Publications by authors named "Hanbo Zhang"

20 Publications

  • Page 1 of 1

Delivery of Basic Fibroblast Growth Factor Through an Forming Smart Hydrogel Activates Autophagy in Schwann Cells and Improves Facial Nerves Generation the PAK-1 Signaling Pathway.

Front Pharmacol 2022 1;13:778680. Epub 2022 Apr 1.

Department of Otorhinolaryngology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.

Although studies have shown that basic fibroblast growth factor (bFGF) can activate autophagy and promote peripheral nerve repair, the role and the molecular mechanism of action of bFGF in the facial nerve are not clear. In this study, a thermosensitive forming poloxamer hydrogel was used as a vehicle to deliver bFGF for treating facial nerve injury (FNI) in the rat model. Using H&E and Masson's staining, we found that bFGF hydrogel can promote the functional recovery and regeneration of the facial nerve. Furthermore, studies on the mechanism showed that bFGF can promote FNI recovery by promoting autophagy and inhibiting apoptosis. Additionally, this study demonstrated that the role of hydrogel binding bFGF in nerve repair was mediated through the activation of the PAK1 signaling pathway in Schwann cells (SCs). These results indicated that poloxamer thermosensitive hydrogel loaded with bFGF can significantly restore the morphology and function of the injured facial nerve by promoting autophagy and inhibiting apoptosis by activating the PAK1 pathway, which can provide a promising strategy for FNI recovery.
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http://dx.doi.org/10.3389/fphar.2022.778680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9011134PMC
April 2022

Fourteen New Species of Foliar Associated with the Invasive Plant and Surrounding Crops.

J Fungi (Basel) 2022 Feb 13;8(2). Epub 2022 Feb 13.

Laboratory for Conservation and Utilization of Bio-Resources, Yunnan University, Kunming 650091, China.

is one of the most invasive weeds in China. Following an outbreak in Yunnan in the 1960s, has been spreading in Southwest China at tremendous speed. Previous research indicated contained many species as endophytes. In this study, we investigated the diversity of in healthy and diseased leaves of the invasive plant and several surrounding crops in Yunnan, Guangxi, and Guizhou provinces in China, and obtained over 1000 strains. After preliminary delimitation using the internal transcribed spacer region (ITS) sequences, 44 representative strains were selected for further study. Their phylogenetic positions were determined by phylogenetic analyses using combined sequences of ITS, actin (), chitin synthase (-1), glyceraldehyde-3-phosphate dehydrogenase (), and beta-tubulin (2). Combined with morphological characteristics, 14 new species were named as , , , , , , , , , , , , , and .
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http://dx.doi.org/10.3390/jof8020185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8879954PMC
February 2022

Treatment Patterns, Toxicity, and Outcomes of Older Adults With Advanced Pancreatic Cancer Receiving First-line Palliative Chemotherapy.

Am J Clin Oncol 2022 02;45(2):55-60

Departments of Internal Medicine.

Objectives: Advanced pancreatic cancer (APC) disproportionately impacts older adults. Randomized trials demonstrate improved overall survival (OS) with combination chemotherapy including 5-fluorouracil, irinotecan, leucovorin, and oxaliplatin (FOLFIRINOX) or nab-paclitaxel and gemcitabine compared with gemcitabine alone, but with increased toxicity. Older adults are at increased risk of side effects from chemotherapy. The aim of this study was to assess the efficacy and toxicity of chemotherapy in older adults with APC.

Methods: Patients diagnosed with APC from 2011 to 2016 were identified using the Manitoba Cancer Registry. Patient and treatment characteristics, toxicity, and outcomes of patients 65 years of age and above treated with palliative chemotherapy were compared by treatment regimen. OS was assessed using the Kaplan-Meier method. A Cox regression was used to identify independent predictors of OS.

