The Preliminary Study on the Association Between PAHs and Air Pollutants and Microbiota Diversity.

The purpose of this study was to investigate the association among polycyclic aromatic hydrocarbons (PAHs) exposure and air pollutants and the diversity of microbiota. Daily average concentrations of six common air pollutants were obtained from China National Environmental Monitoring Centre. The PAHs exposure levels were evaluated by external and internal exposure detection methods, including monitoring atmospheric PAHs and urinary hydroxyl-polycyclic aromatic hydrocarbon (OH-PAH) metabolite levels. We analyzed the diversity of environmental and commensal bacterial communities with 16S rRNA gene sequencing and performed functional enrichment with Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Correlation analysis and logistic regression modeling were conducted to evaluate the relationship of PAHs levels with air pollutants and microbial diversity. Correlation analysis found that the concentrations of atmospheric PAHs were significantly positively correlated with those of PM10, NO2, and SO2. There also was a positive correlation between the abundance of the genus Micrococcus (Actinobacteria) and high molecular weight PAHs, and Bacillus, such as genera and low molecular weight PAHs in the atmosphere. Logistic regression showed that the level of urinary 1-OHPyrene was associated with childhood asthma after sex and age adjustment. The level of urinary 1-OHPyrene was significantly positively correlated with that of PM2.5 and PM10. In addition, the level of 1-OHPyrene was positively correlated with oral Prevotella-7 abundance. Functional enrichment analysis demonstrated that PAHs exposure may disturb signaling pathways by the imbalance of commensal microbiota, such as purine metabolism, pyrimidine metabolites, lipid metabolism, and one carbon pool by folate, which may contribute to public health issues. Our results confirmed that atmospheric PAHs and urinary 1-OHPyrene were correlated with part of six common air pollutants and indicated that PAHs pollution may alter both environmental and commensal microbiota communities associated with health-related problems. The potential health and environmental impacts of PAHs should be further explored.

Microbial contributions to bronchial asthma occurrence in children: A metagenomic study.

Bronchial asthma, a common chronic respiratory disease in children, is traditionally regarded as a noninfectious disease. Current hypotheses, however, argue that asthma can be caused by microbial infection. We, therefore, hypothesize that a variety of microbes are more commonly found in the sputum of children with asthma, and these microbes may contribute to the occurrence and development of asthma. The present study proposes to use metagenomic approach to explore microbial diversity and to identify the microbial community characteristics of sputum from children with asthma. We found that microbial communities in the sputum of children differed significantly between asthmatics and controls. Kruskal-Wallis testing showed that 16 phyla, 104 genera, and 159 species were significantly downregulated, whereas two phyla including Platyhelminthes phylum and Chordata phylum, two genera including Spirometra genus and Homo sapiens, and the Spirometra erinaceieuropaei species were significantly upregulated in asthma patients compared with controls (P < 0.05). Among them, H. sapiens and S. erinaceieuropaei exhibited 2.3- and 2.0-fold overabundance in asthmatics vs controls, respectively. Meanwhile, metastats assay demonstrated that 31 phyla, 400 genera, and 813 species were significantly downregulated, whereas two phyla, 10 genera, and 16 species were significantly upregulated in asthma patients compared with controls (P < 0.05). Among them, Tetrahymena thermophila and Candidatus Zinderia insecticola exhibited 4.7-fold overabundance in asthmatics vs controls. Our study establishes a link between microbial infection and the mechanisms leading to asthma development, which will be useful for developing novel diagnostic biomarkers and aiding in the prevention and control of asthma.

D-α-tocopherol polyethylene glycol succinate-based redox-sensitive paclitaxel prodrug for overcoming multidrug resistance in cancer cells.

