Sleeping more than 8 h: a silent factor contributing to decreased muscle mass in Chinese community-dwelling older adults.

BACKGROUND: Muscle mass loss is an age-related process that can be exacerbated by lifestyle, environmental and other factors, but can be mitigated by good sleep. The objective of this study was to investigate the correlation between varying time lags of sleep duration and the decline in muscle mass among individuals aged 60 years or older by using real-world health monitoring data obtained from wearable devices and smart home health monitoring devices. METHODS: This study included 86,037 observations from 2,869 participants in the Mobile Support System database. Missing data were supplemented by multiple imputation. The investigation utilized generalized estimating equations and restricted cubic spline curve to examine the relationship between sleep duration and low muscle mass. Various lag structures, including 0, 1, 2, 0-1, 0-2, and 1-2 months, were fitted, and the interaction effect of observation time with sleep duration was estimated for each lag structure. Additionally, subgroup analyses were conducted. The models were adjusted for various covariates, including gender, age, body mass index, footsteps, smoking status, drinking status, marital status, number of chronic diseases, number of medications, diabetes mellitus, hyperlipidemia, coronary artery disease, respiratory disease, and musculoskeletal disease and an interaction term between time and sleep duration. RESULTS: The results of the generalized estimating equation showed a significant correlation (p < 0.001) between sleep duration of 8 h or more and low muscle mass in older adults, using 6-7 h of sleep as a reference. This effect was seen over time and prolonged sleep accumulated over multiple months had a greater effect on muscle mass loss than a single month. The effect of long sleep duration on muscle mass loss was significantly greater in females than in males and greater in the over-75 than in the under-75 age group. Restricted cubic spline plots showed a non-linear relationship between sleep duration and low muscle mass (p < 0.001). CONCLUSIONS: This study found an association between sustained nighttime sleep of more than eight hours and decreased muscle mass in older adults, especially older women.

Physical activity during pregnancy and the risk of gestational diabetes mellitus: a systematic review and dose-response meta-analysis.

BACKGROUND: Previous research has indicated the inverse association between physical activity (PA) and gestational diabetes mellitus (GDM). However, the dose-response relationship currently remains undetermined. This study aims to explore the dose-response relationship between PA during the first and second trimesters of pregnancy and GDM risk. METHODS: Studies on the relationship between PA during pregnancy and GDM risk published before April 25, 2023, were searched for in six databases. According to the inclusion and exclusion criteria, all literature was screened for eligibility. The Newcastle-Ottawa Scale (NOS) was used to assess risk of bias. Publication bias was examined using funnel plots, Begg's and Egger's tests, as well as trim-and-fill analysis. We harmonized exposure estimates of PA during pregnancy to the common unit of the metabolic equivalent of task (MET)-h/week. Restricted cubic splines were used to model the dose-response relationship. The criteria from the World Cancer Research Fund were used to assess the certainty of evidence across outcomes. All analyses were performed using Stata 15.1. RESULTS: The results indicated that in contrast with the lowest level of PA, promoting the highest PA level lowers the risk of GDM by 36% (RR = 0.64, 95%CI: 0.53 ~ 0.78). We found a curvilinear dose-response association between PA during the first trimester and incident GDM (Pnonlinearity = 0.012). Compared to inactive pregnant women, for those who achieved the guidelines-suggested minimum level (10 MET-h/week) of PA during the first trimester, the GDM risk was decreased by 13% (RR = 0.87, 95%CI: 0.79 ~ 0.96). A linear relationship was found between PA during the second trimester and the GDM risk (Pnonlinearity = 0.276). The results with a restricted cubic spline model suggested that pregnant women who accumulate 10 MET-h/week have a 1% reduced risk of GDM compared to completely inactive individuals. Twice (20 MET-h/week) or a higher amount of PA (50 MET-h/week) contributed to further reductions in GDM risk. CONCLUSION: There is a dose-response relationship between higher levels of PA in both the first and second trimesters and reduced risk of GDM; the relationship is stronger in the first trimester. Increasing PA during pregnancy can prevent the development of GDM. PROSPERO REGISTRATION NUMBER: CRD42023420564.

Amphiphilic polymeric nanodrug integrated with superparamagnetic iron oxide nanoparticles for synergistic antibacterial and antitumor therapy of colorectal cancer.

