Highlights on mechanisms of drugs targeting MDSCs: providing a novel perspective on cancer treatment.

The hallmark of tumor microenvironment is that it makes up of numerous immunomodulatory cells and factors which exert essential roles in immunoprotection and immunosuppression in addition to tumor cells. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells reported to promote immunosuppression and angiogenesis and facilitate tumor metastasis and invasion. The wide scope of MDSCs functional activities make these cells promising targets for effective cancer treatments. In this review, we briefly discuss the origin, subpopulation, and functions of MDSCs, as well as the potential to target these cells for therapeutic benefit. We focus on the underlying molecular mechanisms of these drugs targeting MDSCs, mainly from the standpoint of molecules related to drug targets.

Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer.

Myeloid-derived suppressor cells (MDSCs) represent heterogeneous immunosuppressive cells in multiple cancer types and display potent immunosuppressive activity on T cells. We have shown the increased expression of IDO in breast cancer. Because IDO plays a pivotal role in immune tolerance via suppressing T cell function, the aim of this study was to investigate the expression of IDO in MDSCs in breast cancer and its role in MDSC-mediated inhibition of immune surveillance. The proportion of MDSCs with the phenotype of CD45(+)CD13(+)CD33(+)CD14(-)CD15(-) significantly increased in primary cancer tissues and patients' peripheral blood. IDO expression was significantly upregulated in MDSCs isolated from fresh breast cancer tissues (fresh MDSCs [fMDSCs]), which correlated with increased infiltration of Foxp3(+) regulatory T cells in tumors and lymph node metastasis in patients. fMDSCs inhibited IL-2 and anti-CD3/CD28 mAb-induced T cell amplification and Th1 polarization but stimulated apoptosis in T cells in an IDO-dependent manner. CD33(+) progenitors isolated from healthy donors' umbilical cord blood were cocultured with breast cancer cell line MDA-MB-231 cells to induce MDSCs. IDO expression was upregulated in induced MDSCs, which required phosphorylation of STAT3, but not STAT1. IDO was required for induced MDSCs' immunosuppressive activity on T cells, which was blocked by IDO inhibitor 1-methyl-L-tryptophan or STAT3 antagonist JSI-124. Consistently, increased STAT3 phosphorylation level was found in fMDSCs. Together, our findings suggest that STAT3-dependent IDO expression mediates immunosuppressive effects of MDSCs in breast cancer. Thus, inhibition of MDSC-induced T cell suppression by blocking IDO may represent a previously unrecognized mechanism underlying immunotherapy for breast cancer.

A randomized phase II study of autologous cytokine-induced killer cells in treatment of hepatocellular carcinoma.

PURPOSE: This prospective study aims to explore the benefit of cytokine-induced killer cell (CIK) treatment in hepatocellular carcinoma patients, which has not yet been thoroughly studied before. METHODS: From January 2004 to May 2009, 132 patients who were initially diagnosed with hepatocellular carcinoma of Barcelona Clinic Liver Cancer (BCLC) stage A, B or C, Child-Pugh scores of A or B and without prior treatment were enrolled in the study. Patients were randomly assigned to either arm 1 (n = 66) to receive CIK treatment plus standard treatment, or arm 2 (n = 66) to receive standard treatment only. The primary end point was overall survival (OS) and the secondary endpoint was progression-free survival as evaluated by Kaplan-Meier analyses and treatment hazard ratios with the Cox proportional hazards model. RESULTS: The 1-year (OS: 74.2% vs. 50.0%, 95% CI: 63.6-84.8% vs. 37.8-62.2, p = 0.002), 2-year (OS: 53.0% vs. 30.3%, 95% CI: 40.8-65.2% vs. 19.1-41.5%, p = 0.002), 3-year (OS: 42.4% vs. 24.2%, 95% CI: 30.4-54.4% vs. 13.8-34.6%, p = 0.005) and median overall and progression-free survivals of arm 1 patients were significantly higher than those of arm 2. Therefore, in patients who are not suitable for surgery, significant benefit is obtained from CIK treatment. The main adverse effects of CIK included fever, allergy and headache pain. CONCLUSIONS: Hepatocellular carcinoma patients who were not suitable for surgery demonstrate prolonged overall and progression-free survival from CIK treatment.