To overcome the multidrug resistance (MDR) of P-glycoprotein (P-gp) substrate anticancer drugs, such as paclitaxel (PTX), a novel dual-functional prodrug, D-α-tocopherol polyethylene glycol succinate (TPGS) based PTX prodrug (TPGS-S-S-PTX), was synthesized here to fulfill the synergistic effect of P-gp inhibiting and intracellular redox-sensitive release. The prodrug could self-assemble into stable micelles in physiological environment with a diameter of ∼140 nm, while it disassociated in reductive condition and released PTX and TPGS active derivatives rapidly. High cell cytotoxicity in PTX-resistant human ovarian cell line A2780/T was observed with enhanced PTX accumulation due to the P-gp inhibition by the TPGS moiety. The IC50 of TPGS-S-S-PTX was 55% and 91% more effective than that of Taxol (clinical formulation of PTX) and uncleavable TPGS-C-C-PTX prodrug, respectively. This was found to be related with the increased apoptosis/necrosis and cell arrest in G2/M phase. In vivo evaluation of the TPGS-S-S-PTX prodrug exhibited an extended half-life, increased AUC (area under the concentration-time curve), enhanced tumor distribution and significant tumor growth inhibition with reduced side effects as compared to Taxol and TPGS-C-C-PTX. This prodrug has great potential in improving efficiency in the treatment of MDR tumors.

The investigation of the role of oral-originated Prevotella-induced inflammation in childhood asthma.

Background and objectives: The oral and gut microbiota play significant roles in childhood asthma pathogenesis. However, the communication dynamics and pathogenic mechanisms by which oral microbiota influence gut microbiota and disease development remain incompletely understood. This study investigated potential mechanisms by which oral-originated gut microbiota, specifically Prevotella genus, may contribute to childhood asthma etiology. Methods: Oral swab and fecal samples from 30 asthmatic children and 30 healthy controls were collected. Microbiome composition was characterized using 16S rRNA gene sequencing and metagenomics. Genetic distances identified potential oral-originated bacteria in asthmatic children. Functional validation assessed pro-inflammatory properties of in silico predicted microbial mimicry peptides from enriched asthma-associated species. Fecal metabolome profiling combined with metagenomic correlations explored links between gut microbiota and metabolism. HBE cells treated with Prevotella bivia culture supernatant were analyzed for lipid pathway impacts using UPLC-MS/MS. Results: Children with asthma exhibited distinct oral and gut microbiota structures. Prevotella bivia, P. disiens, P. oris and Bacteroides fragilis were enriched orally and intestinally in asthmatics, while Streptococcus thermophilus decreased. P. bivia, P. disiens and P. oris in asthmatic gut likely originated orally. Microbial peptides induced inflammatory cytokines from immune cells. Aberrant lipid pathways characterized asthmatic children. P. bivia increased pro-inflammatory and decreased anti-inflammatory lipid metabolites in HBE cells. Conclusion: This study provides evidence of Prevotella transfer from oral to gut microbiota in childhood asthma. Prevotella's microbial mimicry peptides and effects on lipid metabolism contribute to disease pathogenesis by eliciting immune responses. Findings offer mechanistic insights into oral-gut connections in childhood asthma etiology.

A Nomogram Model for Stratifying the Risk of Recurrence in Patients with Meningioma After Surgery.

BACKGROUND: Here, we aimed to investigate the clinical parameters affecting the recurrence of meningiomas, and to construct a predictive nomogram model, so as to predict the recurrence-free survival (RFS) of meningiomas more accurately. METHODS: The Clinical, imaging, and pathological data of 155 primary meningioma patients treated surgically from January 2014 to March 2021 were retrospectively analyzed. Independent prognostic factors affecting postoperative recurrence of meningioma were identified by univariate and multivariate Cox regression analyses. A predictive nomogram was established based on independent influence parameters. Subsequently, time-dependent receiver operating characteristic curve, calibration curve, and Kaplan-Meier method were utilized to evaluate the predictive ability of the model. RESULTS: The multivariate Cox regression analysis showed that tumor size, Ki-67 index, and resection extent had independent prognostic significance, and these parameters were subsequently used to construct a predictive nomogram. Receiver operating characteristic curves indicated that the model was more accurate in predicting RFS than independent factors. Calibration curves suggested that the predicted RFS were similar to the actual observed RFS. In the Kaplan-Meier analysis, the RFS of high-risk cases was obviously shorter than that of low-risk cases. CONCLUSIONS: The tumor size, Ki-67 index, and extent of resection were independent factors affecting the RFS of meningioma. The predictive nomogram based on these factors can be used as an effective method to stratify the recurrence risk of meningioma and provide a reference for patients to choose personalized treatment.