Colorectal cancer (CRC) is one of the most prevalent and deadly malignancies that can be influenced by Fusobacterium nucleatum (Fn), a bacterium that promotes tumor development and chemoresistance, resulting in limited therapeutic efficacy. Traditional antibiotics cannot effectively eliminate Fn at tumor site due to issues like biofilm formation, while chemotherapy alone fails to suppress tumor progression. Therefore, the development of new methods to eliminate Fn and promote antitumor efficacy is of great significance for improving the outcome of CRC treatment. Herein, we developed a nanodrug (OPPL) that integrates oleic acid-modified superparamagnetic iron oxide nanoparticles (O-SPIONs) and an amphiphilic polymer (PPL) to deliver the platinum prodrug and antimicrobial lauric acid (LA) for enhancing the treatment of CRC. We demonstrated that OPPL can synergistically enhance antibacterial and biofilm disruption activities against Fn along with the antimicrobial LA by producing reactive oxygen species (ROS) through its peroxidase-like activity. Furthermore, the OPPL nanodrug can increase intracellular ROS, promote lipid peroxides and deplete glutathione, leading to ferroptosis. By combining chemotherapy and induced ferroptosis, the OPPL nanodrug exhibited high cytotoxicity against CRC cells. In vivo studies showed that the OPPL nanodrug could enhance tumor accumulation, enable magnetic resonance imaging, suppresse tumor growth, and inhibit growth of intratumor Fn. These results suggest that OPPL is an effective and promising candidate for the treatment of Fn-infected CRC. STATEMENT OF SIGNIFICANCE: The enrichment of Fusobacterium nucleatum (Fn) in colorectal cancer is reported to exacerbate tumor malignancy and is particularly responsible for chemoresistance. To this respect, we strategically elaborated multifaceted therapeutics, namely OPPL nanodrug, combining oleic acid-modified superparamagnetic iron oxide nanoparticles (O-SPIONs) with a polymer containing a platinum prodrug and antimicrobial lauric acid. The O-SPION components exert distinctive peroxidase-like activity, capable of stimulating Fenton reactions selectively in the tumor microenvironment, consequently accounting for the progressive production of reactive oxygen species. Hence, O-SPIONs have been demonstrated to not only supplement the antimicrobial activities of lauric acid in overcoming Fn-induced chemoresistance but also stimulate potent tumor ferroptosis. Our proposed dual antimicrobial and chemotherapeutic nanodrug provides an appreciable strategy for managing challenging Fn-infected colorectal cancer.

Activation of pyroptosis by specific organelle-targeting photodynamic therapy to amplify immunogenic cell death for anti-tumor immunotherapy.

Pyroptosis, a unique lytic programmed cell death, inspired tempting implications as potent anti-tumor strategy in pertinent to its potentials in stimulating anti-tumor immunity for eradication of primary tumors and metastasis. Nonetheless, rare therapeutics have been reported to successfully stimulate pyroptosis. In view of the intimate participation of reactive oxygen species (ROS) in stimulating pyroptosis, we attempted to devise a spectrum of well-defined subcellular organelle (including mitochondria, lysosomes and endoplasmic reticulum)-targeting photosensitizers with the aim of precisely localizing ROS (produced from photosensitizers) at the subcellular compartments and explore their potentials in urging pyroptosis and immunogenic cell death (ICD). The subsequent investigations revealed varied degrees of pyroptosis upon photodynamic therapy (PDT) towards cancerous cells, as supported by not only observation of the distinctive morphological and mechanistic characteristics of pyroptosis, but for the first-time explicit validation from comprehensive RNA-Seq analysis. Furthermore, in vivo anti-tumor PDT could exert eradication of the primary tumors, more importantly suppressed the distant tumor and metastatic tumor growth through an abscopal effect, approving the acquirement of specific anti-tumor immunity as a consequence of pyroptosis. Hence, pyroptosis was concluded unprecedently by our proposed organelles-targeting PDT strategy and explicitly delineated with molecular insights into its occurrence and the consequent ICD.

Simultaneous Knockdown of Immune Suppressive Markers by Tumor Microenvironment-Responsive Multifaceted Prodrug Nanomedicine.