Telomeres and telomerase in T cells of tumor immunity.

Telomeres are specific nucleoprotein structures at the end of a eukaryotic chromosomes characterized by repeats of the sequence TTAGGG and regulated by the enzyme telomerase which prevents their degradation, loss, rearrangement and end-to-end fusion. During activation, T lymphocytes actively divide, albeit through only a finite number of cell divisions due to shortening of telomeres. However, studies have demonstrated that human telomerase reverse transcriptase (hTERT), thought to be the major component regulating telomerase activity, can enhance the proliferation of T cells when overexpressed. There are many treatments for cancers, most of which are targeting the telomere and telomerase of tumor cells. However, the hTERT-transduced T cells improve their potential for proliferation, making them an appropriate cell resource for tumor adoptive immunotherapy, a procedure whereby T cells are isolated from patients, expanded ex vivo and eventually delivered back into the patients, provides a new approach for tumor therapy through improved overall survival rates in cancer patients. In this review, we will focus on the telomerase activity in T cells, the regulation of telomerase activity, and hTERT-transduced T cells used in adoptive immunotherapy for cancer.

Can the dual-functional capability of CIK cells be used to improve antitumor effects?

Cytokine-induced killer (CIK) cells, which display both potent anti-tumor ability of T lymphocytes and non-major histocompatibility complex (MHC) restricted killing tumor cells capacity of natural killer (NK) cells are capable of recognizing and lysing a broad array of tumor targets. They have begun to be used in clinical care with good prospects for treatment success. CIK cells are a heterogeneous cell population that contain CD3(+)CD56(+) cells, CD3(-)CD56(+) natural killer (NK) cells and CD3(+)CD56(-) T cells on which much attention has been focused. This review will summarize the connections and differences among CD3(+)CD56(+)CIK cells, CD3(-)CD56(+) NK cells and CD3(+)CD56(-) T cells in the following aspects: the main cell surface molecule, killing mechanism, and clinical applications so that treatment with CIK cells can be optimized and further to enhance the antitumor effect.

Enhanced antitumor effects of DC-activated CIKs to chemotherapy treatment in a single cohort of advanced non-small-cell lung cancer patients.

Cytokine-induced killer (CIK) cells show cytolytic activity against tumor. The purpose of this study was to evaluate the antitumor effect of dendritic cell (DC)-activated CIK cells in vitro and their clinical efficacy of DC-activated CIK cells in combination with chemotherapy (abbreviated below as chemotherapy plus DC + CIK) in patients with advanced non-small-cell lung cancer (NSCLC). A paired study was performed between 61 patients treated with chemotherapy alone (group 1) and 61 patients treated with chemotherapy plus DC + CIK cells (group 2). In group 2, 36 patients with adenocarcinoma and 18 patients with squamous cell carcinoma were analyzed for the survival rate. Compared to unstimulated CIK cells, DC-activated CIK cells significantly enhanced antitumor activity, increased the ratio of CD3(+)CD56(+) cells, promoted cell proliferation and lessened cell apoptosis. In the paired study, the 1- and 2-year overall survival rates in group 2 were 57.2 and 27.0 %, which were significantly higher than that of group 1 (37.3 and 10.1 %) (P < 0.05). There was no significant difference in the survival rate between the adenocarcinoma and squamous carcinoma patients in group 2. The present study suggests that DC-activated CIK cell has enhanced antitumor effects and chemotherapy plus DC + CIK cells improved the clinical outcomes of chemotherapy for advanced NSCLC patients.

Vemurafenib for BRAF V600-mutant Erdheim-Chester disease presenting with bilateral orbital involvement.