PAH-induced metabolic changes related to inflammation in childhood asthma.

Epidemiological studies have shown that PAHs may exert adverse effects on childhood asthma. However, the underlying molecular mechanism remains to be fully elucidated. This study aimed to investigate this process in view of metabolic pathways, especially one-carbon metabolism and tryptophan metabolism. Fifty asthmatic children and 50 control subjects were recruited for this study. Serum IgE and IL-17A levels were detected by ELISA. Serum PAH concentrations were measured by GC-MS. One-carbon-related metabolites and tryptophan metabolites were determined by UPLC-Orbitrap-MS. DNA methylation was analyzed by bisulfite sequencing PCR. ChIP assays were used to examine H3K4me3 enrichment on IL-17A gene. Multivariable linear regression was performed to evaluate the association between PAHs and childhood asthma mediated by intermediators. HE staining in lung tissue, IgE and IL-17A in BALF, metabolic profiles in urine, and Ahr, Il-17a, and Cyp1a1 gene expression were determined in PAH-exposed mice. Serum Fla level was associated with childhood asthma (OR = 1.380, 95% CI: 1.063-1.792), and had a great effect on one-carbon metabolites, especially SAH, SAM, and Ser, which exerted significant mediation effects on the relationship between the Fla concentration and asthma. Moreover, we did find significant mediation effects between serum Fla and asthma by LINE-1 DNA methylation and H3K4me3 levels in the IL-17A promoter region. The differential Trp metabolites, such as Trp, tryptamine, IA, IAA, indole, IAld, and IAAld, indicated that asthmatic children had increased indole-AhR pathway. Mediation analysis failed to show a mediator effect of Trp metabolites in the association between PAHs and childhood asthma. An animal study confirmed that PAH exposure increased methylation levels, and altered Trp metabolite-AhR-IL-17A axis, which may be influenced by gender. PAHs disturbed one-carbon metabolism to influence the methyl group refilling DNA methylation and histone methylation, and disturbed tryptophan metabolism to regulate Th17-cell differentiation, which may elevate serum IL-17A concentration in asthmatic children.

The preliminary investigation of potential response biomarkers to PAHs exposure on childhood asthma.

BACKGROUND: Exposure to polycyclic aromatic hydrocarbons (PAHs) is a potential risk factor for asthma prevalence. This study aims to explore whether PAHs exposure is associated with childhood asthma by altering microbial diversity and metabolic profiles. METHODS: Thirty children with asthma and 30 children as control in Nanjing, China were recruited. Urinary 1-hydroxypyrene (1-OHPyr) level was determined by UPLC-Orbitrap-MS as a PAHs exposure biomarker. Logistic regression was conducted to investigate the association between 1-OHPyr and childhood asthma. Microbial diversity was analyzed by 16S rRNA gene sequencing. Metabolic profiles were obtained by UPLC-Orbitrap-MS methods. Differential microbiota and metabolites were screened and selected as response biomarkers or intermediates. Mediation analysis was conducted to assess the association between PAHs and asthma mediated by intermediates. RESULTS: Participating children with and without asthma aged 6.43 ± 2.23 years. The urinary 1-OHPyr level ranged from 0.10 to 1.51 µmol/mol (creatinine corrected) in the participants. The urinary 1-OHPyr level was associated with childhood asthma (OR = 7.21, 95% CI: 1.03-50.42 per 1 µmol/mol unit). Microbial diversity was decreased in the group with asthma and there was a significant shift in the abundance of Proteobacteria (at the phylum level), Veillonella and Prevotella (at the genus level). The enrichment pathway analysis showed that differentially expressed metabolites were involved in purine metabolism, amino acid metabolism, and lipid and fatty acid metabolism. The urinary 1-OHPyr level was associated with the abundance of Actinomyces sp. oral clone IO076 and 7-methylguanine that showed a mediation effect on the association between urinary 1-OHPyr levels and childhood asthma by mediation analysis. CONCLUSIONS: Urinary 1-OHPyr exposure was associated with childhood asthma, microbial diversity, and metabolic profiles. Microbial diversity and metabolic profiles may be intermediates as response biomarkers to PAHs exposure in childhood asthma. Further research is needed to confirm these study results and determine the underlying mechanism.