Tumors managing to exempt from immune clearance are attributable to their overexpressed immune suppressive molecules (CD47, PD-L1, etc.). Leadingly, the checkpoint blockade-based chemoimmunotherapy by means of knockdown of these immunosuppressive checkpoints, together with immunogenetic chemotherapeutics, is perceived to be a valid therapeutic strategy for improving anti-tumor outcomes. Herein, chemotherapeutic camptothecin was covalently introduced into an intriguing multifaceted nanomedicine. Note that the elaborated nanomedicine was chemically engineered to enable targeted transportation to the tumors via systemic administration, possessing intelligent responsiveness to sequential extracellular and intracellular microenvironments in the targeted tumors for prompted transcellular endocytosis owing to enzymolysis by the tumor-enriched matrix metalloproteinases and the selective liberation of cytocidal camptothecin in the cell interiors owing to thiolysis by glutathione. In addition, this chemotherapeutic nanomedicine allowed facile encapsulation of the negatively charged RNA interference payloads. Consequently, aiming for treatment of intractable triple-negative breast tumors, we attempted the small interfering RNA (siRNA) payloads aiming for CD47 and PD-L1 into the aforementioned nanomedicine. The subsequent investigations demonstrated drastic knockdown of these vital immune suppressive checkpoints by this siRNA-encapsulating chemotherapeutic nanomedicine, conducing to the reversal of the immune checkpoint suppressive microenvironment of triple-negative 4T1 tumors. Namely, the inhibited proceedings of the innate and adaptive anti-tumor immunities were revived, as supported by observation of the activated infiltration and retention of CD68+ macrophages and CD4+ and CD8+ lymphocytes into the tumors. Eventually, most potent anti-tumor efficacies were accomplished by systemic administration of this chemoimmunotherapeutic nanomedicine, which verified the amplified contribution from anti-tumor immunities by means of knockdown of the immune suppressive molecules to the ultimate anti-tumor efficacies. Note that the upregulation of the immune suppressive molecules was constantly reported in a variety of clinical therapies; hence, our facile chemoimmunotherapeutic platform should be emphasized in clinical translation for seeking improved therapeutic outcomes.

pH-responsive organic/inorganic hybrid nanocolloids for transcellular delivery of ribonucleolytic payloads toward targeted anti-glioma therapy.

Proteins have been appreciated to be a superlative modality of therapeutics in view of their direct roles in regulating diverse sets of biological events, nonetheless, the clinical applications of the proteinic therapeutics have been strictly limited to act on the cell surface receptors owing to their inherent cell-impermeable character of the proteins. To this obstacle, we contrived carboxylation reaction upon the proteins (RNase A) into the overall negatively charged pro-RNase, followed by elaboration of intelligent pH-responsive pro-RNase delivery nanocolloids based on co-precipitation of pro-RNase and Arg-Gly-Asp (RGD)-functionalized poly(ethylene glycol) (PEG)-block-polyanion with aids of inorganic calcium phosphate (CaP). The resulting nanocolloids appeared to actively accumulate into glioma due to the specific binding affinities of RGD and glioma-enriched αVß3 and αVß5 integrins. Furthermore, the pH responsiveness to the acidic endolysosomal microenvironment of all compositions of nanocolloids (including: decarboxylation of pro-RNase composition to restore the native RNase A, ionization of CaP composition to elicit osmotic pressure, and charge reversal of PEG-block-polyanion into membrane-disruptive polycation) could stimulate not only efficient endolysosomal escape for translocation into the cytosol but also structural disassembly for ready liberation of the RNase A payloads, eventually exerting non-specific RNA degradation for apoptosis of the affected cells. Systemic dosage of the proposed nanocolloids demonstrated potent anti-tumor efficacies towards xenograft glioma due to massive RNA degradation. Therefore, our proposed RNase A prodrug nanocolloids could represent as a versatile platform for engineering transcellular protein delivery systems, which are expected to spur thriving emergence of a spectrum of proteins in precision intervention of intractable diseases.

Charge-Reversible Pro-Ribonuclease Enveloped in Virus-like Synthetic Nanocapsules for Systemic Treatment of Intractable Glioma.