ECD is considered to have rapid progression and poor prognosis. Studies have shown that vemurafenib is effective for ECD patients with orbital involvement, but not for ECD with multiple organs. The refinement of treatment approaches and the increased awareness of ECD have led to a dramatic improvement in prognosis.

Therapeutic effect of haploidentical peripheral blood stem cell treatment on relapsed/refractory ovarian cancer.

The traditional immunotherapy is limited on relapsed/refractory metastatic ovarian cancer because tumors cause immunosuppression. Since new therapeutic strategies to improve clinical outcomes for patients with relapsed/refractory metastatic ovarian carcinoma are needed, the aim of this study was to evaluate the therapeutic effect of haploidentical peripheral blood stem cells (haplo-PBSCs) adoptive treatment on relapsed/refractory ovarian cancer. Thirteen patients with advanced stage of ovarian cancer and refractory history after surgery and chemotherapy were treated with interleukin-2 activated haplo-PBSCs donated by their parents or children. Clinical outcomes including therapeutic response by measuring tumor size changes using CT scanning, CA-125 levels and survival times were evaluated. T and NK cell population in patients before and after treatment was detected by flow cytometry analysis. The median follow-up time after haplo-PBSCs adoptive treatment was 14 months. At the time of the last follow-up, the median overall survival after haplo-PBSCs adoptive treatment was 9.1 months. Ten patients (76.9%) achieved a relief of symptoms, including abdominal distention, ache, fatigue, and poor appetite. During the first 2 months after treatment, CA125 levels decreased in 10 patients (76.9%). Five patients (38.5%) had a stable disease and 1 patient (8%) had partial response. T cell population (CD3+CD4+ and CD3+CD8+) and CD3-CD16+CD56+ NK cells were increased in patients after haplo-PBSCs adoptive treatment. Our study reveals that haplo-PBSCs adoptive treatment is associated with an anti-tumor effect and increasing immune responses in patients with relapsed/refractory ovarian cancer.

Correction: Ci et al. Enhanced Delivery of Imatinib into Vaginal Mucosa via a New Positively Charged Nanocrystal-Loaded in Situ Hydrogel Formulation for Treatment of Cervical Cancer. Pharmaceutics 2019, 11, 15.

In the original publication [...].

Autologous cytokine-induced killer cell immunotherapy in lung cancer: a phase II clinical study.

OBJECTIVE: Cytokine-induced killer (CIK) cells have the ability to kill tumor in vitro and in vivo. This study was designed to evaluate the clinical efficacy of CIK cell immunotherapy following regular chemotherapy in patients with non-small cell lung cancer (NSCLC) after surgery. METHODS: A paired study, with 87 stage I-IV NSCLC patients in each group, was performed. Patients received either chemotherapy (arm 2) or chemotherapy in combination with autologous CIK cell immunotherapy (arm 1). Progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: Of the 87 paired patients, 50 had early-stage disease (stage I-IIIA) and 37 had advanced-stage disease (stage IIIB-IV). Among early-stage patients, the distribution of 3-year PFS rate and median PFS time showed no statistical difference between the two groups (p = 0.259 and 0.093, respectively); however, the 3-year OS rate and median OS time in arm 1 were significantly higher than those in arm 2 (82 vs. 66 %; p = 0.049 and 73 vs. 53 months; p = 0.006, respectively). Among the advanced-stage patients, the 3-year PFS and OS rates of arm 1 were significantly higher than those of arm 2 (6 vs. 3 %; p < 0.001 and 31 vs. 3 %; p < 0.001, respectively); the median PFS and OS times in arm 1 were also significantly longer than those in arm 2 (13 vs. 6 months; p = 0.001 and 24 vs. 10 months; p < 0.001, respectively). Multivariate analyses indicated that the frequency of CIK cell immunotherapy was significantly associated with prolonged PFS (HR = 0.91; 95 % CI 0.85-0.98; p = 0.012) and OS (HR = 0.83; 95 % CI, 0.74-0.93; p = 0.001) in the arm 1. CONCLUSIONS: The data suggested that CIK cell immunotherapy could improve the efficacy of conventional chemotherapy in NSCLC patients, and increased frequency of CIK cell treatment could further enhance the beneficial effects. A multi-center randomized trial is being carried out in our hospital to further validate these findings.