Chemo-immunotherapy with doxorubicin prodrug and erythrocyte membrane-enveloped polymer nano-vaccine enhances antitumor activity.

There are plenty of evidences to show that combining of chemotherapy and immunotherapy should be a very potent anti-cancer therapeutic method. In this research, we evaluated the anti-tumor activity of doxorubicin prodrug combined with erythrocyte membrane-enveloped polymer nano-vaccine against tumor in vitro and in vivo. We also analyzed the immune cell populations to investigate the effect in the tumor microenvironment and explored the inhibitory of lung metastasis. Our study showed that chemo-immunotherapy could inhibit the growth of melanoma tumor in mice. This combination approach promoted a stronger immune response by up-regulating the expression of dendritic cells and cytotoxic T cells in lymph nodes and increased the secretion of cytokines. It also restricted the immunosuppressive environment through inhibiting expression of regulatory T cells. It suggested that combination of prodrug and nano-vaccine achieved better anti-tumor effect than monotherapy, which should be widely valued and further studied to establish in a more economical and efficient way, expected to apply in the future clinical practice of cancer treatment.

Recent Advances of D-α-tocopherol Polyethylene Glycol 1000 Succinate Based Stimuli-responsive Nanomedicine for Cancer Treatment.

D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) is a pharmaceutical excipient approved by Chinese NMPA and FDA of USA. It's widely applied as a multifunctional drug carrier for nanomedicine. The advantages of TPGS include P-glycoprotein (P-gp) inhibition, penetration promotion, apoptosis induction via mitochondrial-associated apoptotic pathways, multidrug resistant (MDR) reversion, metastasis inhibition and so on. TPGS-based drug delivery systems which are responding to external stimulus can combine the inhibitory functions of TPGS towards P-gp with the environmentally responsive controlled release property and thus exerts a synergistic anti-cancer effect, through increased intracellular drug concentration in tumors cells and well-controlled drug release behavior. In this review, TPGS-based nano-sized delivery systems responsive to different stimuli were summarized and discussed, including pH-responsive, redoxresponsive and multi-responsive systems in various formulations. The achievements, mechanisms and different characteristics of TPGS-based stimuli-responsive drug-delivery systems in tumor therapy were also outlined.

Immunoregulatory Effects of Subcutaneous Immunotherapy on Lymphocyte Subgroups and Cytokines in Children with Asthma.

OBJECTIVE: Asthma is a syndrome that incorporates many immune phenotypes. The immunologic effects of subcutaneous immunotherapy (SCIT) exerts on allergic asthma remain still largely unknown. Here, we investigated the effects of SCIT on cytokine production and peripheral blood levels of lymphocyte subtypes in children with mite-induced moderate and severe allergic asthma. METHODS: The study included 60 kids with mite-induced allergic asthma from 5 to 10 years old. All subjects had received antiasthmatic pharmacologic for 3 months at baseline. Half of the children were treated with SCIT combined with pharmacologic treatment named the SCIT group and the other half only with pharmacologic therapy named the no-SCIT group. Total asthma symptom score (TASS) and total medication score (TMS) were recorded. Flow cytometry was used to identify lymphocyte subtypes: type 2 innate lymphocytes (ILC2s), type 1 (Th1) and type 2 (Th2) helper T cells, T helper 17 (Th17) cells, and regulatory T (Treg) cells. ELISA, flow cytometry, and cytometric bead array were used to assess cytokines IL-13, IFN-γ, IL-4, IL-17, and TGF-ß, at baseline and 3 and 6 months after study treatment in both groups of patients. RESULTS: Both groups can significantly improve clinical symptoms in children with asthma. SCIT can significantly reduce asthma medication after 6 months of treatment. SCIT induced a significantly higher and progressive reduction in ILC2 percentage and IL-13 levels after 3 and 6 months of treatment compared with baseline and compared with no-SCIT patients. Significant differences were detected in the Th1/Th2 cell ratio and IFN-γ/IL-4 cytokine ratio between groups after 6 months of treatment. Similarly, the Th17/Treg ratio and IL-17/TGF-ß ratio in the SCIT group were much lower than those in the no-SCIT group after 3-6 months of treatment. CONCLUSION: SCIT is a promising option to reduce the percentage of ILC2 and regulate Th1/Th2 and Th17/Treg immune balance in the peripheral blood of children with asthma.

pH-sensitive micelles with charge-reversible property for tumor growth inhibition and anti-metastasis.

