for Enhanced Near-Infrared Imaging and Phototherapy by Reducing Glutathione Level in Cancer Cells.

Facile preparation of a tumoral-stimuli-activated theranostic nanoparticle with simple constituents remains a challenge for tumor theranostic nanosystems. Herein we design a simple reductionresponsive turn-on theranostic nanoparticle for achieving fluorescent imaging and phototherapy combination. The theranostic nanoparticle is prepared by a simple one-step dialysis method of reduction active amphiphilic hyperbranched poly(ß-amidoamines) and a near-infrared (NIR) dye indocyanine green (ICG). The fluorescence of ICG is quenched by the aggregation-caused quenching (ACQ) effect. The fluorescent intensity of free ICG at 816 nm was ∼40 times as high as that of particulate ICG. After reductive nanoparticles incubated with dithiothreitol (DTT), the size of the nanoparticles increased from 160 nm to 610 nm by Dynamic light scattering (DLS). As nanoparticles were internalized by cancer cells, the disulfide bonds would be cleaved by intracellular reduction agents like glutathione (GSH), leading to the release of entrapped ICG. The released ICG regained its fluorescence for self-monitoring the release and therapeutic effect of ICG by fluorescence spectra and the quantitative evaluation of NIR fluorescence intensity. Remarkably, nanoparticles can also reinforce antitumor efficacy through photodynamic therapy and GSH depletion property. This study provides new insights into designing turn-on theranostic systems.

Drug Release from Disulfide-Linked Prodrugs: Role of Thiol Agents.

The disulfide bond (SS) has been widely used in prodrugs for the redox-responsive drug release, but its drug release mechanism and rate were seldom compared in different thiol agents. Herein, self-assembling nanoaggregates (NAs) formed by camptothecin (CPT)-oleic acid (OA) prodrugs linked by two frequently used SS linkers (ETCSS and ACSS) were used for such comparative investigation. It is found that the cleavage of ETCSS was directly coupled with CPT release, whereas the breakage of ACSS resulted in the generation of CPT intermediates, the chemical stability of which determined CPT release. In both cases, the redox-responsive drug release was highly dependent on the reactivity between SS and thiol agents, with an order of dithiothreitol > cysteine ≈ glutathione. Moreover, the presence of SS significantly accelerated the extracellular CPT release, which was around 3-4 fold higher than intracellular CPT release. Therefore, the in vitro cytotoxicity of SS-linked CPT-OA NAs could not be ascribed to the glutathione-trigged intracellular drug release but rather to the SS-accelerated extracellular CPT release. The above results would effectively guide the rational design and evaluation of SS-linked prodrug NAs for efficient drug delivery.

The proximity of the G-quadruplex to hemin impacts the intrinsic DNAzyme activity in mitochondria.

The DNAzyme activity of G-quadruplex/hemin in mitochondria has not been characterized. Herein, we report an unexpected difference in the DNAzyme activity between in vitro assays and in mitochondria. Molecular dynamic simulations illustrate how the interaction of the G-quadruplex with hemin may modulate the DNAzyme activity. These results might facilitate a better understanding of the catalytic mechanism of the DNAzyme and help the rational design of stable and active DNAzymes suitable for intracellular catalysis.

D-arginine-loaded metal-organic frameworks nanoparticles sensitize osteosarcoma to radiotherapy.

Osteosarcoma is a common type of bone cancers with a high rate of pulmonary recurrence. High-dose radiation therapy is useful for the ablation of unresectable osteosarcoma. However, it may cause severe adverse effects. To address this problem, we developed D-arginine-loaded metal-organic frameworks (MOF) nanoparticles for improving the radiosensitivity of osteosarcoma. D-arginine, a metabolically inert enantiomer of L-arginine, could produce nitric oxide and down-regulate hypoxia-inducible factor-1alpha (HIF-1α) to alleviate tumor hypoxia. In addition, MOF could also generate free radicals to kill the tumor cells. Results demonstrate that D-arginine-loaded nanoparticles enhanced tumor ablation and prevented the lung metastasis in mice upon radiation therapy. Furthermore, the nanoparticles or radiation alone had relatively low toxicity in cells and mice. Therefore, D-arginine-loaded MOF nanoparticles are relatively safe and highly effective in sensitizing osteosarcoma to radiotherapy.