We have tailored multifaceted chemistries into the manufacture of artificial virus-like delivery vehicles mimicking viral "intelligent" transportation pathways through sequential biological barriers; these vehicles can acquire the ability to dynamically "program transfer" to their target sites. To accomplish this, we created anionic pro-proteins, which facilitate charge reversal when subject to acidic endosomal pH; in this way, carboxylation reactions are performed on proteins with amine-reactive cis-aconitic anhydride. Electrostatic associations then initiate the envelopment of these pro-proteins into multilayered nanoarchitectural vehicles composed of multiple-segmental block copolycationic cyclic Arg-Gly-Asp (RGD)-poly(ethylene glycol)(PEG)-GPLGVRG-polylysine(thiol). Therefore, upon the pro-proteins' initial binding to the tumors via the protruding RGD ligands, the bio-inert PEG surroundings are detached through the enzymolysis of the intermediate GPLGVRG linkage by tumor-enriched matrix metalloproteinases, unveiling the cationic polylysine palisade and imparting intimate affinities to the anionic cytomembranes of the targeted tumors. Essentially, through their active endocytosis into the subcellular endosomal compartments, the pro-proteins are made capable of retrieving the original amine groups through a charge reversal decarboxylation process, consequently eliciting augmented charge densities (charge nonstoichiometric protein@polylysine(disulfide)) to disrupt the anionic endosomal membranes to facilitate translocation into the cytosol. Eventually, the active protein payloads can be liberated from nonstoichiometric protein@polylysine(thiol) by the disassembly of polylysine palisade upon the cleavage of disulfide crosslinking in response to the very high level of glutathione in the cytosol, thereby contributing toward extreme cytotoxic potency. Hence, our elaborated virus-mimicking platform has demonstrated potent antitumor efficacy through the systemic administration of ribonucleases, which will consequently lead to an innovative new therapeutic method by which proteins could reach intracellular targets.

Association of SLC22A1 rs622342 and ATM rs11212617 polymorphisms with metformin efficacy in patients with type 2 diabetes.

Metformin is the first-choice oral anti-hyperglycemic drug for type 2 diabetes mellitus (T2DM) patients. There are controversies about the association of SLC22A1 rs622342, which was not reported in the Chinese population, and ataxia-telangiectasia mutated (ATM) rs11212617 polymorphisms with metformin efficacy in T2DM. Our study was to investigate the effects of the two single nucleotide polymorphisms on the efficacy of metformin in T2DM of Han nationality in Chaoshan China. After enrollment, 82 newly diagnosed T2DM patients went on 2-month metformin monotherapy. According to BMI before treatment, the patients were divided into a normal weight group (≥18.5 and <25 kg/m2) and an overweight group (BMI ≥ 25 and <30 kg/m2). T-test, Pearson χ2 test, and regression analysis, which adjusted for age, BMI, sex, the dose of metformin, education, tea drink, smoking, and sweet, were used to evaluate the effects of rs622342 and rs11212617 on several variables, such as fasting plasma glucose (FPG). Compared with the AA or CC genotype, patients with AC genotype of rs622342 achieved greater reduction in Δ60FPG and Δ(60-30)FPG (P = 0.00820, 0.00089, respectively). For 11212617, the reduction in Δ30FPG and Δ60FPG was significantly different among patients with the AC genotype (P = 0.00026, 0.00820, respectively). Our results indicated that common variants of SLC22A1 rs622342 and ATM rs11212617 were associated with the efficacy of metformin in T2DM of Han nationality in Chaoshan China.

Chemotherapeutic potency stimulated by SNAI1-knockdown based on multifaceted nanomedicine.

Molecular insights into tumorigenesis have uncovered intimate correlation of SNAI1 with tumor malignancy. Herein, to explore merits of SNAI1-knockdown in tumor therapy, we harnessed RNA interference tool (shSNAI1), together with chemotherapeutic doxorubicin. Owing to abundant hydroxyl groups, pullulan was attempted to be covalently conjugated with a multiple of functional moieties, including positively-charged oligoethylenimine components for electrostatic entrapment of polyanionic shSNAI1 and hydrophobic components for entrapment of lipophilic doxorubicin. Notably, the aforementioned covalent conjugations were tailored to be detachable in response to intracellular reducing microenvironment owing to redox disulfide linkage, thereby accounting for selective intracellular liberation of the therapeutic payloads. Moreover, the surface of nanomedicine was modified with hyaluronic acid, endowing not only excellent biocompatibilities but active tumor-targeting function due to its receptors (CD44) overexpressed on tumor cells. Subsequent investigations approved appreciably targeted co-delivery of shSNAI1 and doxorubicin into solid lung tumors via systemic administration and demonstrated critical contribution of SNAI1-knockdown in amplifying chemotherapeutic potencies.