Results: A total of 87 patients aged 65 years and above received palliative chemotherapy: 52 (59.7%) FOLFIRINOX, 21 (24.1%) nab-paclitaxel and gemcitabine, and 14 (16.1%) gemcitabine, with a median age of 69 (65 to 84), 75 (65 to 88), and 73 (67 to 82), Eastern Cooperative Oncology Group (ECOG) performance status difference in hematologic toxicity between regimens (P=0.807). An increase in nonhematologic toxicity was seen with FOLFIRINOX (P<0.001), specifically neuropathy (P=0.008), fatigue (P<0.001), and nausea/vomiting (P=0.008). FOLFIRINOX was associated with improved radiologic response (P=0.05) and OS (P=0.035). PS, baseline carbohydrate antigen 19-9 level, and chemotherapy regimen were independent predictors of survival.

Conclusions: FOLFIRINOX is associated with improved response and OS in older adults with APC. FOLFIRINOX has a manageable safety profile in this population and should be considered in fit older adults with APC.
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http://dx.doi.org/10.1097/COC.0000000000000882DOI Listing
February 2022

The Influence of Adjuvant Chemotherapy Dose Intensity on Five-Year Outcomes in Resected Colon Cancer: A Single Centre Retrospective Analysis.

Curr Oncol 2021 10 9;28(5):4031-4041. Epub 2021 Oct 9.

Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5W9, Canada.

There is evidence that achieving a dose intensity > 80% in adjuvant colon cancer treatment improves survival. In total, 192 consecutive patients with resected stage III and high-risk stage II colon cancer that received adjuvant chemotherapy were retrospectively analyzed. Patients who received at least 6 weeks of adjuvant therapy were included. The primary objective was to assess the influence of dose index (DI) and relative dose intensity (RDI) on DFS and OS at 3 and 5 years in patients receiving fluorouracil-based doublet therapy with oxaliplatin (FOLFOX) (5-FU and oxaliplatin assessed separately), or capecitabine monotherapy. In the capecitabine group, DFS rates for 3 and 5 years were 66.7% and 57.6%, respectively, while OS rates were 80.3% and 66.7%, respectively. Those who received FOLFOX had DFS rates of 76.9% and 71.2% at 3 and 5 years, respectively. OS rates were 86.4% and 76.7% at 3 and 5 years, respectively. Median RDI was 73.8% for capecitabine and 76.3% and 85.6% for the oxaliplatin and 5-FU components respectively. Based on a multivariate analysis in patients receiving FOLFOX, those with an oxaliplatin DI > 80% had improvements in DFS and OS compared to those with an oxaliplatin DI of ≤80%. Otherwise, there was no significant difference in DFS or OS when comparing patients who achieved an RDI or a DI of above versus below 80% in the patients receiving adjuvant chemotherapy for resected colon cancer.
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http://dx.doi.org/10.3390/curroncol28050342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8535138PMC
October 2021

PSMA Theranostics: Current Landscape and Future Outlook.

Cancers (Basel) 2021 Aug 10;13(16). Epub 2021 Aug 10.

Department of Medical Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada.

Introduction: Prostate-specific membrane antigen (PSMA) is a promising novel molecular target for imaging diagnostics and therapeutics (theranostics). There has been a growing body of evidence supporting PSMA theranostics approaches in optimizing the management of prostate cancer and potentially altering its natural history.

Methods: We utilized PubMed and Google Scholar for published studies, and clinicaltrials.gov for planned, ongoing, and completed clinical trials in PSMA theranostics as of June 2021. We presented evolving evidence for various PSMA-targeted radiopharmaceutical agents in the treatment paradigm for prostate cancer, as well as combination treatment strategies with other targeted therapy and immunotherapy. We highlighted the emerging evidence of PSMA and fluorodeoxyglucose (FDG) PET/CT as a predictive biomarker for PSMA radioligand therapy. We identified seven ongoing clinical trials in oligometastatic-directed therapy using PSMA PET imaging. We also presented a schematic overview of 17 key PSMA theranostic clinical trials throughout the various stages of prostate cancer.

Conclusions: In this review, we presented the contemporary and future landscape of theranostic applications in prostate cancer with a focus on PSMA ligands. As PSMA theranostics will soon become the standard of care for the management of prostate cancer, we underscore the importance of integrating nuclear medicine physicians into the multidisciplinary team.
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http://dx.doi.org/10.3390/cancers13164023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391520PMC
August 2021

Utility of the modified frailty index in predicting toxicity and cancer outcomes for older adults with advanced pancreatic cancer receiving first-line palliative chemotherapy.