Physical properties, such as surface charge, of nanomedicines play a crucial role in their in vivo behaviors, which could eventually determine the tumor inhibition effect. Although drug delivery systems with positive charge are effective for cell internalization, this property is universally applicable to the lack of selectivity of both tumors and normal tissues, resulting in rapid blood clearance and undesired side effects. By employing charge-reversible strategies, the dilemma can be overcome and enhanced cellular uptake, prolonged circulation time and high biocompatibility can be realized. Here, we constructed Vitamin E-based micelles with charge-reversible property for the delivery of the antineoplastic agent paclitaxel. In the slightly acidic tumor microenvironment, the micelles converted from negative to positive charge due to the cleavage of the pH-sensitive bond, leading to enhanced cellular uptake and subsequently enhanced drug release. The micelles demonstrated improved antitumor efficiency both in vitro and in vivo and improved anti-metastasis effect in 4T1 orthotopic tumor model compared with those of clinically formulated Taxol and non-sensitive micelles. Besides, the micelles showed high biocompatibility and reduced side effects. Overall, these findings highlight that the micelles with charge-reversible property have great potential for cancer therapy in clinic.

Nanotechnology based therapeutic modality to boost anti-tumor immunity and collapse tumor defense.

Cancer is still the leading cause of death. While traditional treatments such as surgery, chemotherapy and radiotherapy play dominating roles, recent breakthroughs in cancer immunotherapy indicate that the influence of immune system on cancer development is virtually beyond our expectation. Manipulating the immune system to fight against cancer has been thriving in recent years. Further understanding of tumor anatomy provides opportunities to put a brake on immunosuppression by overcoming tumor intrinsic resistance or modulating tumor microenvironment. Nanotechnology which provides versatile engineered approaches to enhance therapeutic effects may potentially contribute to the development of future cancer treatment modality. In this review, we will focus on the application of nanotechnology both in boosting anti-tumor immunity and collapsing tumor defense.

Enhanced tumor therapy via drug co-delivery and in situ vascular-promoting strategy.

Conventional tumor starving therapy by reducing its vessel density may be effective at early treatment but potentially contributes to tumor hypoxia, drug resistance and metastasis. A new strategy through enhancing tumor angiogenesis in combination with effective chemotherapeutic drugs, has shown successful tumor growth and spread inhibition. To achieve in situ release of angiogenic and antitumor drugs in tumor, we designed a precise ratiometric polymeric hybrid micelle system for co-delivering nitric oxide and paclitaxel. The hybrid micelles could accumulate in tumor via the long blood circulation and enhanced permeability and retention (EPR) effect, promote the drug accumulation and penetration in tumor by in situ increased vascular permeability, blood perfusion and vessel density, achieve the synergistic antitumor effect of nitric oxide and paclitaxel through modified tumor microenvironment, overcome multidrug resistance and inhibit metastasis. This study presents a combinational therapy against tumor progression and spread, which shows great potential in cancer therapy of the future.

Redox/pH dual-sensitive hybrid micelles for targeting delivery and overcoming multidrug resistance of cancer.

A redox/pH dual-sensitive graft copolymer, poly(ß-amino ester)-g-d-α-tocopherol polyethylene glycol succinate (PBAE-g-TPGS), was synthesized through a Michael-type step polymerization using disulfide linkage-containing TPGS macromonomers. Pluronic F127 (F127) and folate-F127 conjugation were introduced to prepare paclitaxel (PTX)-loaded hybrid micelles to improve their biocompatibility and serum stability and also to achieve targeted delivery. The hybrid micelles exhibited in vitro redox/pH-sensitive PTX release, enhanced cellular uptake through receptor-mediated endocytosis, and strengthened anticancer activities in both the drug-sensitive human breast cancer MCF-7 and drug-resistant MCF-7/ADR cells. P-Glycoprotein inhibition by TPGS and folate-mediated targeted delivery helped overcome multidrug resistance (MDR) and increase the therapeutic efficiency of the drug, leading to good anticancer effects in the MCF-7/ADR xenograft model. Overall, the folate-modified redox/pH-sensitive hybrid micelles provided a three-step approach to enhance anticancer activities via targeted delivery, controlled release, and depressed drug efflux; thus, these micelles may be a powerful weapon against MDR cancers in the future.