A Phase IB Trial of Autologous Cytokine-Induced Killer Cells in Combination with Sintilimab, Monoclonal Antibody Against Programmed Cell Death-1, plus Chemotherapy in Patients with Advanced Non-Small-Cell Lung Cancer.

INTRODUCTION: Can the Cytokine-induced killer (CIK) cells in combination with immune checkpoint inhibitor further improve the efficacy of chemotherapy in non-small cell lung cancer (NSCLC) patients? What are the adverse reactions of this combination therapy? But these problems are not clear. Therefore, we conducted a phase 1b trial to evaluate the safety and efficacy of autologous CIK cells therapy combined with Sintilimab, antibody against programmed cell death-1, plus chemotherapy in untreated, advanced NSCLC patients. PATIENTS AND METHODS: Patients with stage IIIB/IIIC/IV NSCLC received Sintilimab, platinum-based doublet chemotherapy, and CIK cells every 3 weeks for 4 cycles, then maintenance treatment with Sintilimab in squamous and with Sintilimab plus pemetrexed in non-squamous NSCLC until disease progression or unacceptable toxicity or 2 years. The primary endpoints were safety and objective response rate (ORR). RESULTS: Thirty-four patients received the treatment. 94.1% of patients experienced treatment-related adverse events (TRAEs). Grade 3 or greater TRAEs occurred in 64.7% of patients. One (2.9%) patient died of grade 5 immune-related pneumonia. The ORR and DCR were 82.4% (95% CI, 65.5%-93.2%) and 100.0% (95% CI, 89.7%-100.0%), respectively. Objective responses were evaluated in 14 of 15 non-squamous patients (93.3%; 95% CI, 68.1%-99.8%) and in 14 of 19 squamous patients (73.7%; 95% CI, 48.8%-90.9%). Median PFS was 19.3 months (95% CI, 8.3 months to not available). CONCLUSION: Autologous CIK cells immunotherapy in combination with Sintilimab plus chemotherapy was well tolerable and showed encouraging efficacy in patients with previously untreated, advanced NSCLC (ClinicalTrials.gov number, NCT03987867).

Increased prevalence of regulatory T cells in the lung cancer microenvironment: a role of thymic stromal lymphopoietin.

Expansion of CD4+CD25+ regulatory T cells (Tregs) in tumor microenvironment was one of the mechanisms by which cancer cells escaped host defense. Thymic stromal lymphopoietin (TSLP) contributes to the generation of natural Tregs in thymus. Therefore, the purpose of this report was to investigate the role of TSLP in the increasing prevalence of Tregs in lung cancer microenvironment. The expression ratio of TSLP protein in tumor tissues was significantly increased compared with that in benign lesion and non-cancer lung tissue. The prevalence of Tregs in tumor microenvironment was correlated with the expression of TSLP in lung cancer. Dendritic cells (DCs) were induced from peripheral blood mononuclear cells (PBMCs) collected from lung cancer patients and left unstimulated (imDCs) or exposed to hTSLP (TSLP-DCs) or LPS (LPS-DCs). TSLP-DCs expressed intermediate levels of CD83 and high levels of CD86, CD11C, and HLA-DR, which showed a characteristic of less mature DCs. TSLP-DCs secreted low levels of IL-6, IL-12, IL-10, TNF-α and IFN-γ, and high levels of TGF-ß and MDC. The percentage of Tregs in CD4+CD25- T cells cocultured with TSLP-DCs group was statistically higher than that of LPS-DCs and imDCs. Transwell assays showed that TSLP-DCs exhibited increased ability to attract the migration of CD4+CD25- Tregs, when compared with imDCs. These results indicated that TSLP proteins were expressed in lung tumor tissue and correlated with the prevalence of Tregs. TSLP-DCs could induce CD4+CD25- T cells to differentiate into CD4+CD25+foxp3+ T cells and the migration of CD4+CD25+ T cells.