J Geriatr Oncol 2021 01 11;12(1):112-117. Epub 2020 Aug 11.

Department of Internal Medicine, University of Manitoba, 820 Sherbrook St, R3A 1R9 Winnipeg, MB, Canada; CancerCare Manitoba, Department of Hematology and Medical Oncology, 675 McDermot Ave, R3E 0V9 Winnipeg, MB, Canada; Research Institute in Oncology and Hematology, CancerCare Manitoba, 675 McDermot Ave, R3E 0V9 Winnipeg, MB, Canada. Electronic address:

Background: Pancreatic cancer primarily affects older adults and is associated with a high morbidity and mortality. Identifying frail patients with advanced pancreatic cancer (APC) helps to mitigate the risks of chemotherapy (CT). The modified Frailty Index (mFI) is an 11-point deficit measure used to identify frail patients. Although validated in surgical fields, it has not been assessed in an APC population.

Methods: A retrospective cohort study evaluated consecutive patients, aged ≥65 years, diagnosed with APC from 2011 to 2016 and treated with first line palliative-intent CT. mFI was categorized as: 0, 1, 2 and ≥ 3. Descriptive analysis was completed comparing patient characteristics, CT toxicity, response to treatment, and overall survival (OS) by mFI score.

Results: 87 patients with APC received palliative CT. Median age was 71 (65-88), 54% male. A mFI score of 0, 1, 2, and ≥ 3 occurred for 20 (23%), 28 (32.2%), 25 (28.7%) and 14 (16.1%) patients respectively. Patients with mFI scores of 0-1 were more likely to receive: 5-fluorouracil, irinotecan and oxaliplatin. CT toxicity, emergency room (ED) and urgent cancer clinic (UCC) presentation, and hospitalization length did not differ by mFI. Longer OS was associated with better ECOG and receipt of combination CT.

Conclusion: This is the first assessment of the mFI in an APC population receiving CT. The mFI score did not correlate with toxicity, ED/UCC visits, hospitalization length or OS. Ongoing assessment of tools that accurately identify frailty in patients with APC is critical to help better select candidates for aggressive CT.
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http://dx.doi.org/10.1016/j.jgo.2020.07.004DOI Listing
January 2021

Efficacy and Tolerability of Second-line Nab-paclitaxel and Gemcitabine After Failure of First-line FOLFIRINOX for Advanced Pancreas Cancer: A Single-institution Experience.

Clin Colorectal Cancer 2018 09 8;17(3):e451-e456. Epub 2018 Mar 8.

Section of Haematology/Oncology, University of Manitoba, Winnipeg, MB, Canada.

Background: Advanced pancreatic cancer (APC) has a poor prognosis. Current first-line chemotherapy options include FOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin), NG (nab-paclitaxel, gemcitabine), and GEM (gemcitabine) alone. The optimal second-line regimen is unclear. For patients with disease progression with FOLFIRINOX who have a good performance status, NG might be a reasonable second-line option.

Patients And Methods: Patients in whom APC was diagnosed from 2012 to 2016 who underwent chemotherapy at CancerCare Manitoba were identified from the Manitoba Cancer Registry. Pharmacy records were used to identified those patients who had received first-line FOLFIRINOX, followed by second-line NG, GEM alone, or best supportive care. A retrospective analysis was performed to identify the patient and treatment characteristics, toxicity, radiologic response, and survival. Edmonton Symptom Assessment System, revised, scores were analyzed to assess symptom control.

Results: A total of 146 patients had received first-line FOLFIRINOX. Of those with disease progression who were offered second-line therapy, 30 received NG, 8 GEM alone, and 22 best supportive care. NG was more toxic than GEM alone; however, the dose intensity was similar between the 2 groups. The median progression-free survival was 3.61 months in the NG group and 2.51 months in the GEM-alone group. The median overall survival was 5.69 months in the NG group and 3.82 months in the GEM-alone group. No significant differences were found in the Edmonton Symptom Assessment System, revised, scores when stratified by the treatment received.