A surface convertible nanoplatform with enhanced mitochondrial targeting for tumor photothermal therapy.

Photothermal therapy emerges as a promising approach in antitumor treatment. A major challenge for conventional photothermal therapy is its unselective hyperthermia distribution within tumor tissues, which leads to detrimental effects on surrounding healthy tissues and compromised therapeutic effectiveness. In this study, a targeted photothermal delivery nanoplatform (P-D-CS-CNTs) was facilely fabricated by decoration of an acidity-labile polyethylene glycol (PEG) derivative onto chitosan nanoparticles encapsulating single-walled carbon nanotubes. P-D-CS-CNTs displayed a good stability in serum at normal physiological pH and convertibility of surface charges upon exposure to tumoral acidic pH, which was attributed to the acidity-triggered dePEGylation. The confocal laser scanning microscopic observations suggested that such surface-convertibility of nanoparticles facilitated tumor cell uptake, endo/lyososomal escape, and enhanced mitochondrial targeting. Furthermore, upon irradiation with an 808 nm laser, P-D-CS-CNTs could sabotage mitochondria with mild hyperthermia, which further induced the ROS burst from damaged mitochondria. The overdosed ROS ultimately resulted in mitochondrial damage and cell death. These findings indicate that the surface-convertible nanoplatform is promising for improved photothermal anticancer therapy.

AMPK mediates the neurotoxicity of iron oxide nanoparticles retained in mitochondria or lysosomes.

Environmental factors may play a critical role in the etiology and pathogenesis of Parkinson's disease (PD). However, the association of PD with specific chemical species remains largely unknown. Here we prepared three kinds of iron oxide nanoparticles and examined their cytotoxicity in a cellular model of PD. We found that lysosome-targeted nanoparticles showed significant cytotoxicity in SH-SY5Y cells. Inhibition of AMPK could aggravate the neurotoxicity of lysosome-targeted nanoparticles as well as mitochondrion-targeted nanoparticles. Alteration of mitochondrial membrane potentials was found to be in agreement with the neurotoxicity of iron nanoparticles. These results suggested an important role of AMPK in regulating iron nanoparticle-associated neurotoxicity.

Light-Triggered PEGylation/dePEGylation of the Nanocarriers for Enhanced Tumor Penetration.

Nanocarriers-derived anticancer therapeutics typically suffers from poor tumor penetration and suboptimal antitumor efficacy. Although PEGylation improves the stability of nanoparticles and prolongs drug circulation, it further increases the size of nanoparticles and adversely affects the tumor penetration. Here, we developed a light-triggered PEGylation/dePEGylation strategy, whereby near-infrared (NIR)-/pH- dual responsive dePEGylation activates iRGD for tumor targeting. The embedded up-conversion nanoparticles (UCNPs) could efficiently convert NIR to UV-vis which cleaved the linker to remove PEG. NIR-induced dePEGylation remarkably improved vascular extravasation of drugs and deep tumor penetration. Therefore, the stimuli-responsive nanocarriers facilitated the tumor-targeted delivery of drugs through blood circulation and enhanced the antitumor effects.

A thermoresponsive nanocarrier for mitochondria-targeted drug delivery.

Mitochondria emerge as an important target for cancer therapy. Herein, by taking advantage of the recently reported high temperature of mitochondria, a well-tuned thermoresponsive nanocarrier was developed for specifically delivering the anticancer drug, paclitaxel (PTX), to mitochondria in cancer cells. The temperature-dependent delivery of drugs to mitochondria represents a novel anticancer strategy.

Doxorubicin-Metal Coordinated Micellar Nanoparticles for Intracellular Codelivery and Chemo/Chemodynamic Therapy in Vitro.