Sputum metabolomic profiling of bronchial asthma based on quadruple time-of-flight mass spectrometry.

To improve diagnosis of asthma, we tend to confirm potential biomarkers by comparing sputum metabolome profiles between asthma patients and healthy controls, using ultra-high-performance liquid chromatography coupled to quadruple time-of-flight mass spectrometry (UHPLC-QTOF/MS). Thirty endogenous metabolites contributing to the separation of asthma patients and healthy controls were tentatively identified in positive mode, such as 1-hexadecanoyl-sn-glycerol, glycerol 1-stearate, sphingosine, Phe-Ser, Tyr-Ala and Phe-Gln, and 12 endogenous metabolites were identified in negative mode, such as cytidine 2',3'-cyclic phosphate, 1-hexadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phospho-(1'-rac-glycerol), 1-octadecanoyl-2-(9Z-octadecenoyl)-sn-glycero-3-phosphoserine, thymidine, gamma-L-glutamyl-L-valine and adenine. Those differential metabolites were mainly participatedin glycerophospholipid metabolism, retrograde endocannabinoid signaling and metabolic pathways in positive mode and 2-oxocarboxylic acid metabolism, biosynthesis of amino acids, phenylalanine, tyrosine and tryptophan biosynthesis, valine, leucine and isoleucine degradation and metabolic pathways in negative mode. Importantly, several metabolic pathways including glycerophospholipid metabolism, inositol phosphate metabolism, and glycolysis or gluconeogenesis were found most important. These findings suggest sputum metabolomics can be used for the early diagnosis and risk prediction of asthma.

A novel paclitaxel-loaded poly(d,l-lactide-co-glycolide)-Tween 80 copolymer nanoparticle overcoming multidrug resistance for lung cancer treatment.

Drug resistance has become a main obstacle for the effective treatment of lung cancer. To address this problem, a novel biocompatible nanoscale package, poly(d,l-lactide-co-glycolide)-Tween 80, was designed and synthesized to overcome paclitaxel (PTX) resistance in a PTX-resistant human lung cancer cell line. The poly(d,l-lactide-co-glycolide) (PLGA)-Tween 80 nanoparticles (NPs) could efficiently load PTX and release the drug gradually. There was an increased level of uptake of PLGA-Tween 80 in PTX-resistant lung cancer cell line A549/T, which achieved a significantly higher level of cytotoxicity than both PLGA NP formulation and Taxol(®). The in vivo antitumor efficacy also showed that PLGA-Tween 80 NP was more effective than Taxol(®), indicating that PLGA-Tween 80 copolymer was a promising carrier for PTX in resistant lung cancer.

A safe, simple and efficient doxorubicin prodrug hybrid micelle for overcoming tumor multidrug resistance and targeting delivery.

A pH-sensitive prodrug, TPGS-CHN-DOX, was introduced by conjugating anticancer drug, doxorubicin (DOX), onto d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) via a cleavable Schiff base linkage. The prodrug was mixed with a PEGylated lipid to form a simple but multifunctional hybrid micelle system, which can realize high drug loading capability and biocompatibility, extended blood circulation time, inhibited drug resistance in cancer cells, improved therapeutic response, reduced side effects, and easy functionalities for targeting delivery. The hybrid micelles exhibited in vitro pH-sensitive drug release, enhanced cellular uptake and strengthened cytotoxicity on both drug-sensitive human breast cancer MCF-7 and resistant MCF-7/ADR cells. P-glycoprotein functional inhibition and mitochondria-associated cell apoptosis induced by TPGS were thought to play an important role in overcoming the multidrug resistance. As a result, the hybrid micelles demonstrated good anticancer efficacy in MCF-7/ADR xenograft model. Additionally, after modifying with a tumor-specific targeting peptic ligand, cRGD, the tumor growth/metastasis inhibition was further evidenced in integrin receptor overexpressed melanoma cancer B16F10 and even murine hepatocarcinoma H22 models. This TPGS-based pH-sensitive prodrug provides a safe and "Molecular economical" way in the rational design of prodrugs for overcoming multidrug resistance and targeting delivery, which can improve the potency for clinical use.