Alloreactive natural killer cells promote haploidentical hematopoietic stem cell transplantation by expansion of recipient-derived CD4(+) CD25(+) regulatory T cells.

Alloreactive NK cells (Allo-NKs) have been shown to exert advantageous effects on the outcomes of haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) for cancer treatment. However, the mechanisms of action of Allo-NKs remain unclear. We established a novel Haplo-HSCT conditioning regimen composed of Allo-NKs and a low dose of immunosuppressive drugs (Allo-NKs + Chemo) to investigate alternative mechanisms besides direct cytotoxicity. The inhibitory effects of different cell subsets on the donor-recipient mixed lymphocyte reactions (MLRs) were evaluated after Haplo-HSCT. The quantities and functions of CD4(+) CD25(+) regulatory T cells (Tregs) and dendritic cells (DCs) in the spleen and the thymus were examined. Our results showed that the Allo-NKs + Chemo regimen induced systemic tolerance, and that CD4(+) CD25(+) Tregs played a significant role in inducing and maintaining systemic tolerance after Haplo-HSCT. Alloreactive NK cells promoted the expansion of recipient-derived CD4(+) CD25(+) CD127(-) Tregs in the thymus and the spleen which could be amplified in vitro by the immature donor-derived DC subset isolated from the thymus of Allo-NKs + Chemo-treated mice. Our findings suggested that Allo-NKs are capable of inducing systemic tolerance after Haplo-HSCT by assembling donor-derived immature DCs to expand recipient-derived Treg cells in the thymus.

Upregulated expression of indoleamine 2, 3-dioxygenase in primary breast cancer correlates with increase of infiltrated regulatory T cells in situ and lymph node metastasis.

IDO has been reported to induce immunotolerance and promote metastasis in solid malignancy, but the mechanisms involved were not fully understood. In this study, the expression of IDO in primary breast cancer was examined and the correlation between the expression levels of IDO and the densities of Foxp3(+) Tregs in situ was studied. The IDO stably-expressing CHO cells(IDO/CHO) were generated to evaluate the induction of Foxp3(+) Tregs after coculturing with CD3(+) T cells in vitro. The IDO expression in cancer was higher than that in benign diseases both at RNA and protein levels. The IDO expression was significantly upregulated in tumors of more advanced stages and with more extensive lymph node metastasis, and displayed positive linear correlation with the density of Foxp3(+) Tregs. We further demonstrated that CD4(+)CD25(+)CD127(-) Tregs could be amplified by coculturing CD3(+) T cells with IDO/CHO cells in vitro which displayed increasing Foxp3 expression both at mRNA and protein levels. Our results implied that up-regulation of IDO in primary breast cancer may inhibit local immune surveillance and promote metastasis by favoring development and infiltration of Foxp3(+) Tregs in the tumor microenvironment.

Response to gefitinib/crizotinib combination in a pulmonary sarcomatoid carcinoma patient harboring concurrent EGFR mutation and MET amplification.

Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung cancer (NSCLC) with an extremely poor prognosis making it a therapeutic challenge. However, the development of genetic variation molecular diagnosis and targeted agents has brought the treatment of such malignancies to the precision era. Co-existing mutations of EGFR and MET have been reported in NSCLC, but rarely found in PSC. We herein present a rare case of a 74-year-old female patient diagnosed with PSC, carrying an activating mutation in exon 21 L858R of EGFR and a concurrent MET amplification prior to treatment. Combined application of gefitinib and crizotinib, inhibitors targeting EGFR and MET, respectively, was prescribed. The patient experienced a partial response and was stable for 9.7 months off therapy. The observation stresses the importance of genetic testing and paves the way for combined targeted strategies in PSC.