Low cargo-loading capacity and inadequate stability have severely retarded the clinical translation of micellar nanomedicines. Herein, we present a nanosystem prepared by self-assembly of doxorubicin (DOX) and Fe2+ with drug-metal coordination interactions, followed by a surface decoration of multiarmed PEG-dipyridine. The micellar nanoparticles possessed high drug-loading capability and stability in physiological conditions. Results showed that nanoparticles facilitated the intracellular codelivery of Fe2+ and DOX. Moreover, intracellular overload of Fe2+ significantly enhanced the generation of ROS via the Fenton reaction. This strategy provides a facile method of preparing metal coordinated micellar nanoparticles for synergistic chemo/chemodynamic therapy.

Gold Nanoparticle-Based Probe for Analyzing Mitochondrial Temperature in Living Cells.

Validation of recent findings of hot mitochondria in cancer cells is critically needed, since a single fluorescent probe cannot rule out the possibility of varied cellular uptake efficiencies. Here we developed a ratiometric nanoprobe, named the mitochondria-targeted thermoresponsive-gold nanoparticle (MTT-AuNP), for analyzing mitochondrial temperatures. Results confirmed a relatively high mitochondrial temperature in murine bladder cancer MB49 cells. High temperatures in mitochondria might have far-reaching implications for developing mitochondria-targeted therapeutics.

pH-Sensitive Poly(ß-amino ester)s Nanocarriers Facilitate the Inhibition of Drug Resistance in Breast Cancer Cells.

Multidrug resistance (MDR) remains an unmet challenge in chemotherapy. Stimuli-responsive nanocarriers emerge as a promising tool to overcome MDR. Herein, pH-sensitive poly(ß-amino ester)s polymers (PHP)-based micellar nanoparticles were synthesized for enhanced doxorubicin (DOX) delivery in drug resistant breast cancer MCF-7/ADR cells. DOX-loaded PHP micelles showed rapid cell-internalization and lysosomal escape in MCF-7/ADR cells. The cytotoxicity assays showed relatively higher cell inhibition of DOX-loaded PHP micelles than that of free DOX against MCF-7/ADR cells. Further mechanistic studies showed that PHP micelles were able to inhibit P-glycoprotein (P-gp) activity by lowering mitochondrial membrane potentials and ATP levels. These results suggested that the enhanced antitumor effect might be attributed to PHP-mediated lysosomal escape and drug efflux inhibition. Therefore, PHP would be a promising pH-responsive nanocarrier for enhanced intracellular drug delivery and overcoming MDR in cancer cells.

Near-Infrared/pH Dual-Sensitive Nanocarriers for Enhanced Intracellular Delivery of Doxorubicin.

Herein, we designed near-infrared (NIR)/pH dual-sensitive nanocarriers and evaluated its application to intracellular drug delivery. The nanocarriers were prepared based on amphiphilic poly(ß-amino ester) (PBAE) containing o-nitrobenzyl moieties in the backbones and upconversion nanoparticles (UCNPs). UCNPs can convert NIR to UV that subsequently removes PEG segments from PBAE copolymers, which could enhance the protonation of PBAE in endo/lysosomes and facilitate the escape of the nanoparticles from lysosomes. In addition, we found the colocalization of the nanoparticles with mitochondria inside the cells, presumably resulting from high hydrophobicity and positive charges of the nanoparticles. The results showed that the nanocarriers with the aid of NIR could enhance the intracellular delivery of DOX, as compared with free DOX and NIR-free control. Furthermore, PBAE@UCNPs-DOX with NIR potently inhibited tumor growth in mice. Therefore, the intelligent micellar nanoparticles might provide a simple yet effective nanoplatform to achieve mitochondrion-targeting drug delivery.

Two mTOR inhibitors, rapamycin and Torin 1, differentially regulate iron-induced generation of mitochondrial ROS.

It is generally believed that gene-environment interaction may contribute to neurodegeneration. Of particular note is that iron overload may be one of the risk factors for neurodegeneration. However, the mechanisms underlying iron-associated neurotoxicity are not fully understood. Here we explored the effects of mechanistic target of rapamycin (mTOR) inhibition in iron-stressed human neuroblastoma cells. Two mTOR inhibitors, rapamycin and Torin 1, had similar effects in cells exposed to a relatively low concentration of iron. At a higher concentration of iron, Torin 1, instead of rapamycin, could further aggravate iron-induced cytotoxicity, and mitochondrial ROS levels were significantly higher in Torin 1-treated cells. These results suggest that mTOR inhibition may not be able to alleviate iron-induced neurotoxicity.