Conclusion: For select patients with APC in whom first-line FOLFIRINOX fails, a role might exist for second-line NG. In our institution, second-line NG was associated with improvement in survival compared with second-line GEM alone, with a manageable toxicity profile.
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http://dx.doi.org/10.1016/j.clcc.2018.03.003DOI Listing
September 2018

Suppress orthotopic colon cancer and its metastasis through exact targeting and highly selective drug release by a smart nanomicelle.

Biomaterials 2018 04 2;161:144-153. Epub 2018 Feb 2.

College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China. Electronic address:

The treatment of metastatic cancer is a huge challenge at the moment. Highly precise targeting delivery and drug release in tumor have always been our pursuit in cancer therapy, especially to advance cancer with metastasis, for increasing the efficacy and biosafety. We established a smart nanosized micelle, formed by tocopherol succinate (TOS) conjugated hyaluronic acid (HA) using a disulfide bond linker. The micelle (HA-SS-TOS, HSST) can highly specifically bind with CD44 receptor over-expressed tumor, and response selectively to high GSH level in the cells, inducing disulfide bond breakage and the release of the payload (paclitaxel, PTX). To predict the antitumor efficacy of the micelles more clinically, we established an orthotopic colon cancer model with high metastasis rate, which could be visualized by the luciferase bioluminescence. Our data confirmed CD44 high expression in the colon cancer cells. Highly matching between the micellar fluorescence and bioluminescence of cancer cells in intestines demonstrated an exact recognition of our micelles to orthotopic colon tumor and its metastatic cells, attributing to the mediation of CD44 receptors. Furthermore, the fluorescence of the released Nile Red from the micelles was found only in the tumor and its metastatic cells, and almost completely overlapped with the bioluminescence of the cancer cells, indicating a highly selective drug release. Our micelles presented an excellent therapeutic effect against metastatic colon cancer, and induced significantly prolonged survival time for the mice, which might become a promising nanomedicine platform for the future clinical application against advanced cancers with high CD44 receptor expression.
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http://dx.doi.org/10.1016/j.biomaterials.2018.01.043DOI Listing
April 2018

Preparation of artificial red cell and its application on alleviation of tumor hypoxia.

Colloids Surf B Biointerfaces 2017 Dec 20;160:446-454. Epub 2017 Sep 20.

College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China. Electronic address:

Hemoglobin-based oxygen carriers were developed as an alternative for blood transfusion. However, the research progress for their further clinic applications was slow in recent several years. Hypoxia is found in most solid tumors, which is responsible for the tumor formation, increased metastasis, drug resistance during therapeutic process as well as poor patient survival. In this work, novel hemoglobin (Hb) loaded nanoliposomes, as artificial red cells for oxygen delivery, were optimized by screening various types of phospholipids and analyzing different mole ratio of phospholipid to cholesterol. The nanoliposomes presented a high encapsulating efficiency to hemoglobin and also significantly enhanced its stability. The obtained hemoglobin loaded nanoliposome (HLL) could be lyophilized for long term storage. HLL did not cause significant cell death in the concentration range of 0-100μg equivalent Hb/mL under normoxia and hypoxia incubation conditions, suggesting the low cytotoxicity and high biocompatibility of HLL. Importantly, HLL could efficiently accumulate into subcutaneous and deep orthotopic tumors, inducing a significant decrease of hypoxia-inducible factors 1α subunits (HIF-1α) in the tumors and remarkably reduced expression of vascular endothelial growth factor (VEGF). The study of acute and chronic toxicity indicated that HLL did not induce obvious damage to main organs of mice after intravenous injections with total Hb dose of 120mg/kg. We presented a promising method for relieving the hypoxia degree in solid tumors and down-regulating HIF-1α protein by directly delivering oxygen into tumors, which will be very helpful for subsequent cancer therapy.
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http://dx.doi.org/10.1016/j.colsurfb.2017.09.039DOI Listing
December 2017

Near infrared light mediated photochemotherapy for efficiently treating deep orthotopic tumors guided by ultrasound imaging.

Drug Deliv 2017 Nov;24(1):1441-1452

a College of Pharmaceutical Sciences , Zhejiang University , Hangzhou , People's Republic of China.