Bioresorbable Depot for Sustained Release of Immunostimulatory Resiquimod in Suppressing Both Primary Triple-Negative Breast Tumors and Metastatic Occurrence.

In light of immune facilities trafficking toward the pathological sites along upward gradient of immunostimulatory cytokines, a localized resiquimod (Toll-like receptor 7/8 agonist) release depot was manufactured for pursuit of precision immunostimulation toward intractable triple-negative breast carcinoma. In principle, resiquimod/poly(lactic-co-glycolic acid) microspheres were fabricated and embedded into injectable and biodegradable poly(ethylene glycol) (PEG)-based hydrogel. The subsequent investigations approved persistent retention of immunostimulatory resiquimod in tumors upon peritumoral administration, which consequently led to localized and consistent secretion of immunostimulatory cytokines. Initially, not only innate tumor phagocytosis but also adaptive antitumor immunities were successfully cultivated for in situ suppression of the growth of primary solid tumors, more importantly, capable of inhibiting distant pulmonary metastasis, as evidenced by observation of enormous lymphocytes selectively gathering in the pulmonary artery. Hence, our presented study provided an important clinical indication of using immunostimulatory drugs to activate potent innate and adaptive antitumor immunities for precision antitumor therapy. Further immunomodulatory strategies, such as checkpoint blockage and tumor immunogenicity, could also be complementary for development of advanced antitumor immunotherapeutics in treatment of a number of intractable tumors.

Synthetic infrared nano-photosensitizers with hierarchical zoom-in target-delivery functionalities for precision photodynamic therapy.

Surgical assailment at the vulnerable subcellular organelles (e.g. mitochondria) by photodynamic therapy (PDT) is perceived as the most devastating approach to eradicate the tumors. Herein, we programmed a novel near-infrared (NIR) PDT construct illustrating appreciable hierarchical zoom-in targeting scenario, namely, primary cell-level targeting to carcinoma post systemic dosage and subcellular level targeting to mitochondria. Pertaining to tumor-targeting function, charge reversal chemistry selectively responsive to acidic tumoral microenvironments (pH 6.8) was implemented as the external corona of PDT constructs. This charge transformative exterior entitled minimal biointerfacial reactions in systemic retention but intimate affinities to cytomembranes selectively in tumoral microenvironments, thereby resulting in preferential uptake by tumors. Furthermore, the proposed PDT constructs were equipped with mitochondria targeting triphenylphosphonium (TPP) motif, which appeared to propel intriguing 88% colocalization with mitochondria. Therefore, overwhelming cytotoxic potencies were accomplished by our carefully engineered photodynamic constructs. Another noteworthy is the photodynamic constructs characterized to be excited at tissue-penetrating NIR (980 nm) based on energy transfer between their internal components of anti-Stoke upconversion nanoparticles (UCN, donor) and photodynamic chlorin e6 (Ce6, acceptor). Therefore, practical applications for photodynamic treatment of intractable solid carcinoma were greatly facilitated and complete tumor eradication was achieved by systemic administration of the ultimate multifunctional NIR photodynamic constructs.

Spatiotemporal Concurrent Liberation of Cytotoxins from Dual-Prodrug Nanomedicine for Synergistic Antitumor Therapy.