Iron modulates the activity of monoamine oxidase B in SH-SY5Y cells.

Both monoamine oxidase B (MAO-B) and iron accumulation are associated with neurologic diseases including Parkinson's disease. However, the association of iron with MAO-B activity was poorly understood. Here we took advantage of highly sensitive and specific fluorescence probes to examine the change in MAO-B activity in human dopaminergic neuroblastoma (SH-SY5Y) cells upon iron exposure. Both ferric and ferrous ions could significantly enhance the activity of MAO-B, instead of MAO-A, in SH-SY5Y cells. In addition, iron-induced increase in MAO-B probe fluorescence could be prevented by pargyline and other newly developed MAO-B inhibitors, suggesting that it was MAO-B activity-dependent. These findings may suggest MAO-B is an important sensor in iron-stressed neuronal cells.

Iron-induced generation of mitochondrial ROS depends on AMPK activity.

Deregulated iron homeostasis is generally believed to be implicated in neurodegenerative diseases, including Parkinson's disease. Nevertheless, it is not fully understood how iron overload can elicit neuronal cell damage. Here we examined mitochondrial reactive oxygen species (ROS) levels in human dopaminergic neuroblastoma SH-SY5Y cells upon iron exposure. A relatively high concentration of iron could significantly increase mitochondrial ROS levels in SH-SY5Y cells. Pharmacological activation of AMP-activated protein kinase (AMPK) almost completely inhibited the effect of iron on mitochondrial ROS. By contrast, AMPK inhibition aggravated the neurotoxicity of iron and enhanced the production of mitochondrial ROS. Collectively, these findings suggested that excess iron may be able to perturb mitochondrial function, and AMPK activity is important for the association of iron and mitochondria.

Facile construction of mitochondria-targeting nanoparticles for enhanced phototherapeutic effects.

Phototherapy, as a noninvasive therapeutic procedure, has been applied to treat tumors. However, the application of phototherapy is often compromised by its low efficiency. Herein, we developed a novel nanoplatform based on cationic amphiphilic polymer-wrapped carbon nanotubes (rPAA@SWCNTs) with a photosensitizer, indocyanine green (ICG), for phototherapy. The as-prepared nanoparticles exhibited excellent mitochondria targeting due to the synergistic properties of highly positive charges from the polycations on the corona and the high hydrophobicity from the carbon nanotubes in the core. Moreover, the high buffer capacity of the polycations facilitated the endosomal escape of nanoparticles via a proton-sponge effect. When irradiated with an 808 nm NIR laser, ICG/rPAA@SWCNTs could precisely damage mitochondria with high efficiency and produce reactive oxygen species (ROS) and hyperthermia, which further induced the ROS burst from damaged mitochondria. The overproduced ROS accumulated in mitochondria ultimately resulted in mitochondrial damage and cell death. Therefore ICG/rPAA@SWCNTs may be able to achieve an amplifying phototherapeutic effect.

The Application of Stimuli-responsive Nanocarriers for Targeted Drug Delivery.

Nanocarriers are widely used for delivering drugs to tumors and are progressing in a stable trend, because malignant tumors remain a major health burden throughout the world and effective therapeutic strategies are urgently needed. Furthermore, as an integrated platform, nanocarriers have the potential to dramatically improve cancer diagnosis, imaging, and therapy, while reducing the toxicity associated with the current approaches. Significantly, intelligent nanocarriers are the new generation of the nanocarriers, exhibiting superior tumor targeting and improved therapeutic efficacy. In this review, we discuss recent development in the design of nanoscale stimuli-responsive systems which will be able to control drug biodistribution in response to specific stimuli, either exogenous or endogenous. Meanwhile, the recent progress in engineering intelligent and versatile nanomaterials for targeting the tumor microenvironment is summarized.