Dendritic cell-activated cytokine-induced killer cells enhance the anti-tumor effect of chemotherapy on non-small cell lung cancer in patients after surgery.

BACKGROUND AIMS: Cytokine-induced killer (CIK) cells have shown cytolytic activity against several tumor cells in vitro and in animal tumor models. Furthermore, CIK cells activated by dendritic cell (DC) stimulation show increased anti-tumor activity. This study aimed to evaluate the clinical efficacy of DC-activated CIK cell treatment following regular chemotherapy and the effects of this therapy on immune responses in patients with non-small cell lung cancer (NSCLC) after surgery. METHODS: A paired study, with 42 patients in each group with stage I-IIIa NSCLC after surgery, was performed. Patients received chemotherapy alone (CT) or chemotherapy and DC-activated CIK cell treatment (immuno-CT). Disease-free survival (DFS) and overall survival were evaluated. CIK cell cytotoxicity against tumor cells was detected using a lactate dehydrogenase-based method. Serum cytokine levels in the immuno-CT group were detected using cytokine antibody arrays. RESULTS: The cytotoxicity of CIK cells was significantly enhanced by DC activation. The 2-year overall survival rate in the immuno-CT group was significantly improved compared with the CT group (94.7 +/- 3.6% versus 78.8 +/- 7.0%, P < 0.05). The 2-year DFS of these two groups showed no significant difference. DC-activated CIK cell treatment increased production of cytokines that have known anti-tumor effects, including IFN-gamma, MIG, TNF-alpha and TNF-beta, in patients who had no progression, but they were not found in patients who developed recurrence/metastasis. CONCLUSIONS: This study suggests that the role of DC-activated CIK cells in improvement of chemotherapy for malignant tumor treatment is associated with up-regulation of the production of cytokines involved in the anti-tumor effect.

Synchronous infiltrating ductal carcinoma and primary extramedullary plasmacytoma of the breast.

BACKGROUND: Extramedullary plasmacytomas are seldom solitary and usually progress to diffuse myelomatosis. Plasmacytomas of the breast are rare, especially when not associated multiple myeloma. Synchronous infiltrating ductal carcinoma and primary extramedullary plasmacytoma of the breast have not previously reported. CASE PRESENTATION: A 27-years-old woman with an untreated upper outer quadrant breast mass for 1-year was referred to our cancer hospital for surgical evaluation of increasing breast pain. Postoperatively, microscopic examination revealed an infiltrating ductal carcinoma complicated by an extramedullary plasmacytoma divided by fibrous tissue in one section. Following surgery, the patient received chemotherapy for the carcinoma and radiotherapy for the plasmacytoma. CONCLUSION: In this case, careful histopathology examination was essential to make the correct diagnosis and therapy for these synchronous lesions. The patient finished chemotherapy and radiotherapy without significant adverse effects.

[A preliminary study on the effects of feto-maternal microchimerism in activated human leukocyte antigen haploidentical mobilized peripheral blood stem cells on treatment of solid tumors].

OBJECTIVE: To study the effect of feto-maternal microchimerism in the treatment of activated human leukocyte antigen (HLA) haploidentical mobilized peripheral blood cells against solid tumors. METHODS: Genomic DNA samples of 25 pairs of HLA haploidentical donors and recipients were extracted. The donor-derived HLA-DRB loci were detected with nested PCR-sequence specific primer (SSP) typing. The mixed lymphocyte proliferation action between the patients and respective donors, the engraftment of donor's cells and the serum levels of Th1/Th2 type of cytokines were measured with MTT, FISH and ELISA method respectively. The survival time of patients with or without feto-maternal microchimerism were compared as well. RESULTS: Using nested PCR-SSP typing, the positive rates of feto-maternal microchimerism in the 25 pairs of HLA haploidentical donors and recipients were 40% in the maternal/children pairs and 0 in the paternal/children pairs. The chimerism positive patients showed less proliferation activity when cocultured with respective donors as compared with unrelated ones (P = 0.03). Only one chimerism positive patient experienced the engraft of donor's cell 3 months after treatment as the donor derived XX chromosome was identified with FISH. When the data of chimerism positive patients were deleted, the serum levels of IFNgamma 1 month after treatment dropped dramatically from 171.4 (26.3 approximately 258.4) ng/L to 29.4 (1.2 approximately 39.9) ng/L. The survival time in chimerism positive patients of the maternal/children pairs was significantly longer than that in chimerism negative patients, which was (31.2 +/- 4.3) months and (11.1 +/- 3.3) months, respectively (P = 0.036). CONCLUSION: Feto-maternal microchimerism might induce anergy in the HLA haploidentical donors, favor the engraftment of donor's progenitors and maintenance of positive microenvironment and prolong the survival time.