Nanomedicine developed to date by means of directly encapsulating cytotoxins suffers from crucial drawbacks, including premature release and detoxification prior to arrival at pharmaceutics targets. To these respects, redox-responsive polymeric prodrugs of platinum (Pt) and camptothecin (CPT), selectively and concomitantly activated in the cytoplasm, were elaborated in manufacture of dual prodrug nanomedicine. Herein, multiple CPTs were conjugated to poly(lysine) (PLys) segments of block copolymeric poly(ethylene glycol) (PEG)-PLys through the redox responsive disulfide linkage [PEG-PLys(ss-CPT)] followed by reversible conversion of amino groups from PLys into carboxyl groups based on their reaction with cis-aconitic anhydride [PEG-PLys(ss-CPT&CAA)]. On the other hand, Pt(IV) in conjugation with dendritic polyamindoamine [(G3-PAMAM-Pt(IV)] was synthesized for electrostatic complexation with PEG-PLys(ss-CPT&CAA) into dual prodrug nanomedicine. Subsequent investigations proved that the elaborated nanomedicine could sequentially respond to intracellular chemical potentials to overcome a string of predefined biological barriers and facilitate intracellular trafficking. Notably, PEG-PLys(ss-CPT&CAA) capable of responding to the acidic endosomal microenvironment for transformation into endosome-disruptive PEG-PLys(ss-CPT), as well as release of G3-PAMAM-Pt(IV) from nanomedicine, prompted transclocation of therapeutic payloads from endosomes into cytosols. Moreover, concurrent activation and liberation of cytotoxic CPT and Pt(II) owing to their facile responsiveness to the cytoplasmic reducing microenvironment have demonstrated overwhelming cytotoxic potencies. Eventually, systemic administration of the dual prodrug construct exerted potent tumor suppression efficacy in treatment of intractable solid breast adenocarcinoma, as well as an appreciable safety profile. The present study illustrated the first example of nanomedicine with a dual prodrug motif, precisely and concomitantly activated by the same subcellular stimuli before approaching pharmaceutic action targets, thus shedding important implication in development of advanced nanomedicine to seek maximized pharmaceutic outcomes.

Camptothecin Nanoprodrug Possessing Dual Responsiveness to Endolysosomal pH and Cytosolic Redox for Amplified Cytotoxic Potency.

Selective activation of prodrug nanomedicine in cell interiors is deemed to be crucial in pursuit of precision anti-tumor therapy. In the present study, we attempted to synthesize an amphiphilic diblock copolymer poly(ethylene glycol)-polylysine (PEG-PLys) based on ring-opening polymerization. The γ terminal amines of lysine units were conjugated with camptothecin (CPT) through redox-responsive disulfide linkage, followed by conversion of the rest of the amines of PLys into carboxyl groups. Core-shell architectural nanoparticles could be achieved by self-assembly of the yielded amphiphiles characterized to possess CPT-linked PLys segments as the internal core and PEG segments as the external shell. Furthermore, attempts were made to precipitate CaPO3 on the yielded core with the aid of the carboxyl groups. Subsequent investigations confirmed uniform nanoscale formation with a hydrodynamic diameter of approximately 63.0 nm and excellent colloidal stabilities. Most importantly, the proposed dually responsive prodrug construct was determined to possess intriguing sequentially intracellular microenvironment-responsive functionalities: (1) the inorganic CaPO3 precipitate could not only exclude the internal payloads from premature reactions but also rapidly dissolve in acidic endosomal compartments, with the induced osmotic pressure thereby facilitating translocation of the prodrug into the cytosol; (2) CPT could be readily metabolized due to disulfide cleavage responsive to the redox potential in cytosolic compartments. Hence, the amalgamated dual-responsiveness eventually contributes to drastic cytotoxic potency, which portends prosperous utilities as precision therapeutics in the treatment of a variety of intractable tumors.

Mitochondria specific oxidative injury by near-infrared energy transfer nanoclusters for amplified photodynamic potency.

To promote practical applications of photodynamic therapy, near-infrared (NIR) photosensitizers are manufactured based on fluorescence resonance energy transfer (FRET) between donors of anti-stoke NIR upconversion nanoparticles and acceptors of photodynamic chlorin e6. The manufactured FRET constructs displayed deep tissue penetration and FRET activation under 980 nm irradiation. Furthermore, surface decoration with mitochondria-targeting (4-marboxybutyl) triphenyl phosphonium bromide (TPP) led to mitochondrion-targeted accumulation of singlet oxygen resulting in potent cell apoptosis. Notably, in vivo anti-tumor test validates the complete ablation of intractable solid tumors based on single-dose treatment of our proposed photodynamic constructs. Therefore, the obtained results herald the tempting perspective of our carefully engineered photodynamic constructs, which could have broad utilities in clinical treatment of intractable premalignancies.

Poly(lactobionamidoethyl methacrylate)-based amphiphiles with ultrasound-labile components in manufacture of drug delivery nanoparticulates for augmented cytotoxic efficacy to hepatocellular carcinoma.