RGD-decorated redox-responsive d-α-tocopherol polyethylene glycol succinate-poly(lactide) nanoparticles for targeted drug delivery.

Developing multifunctional nanoparticles (NPs) to improve therapeutic efficacy is highly desirable in cancer therapy. In an attempt to respond to such a challenge, a novel copolymer, d-α-tocopherol polyethylene glycol succinate-SS-poly(lactide) (TPGS-SS-PLA) with a disulfide linkage between the TPGS and PLA units, was synthesized for paclitaxel (PTX) delivery. PTX-loaded NPs were fabricated using a nanoprecipitation method to form a particle size of ∼130 nm with good in vitro stability, which can be disassociated under intracellular reductive conditions to release PTX rapidly. The detached TPGS can further promote the drug retention and cytotoxicity through its P-glycoprotein inhibiting property. Integrin-specific targeting peptide, cyclic RGD (cRGD), was further conjugated to the surface of the NPs for targeting the drug delivery. The RGD-decorated NPs exhibited enhanced cellular uptake, PTX accumulation and cell cytotoxicity as compared to non-targeted NPs on murine melanoma B16F10 cells, PTX-sensitive human ovarian A2780 cells and PTX-resistant A2780/T cells. In vivo evaluation of the targeted NPs further showed an extended half-life, increased AUC (area under the concentration-time curve), and significant tumor growth inhibition in mouse sarcoma S180- and B16F10-tumor bearing mice, with reduced side effects as compared to Taxol® and non-targeted NPs. These results indicate that the RGD decorated redox-sensitive NPs could deliver chemotherapies specifically inside the cell via receptor-mediated endocytosis with enhanced efficacy, especially in integrin αvß3/αvß5-rich tumor cells. Such a targeted nanocarrier against receptor clustering prepared from a non-cytotoxic and biodegradable copolymer might have great potential in cancer treatment.

Lipid-enveloped zinc phosphate hybrid nanoparticles for codelivery of H-2K(b) and H-2D(b)-restricted antigenic peptides and monophosphoryl lipid A to induce antitumor immunity against melanoma.

Nanoimmunotherapy, the application of nanotechnology for sustained and targeted delivery of antigens to dendritic cells (DCs), has attracted much attention in stimulating antigen-specific immune response for antitumor therapy. In order to in situ deliver antigens to DCs for efficient antigen presentation and subsequent induction of strong cytotoxic T lymphocytes (CTL) response, here we developed a multi-peptide (TRP2180-188 and HGP10025-33) and toll-like receptor 4 agonist (monophosphoryl lipid A) codelivery system based on lipid-coated zinc phosphate hybrid nanoparticles (LZnP NPs). This delivery system equips with the chelating property of zinc to realize the high encapsulation efficiency with antigenic peptides and the influence on immune system with adjuvant-like feature. The combination of H-2K(b) and H-2D(b)-restricted peptides could provide multiple epitopes as the target of specific MHC alleles, making tumor more difficult to escape from the surveillance of immune system. The formulated LZnP nano-vaccine with the size of 30nm and outer leaflet lipid exhibited antitumor immunity as the secretion of cytokines in vitro and increased CD8(+) T cell response from IFN-γ ELISPOT analysis ex vivo. The antitumor effects were further evidenced from the prophylactic, therapeutic and metastatic melanoma tumor models compared with free antigens and single peptide-loaded nano-vaccines. These results validate the benefit of LZnP-based vaccine for antitumor immunity and indicate that co-delivery of tumor antigens along with adjuvant may be an optimized strategy for tumor immunotherapy.