Mass Transfer Behavior of Benzene in Hierarchically Structured ZSM-5.

A series of ZSM-5 zeolites with hierarchical porous structure were synthesized using NaOH solutions treatment method. The structural and acidity properties of hierarchical ZSM-5 zeolites as-synthesized were characterized by X-ray diffraction (XRD), N2 adsorption, scanning electron microscope (SEM), NH3-temperature programmed desorption (TPD), and pyridine Fourier transform infrared spectroscopy (Py-FTIR). The adsorption and diffusion performances of benzene in hierarchical ZSM-5 zeolites were studied by an intelligent gravimetric analyzer (IGA). It was found that mass transfer (adsorption and diffusion) performance of benzene was significantly affected by synergetic effect of hierarchical structure, acid amount, acidity, adsorption sites of ZSM-5 zeolites. After suitable alkali treatment, the crystal structure of ZSM-5 was retained and finely tailored. Hierarchical ZSM-5 was obtained with a uniform size of mesoporous and microporous structure. Acidity of hierarchical ZSM-5 zeolites was improved, which produced more adsorption sites and thus increased the adsorption performance of benzene in hierarchical ZSM-5. As a result, connectivity in hierarchical ZSM-5 was improved with increasing of mesopores in hierarchical ZSM-5. Hierarchical ZSM-5 well-contributed to the adsorption performance of benzene on active sites and improved catalytic performance of hierarchical ZSM-5.

RGD-modified PEGylated paclitaxel nanocrystals with enhanced stability and tumor-targeting capability.

Nanocrystals has been constructed for insoluble drugs as a novel type of nanoscale drug delivery systems with high drug loading. How to prepare nanocrystals with good stability and tumor targeting capability is still challenging. This study was to modify paclitaxel nanocrystals with polyethylene glycol (PEG) for stabilization and RGD peptide for tumor targeting. Inspired by the structure of mussel's foot protein, polydopamine (PDA) was introduced to the drug delivery system for the modification of nanocrystals. Briefly, PDA was coated on the surface of nanocrystals to form a reaction platform for further PEGylation and RGD peptide conjugation. PEGylated nanocrystals with RGD peptide modification (NC@PDA-PEG-RGD) were prepared with near-spheroid shape, drug loading 45.12 ±â€¯1.81% and a hydrodynamic diameter 419.9 ±â€¯80.9 nm. The size of NC@PDA-PEG-RGD remained basically unchanged for at least 72 h in the presence of plasma while the size of unmodified nanocrystals (NC) increased and exceeded 1000 nm in 12 h. Cellular uptake and cellular growth inhibition experiments using the lung cancer cell line A549 demonstrated the superiority of NC@PDA-PEG-RGD over NC or PEGylated nanocrystals without RGD modification (NC@PDA-PEG). In A549 model tumor bearing-mice, NC@PDA-PEG-RGD showed significantly higher intratumor accumulation and slower tumor growth than NC@PDA-PEG or free paclitaxel. In summary, our study suggested the superiority of RGDmodified PEGylated paclitaxel nanocrystals as a lung cancer-targeted delivery system and the potential of PDA coating technique for targeting functionalization of nanocrystals.