Ultrasound-responsive chemistry was exploited in manufacture of drug delivery nanoparticulates for pursuit of on-demand ultrasound-stimulated drug release function. In principle, the ultrasound-labile oxyl-alkylhydroxylamine (-oa-) linkage was tailored between the segments of amphiphiles. Consequently, the hydrophobic chemotherapeutic doxorubicin could be readily assembled with the hydrophobic segments of amphiphiles into interior compartments, whereas the hydrophilic segments represented as the external surroundings. Upon ultrasonication, the proposed phase-segregated self-assemblies were determined to be subjected to evident structural rearrangement as a consequence of -oa- cleavage. Simultaneously, the release rate of doxorubicin payloads appeared to accelerate due to the ultrasound-induced structural destabilization, consequently eliciting potent cytotoxic efficacy at the affected cells. Another noteworthy characteristic of the proposed self-assemblies was poly (lactobionamidoethyl methacrylate) (pLAMA) as the hydrophilic components of the amphiphiles, characterized to possess galactosylated residues. In view of the specific affinity of galactosylated residues (and lactosylated residues) to asialoglycoprotein receptors (overexpressed on the surface of intractable hepatocellular carcinoma), the proposed self-assemblies were determined to impart preferential affinities to hepatocellular carcinoma. Together with the strategic ultrasound-stimulated drug release property, our proposed drug delivery system demonstrated appreciably pharmaceutical efficacy on hepatocellular carcinoma.

A red-emitting fluorescent probe with large Stokes shift for real-time tracking of cysteine over glutathione and homocysteine in living cells.

Fluorescent probes with high quality for highly selective detection of cysteine (Cys) are still urgently in demand because of the indispensable roles Cys plays in the biological systems. Herein, a red-emitting fluorescent probe CP was developed for the highly selective detection of Cys over glutathione (GSH) and homocysteine (Hcy) by incorporating acryloyl group as the recognition unit into the 2-(2-(4-hydroxystyryl)-6-methyl-4H-pyran-4-ylidene) malononitrile (P-OH) fluorophore which is characterized by red emission, noteworthy Stokes shift, and appreciable photostability. Basically, CP demonstrated appreciable sensing performance toward Cys including short response time of 4 min, high sensitivity with approximately 147-fold emission enhancement, low detection limit of 41.696 nM, and good selectivity both in the solution and living cells, indicating its promising potential of visualizing Cys in biological systems.

Integument of Cytoplasmic Membrane onto Cationic DNA Condensates for Selective Gene Expression at Homologous Cells.

The surface properties of drug/gene delivery systems are critical important to their ultimate therapeutic performance. In the present studies, cytoplasmic membranes deriving from cancerous cells (Hep-G2) were attempted as the external integument onto the polycationic theranostic DNA delivery systems with the aim of diminishing unfavorable biointerfacial reactions of nanomedicine. Herein, a multiple of polycationic oligoethylenimine (OEI) segments were installed onto the surface of luminescent carbon quantum dots (CQD, facile bioimaging utilities) for complexation with plasmid DNA (pDNA) into DNA delivery constructs, followed by surface integument by cytoplasmic membranes. The subsequent investigations verified this strategic integument capable of shielding the unfavorable surface positive net charge of the polycationic DNA delivery constructs and thereby markedly diminishing the potential nonspecific reactions in biological milieu. Leadingly, improved biocompatibilities as well as additional protection of inner vulnerable DNA cargos from enzymatic degradation, have been accomplished. More importantly, preferential affinities to the homologous cells were identified as a result of this membrane integument based on facile fluorescence quantification for the intracellular CQD. Significant higher cellular uptake efficiency for the polycationic constructs based on Hep-G2 membrane integument was confirmed in the homologous Hep-G2 cells in contrast to the heterologous MCF-7 and HeLa cells (approximately 4-fold). Note that this homologous privilege was observed for the delivery constructs not only from cancerous HeLa and MCF-7 membrane integuments but also normal cells (COS-7), heralding the intriguing potentials of this membrane-integument strategy in pursuit of targeting functions. Eventually, gene expression activities were also determined to prevail in the homologous cells. Therefore, our proposed surface integument strategy by homologous cell membrane could imply an alternative facile and versatile avenue in construction of active-targeted nanomedicine.

Ultrasound-Responsive Nanoparticulate for Selective Amplification of Chemotherapeutic Potency for Ablation of Solid Tumors.

Precision medicine requests preferential transportation of the pharmaceutical substances to the pathological site and impartation of localized therapeutic activities to the targeted cells. To accomplish this goal, we attempted a facile nanoscaled ultrasound-responsive delivery system, characterized by doxorubicin assembled with an amphiphilic copolymer (multiple of hydrophobic stearic segments tethered onto the hydrophilic pullulan backbone through ultrasound-labile oxyl-alkylhydroxylamine linkage). As a consequence of the strategically installed ultrasound-labile oxyl-alkylhydroxylamine linkage to elicit the tailored segregation of the hydrophilic pullulan and the hydrophobic stearic segments upon ultrasound impetus, the constructed nanoscaled self-assembly presented distinctive structural destabilization behaviors and afforded spatiotemporal controlled liberation of the cytotoxic drugs. It is worthy to note that the ultrasound was determined to markedly lower the IC50 of the proposed system from over 10 µg/mL to 2.33 µg/mL (approximate 4-fold), thereby serving as a facile impetus to amplify the cytotoxic potency of the proposed drug delivery vehicles. Furthermore, drastic tumor ablation was validated by dosage of the proposed doxorubicin delivery system to T41 tumor-bearing mice accompanied by the tumor-localized ultrasound impetus, while no observable adverse side effect was confirmed. Therefore, the results advocated our ultrasound-responsive delivery vehicle as a tempting strategy for precise spatiotemporal control of the release of the drug cargo, thus affording selectively amplified cytotoxic potency to the ultrasound-imposed site, which should be highlighted as important progress toward precision medicine.

A NIR fluorescent probe for the detection and visualization of hydrogen sulfide using the aldehyde group assisted thiolysis of dinitrophenyl ether strategy.

In view of the significant physiological and pathological roles H2S plays in living systems, it is crucial to develop fluorescent probes for H2S detection with high sensitivity and good selectivity. Herein, a novel NIR fluorescent probe NDCM-2 based on the dicyanoisophorone derivative was designed and synthesized by employing ortho-aldehyde assisted thiolysis of 2,4-dinitrophenyl (DNP) ether as the sensing strategy to achieve highly specific H2S detection in living systems. The studies demonstrated that probe NDCM-2 exhibited excellent sensing performance toward H2S with 160-fold NIR fluorescence enhancement, a rapid response within 15 min, excellent sensitivity with a detection limit of 58.797 nM, a large Stokes shift of 170 nm and good selectivity. In light of these unique properties, NDCM-2 has been successfully applied for the fluorescence imaging of H2S in biological systems (living cells, tissues and mice), demonstrating that it would be an effective tool for H2S detection in living systems.

Co-delivery of doxorubicin and shRNA of Beclin1 by folate receptor targeted pullulan-based multifunctional nanomicelles for combinational cancer therapy.

Doxorubicin (DOX) is a widely-used effective antitumor agent. However, its clinical application is limited due to its side effects including anti-apoptotic defense of cancer cells caused by DOX-induced autophagy and deleterious effects in normal tissues. Therefore, in this study, a new folate (FA)-decorated amphiphilic bifunctional pullulan-based copolymer (named as FPDP) was developed as an efficient nano-carrier for the co-delivery of DOX and short hairpin RNA of Beclin1, a pivotal autophage-related gene, to enhance the anticancer effect of DOX by the blockade of the Beclin1 protein mediated autophagy process. In FPDP molecules, pullulan was modified with lipophilic desoxycholic acid for the formation of micelles, the introduced low molecular weight (1 kDa) branched polyethylenimine (PEI) was for shBeclin1 delivery, and folate (FA) was employed as the tumor-targeting group. FPDP micelles demonstrated an average diameter of 161.9 nm, good biocompatibility, applicable storage stability, excellent loading capacities for both DOX and shBeclin1 and a sustained drug release profile. In vitro cell culture experiments demonstrated that the uptake amount of FPDP/DOX micelles in folate receptor positive (FR+) HeLa cells was more than that in folate receptor negative (FR-) HepG2 cells, leading to significantly higher cytotoxicity against FR+ HeLa cells. The simultaneous co-delivery of shBeclin1 and DOX to HeLa cells with FPDP micelles led to efficient reduction in the expression level of Beclin1 as well as synergistic cell apoptotic induction. Furthermore, in vivo studies revealed superior antitumor efficacy of tumor-targeted FPDP/DOX/shBeclin1 in comparison with non-FR-targeted PDP micelles and free DOX. These results highlighted that co-delivery of DOX and shRNA of Beclin1 with FPDP micelles has the potential to overcome the limitations of DOX in clinical cancer therapy.