Recently, Combined cancer photothermal-chemotherapy has become a highly promising strategy in cancer treatment for its enhanced therapeutic efficacy, controlled drug release and reduced systemic toxicity. Almost all the reported strategies based on photothermal-chemotherapy have only focused on the treatment of superficial or subcutaneous cancer, which are not considered as a more clinically relevant and better predictive models of drug efficacy than orthotopic tumor models. Here, we reported an EphB4 receptor-targeting polymeric nanoplatform containing hollow gold nanospheres (HAuNS) and the anticancer drug paclitaxel (PTX) for cancer photothermal-chemotherapy. With the modification of the TNYL peptide, HP-TCS could specifically internalize into EphB4-positive SKOV3 and CT26 cells, further inducing the selective killing of the cells in co-cultured system, namely, EphB4-positive and EphB4-negative cells. Obvious targeting of the micelles into implanted orthotopic or subcutaneous tumors with high EphB4 expression was observed. Interestingly, increased accumulation of HP-TCS was observed in orthotopic colon tumors when compared with ectopic tumors. Highly specific accumulation of HP-TCS in EphB4-positive tumors significantly increased the feasibility of photothermal-chemotherapy mediated by the near infrared reflection (NIR) laser. Then, a systemic antitumor efficiency study was performed in implanted subcutaneous and visual orthotopic tumor models. Precise NIR laser irradiation could be localized on tumors under the guidance of B-mode ultrasound imaging, causing a rapid photothermal ablation effect limited to the region of tumors. Tumor growth was significantly inhibited by the photothermal-chemotherapy due to the triggered release of PTX. Our study provided a promising strategy of NIR laser-mediated photothermal-chemotherapy based on HP-TCS against the tumors (specially, deep orthotopic tumors) with high EphB4 expression.
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http://dx.doi.org/10.1080/10717544.2017.1375574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241057PMC
November 2017

Specifically Increased Paclitaxel Release in Tumor and Synergetic Therapy by a Hyaluronic Acid-Tocopherol Nanomicelle.

ACS Appl Mater Interfaces 2017 Jun 6;9(24):20385-20398. Epub 2017 Jun 6.

College of Pharmaceutical Sciences, Zhejiang University , 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China.

Recently, interest in tumor-targeted and site-specific drug release from nanoparticles as a means of drug delivery has increased. In this study, we report a smart nanosized micelle formed by hyaluronic acid (HA) conjugated with d-α-tocopherol succinate (TOS) using a disulfide bond as the linker (HA-SS-TOS, HSST). HSST micelles can specifically bind to the CD44 receptors that are overexpressed by cancer cells. The high levels of glutathione (GSH) in tumor cells selectively break the disulfide bond linker. This effect results in the synchronous release of the payload and a TOS fragment. These two components subsequently demonstrate synergetic anticancer activity. First, we demonstrate that drug release from HSST occurs rapidly in physiological high redox conditions and inside cancer cells. Significant GSH-triggered drug release was also observed in vivo. Furthermore, an in vivo biodistribution study indicated that the HSST micelles efficiently accumulated at the tumor sites, primarily due to an enhanced permeability and retention effect and the efficient binding to the cancer cells that overexpressed the CD44 receptor. Interestingly, the synchronous release of paclitaxel (PTX) and the TOS fragment from the PTX-loaded HSST caused synergetic tumor cell killing and tumor growth inhibition. Our work presents a useful candidate for a drug delivery system that can specifically accumulate at tumor tissue, selectively release its payload and a TOS fragment, and thus display a synergetic anticancer effect.
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http://dx.doi.org/10.1021/acsami.7b02606DOI Listing
June 2017

Overcoming photodynamic resistance and tumor targeting dual-therapy mediated by indocyanine green conjugated gold nanospheres.

J Control Release 2017 07 15;258:171-181. Epub 2017 May 15.

College of Pharmaceutical Sciences, Zhejiang University, Yuhangtang Road 866, Hangzhou 310058, PR China. Electronic address:

Photodynamic therapy (PDT) and photothermal therapy (PTT) have captured much attention due to the great potential to cure malignant tumor. Nevertheless, photodynamic resistance of cancer cells has limited the further efficacy of PDT. Unfortunately, the resistance mechanism and efforts to overcome the resistance still have been rarely reported so far. Here, we report a nanosystem with specific tumor targeting for combined PDT and PTT mediated by near-infrared (NIR) light, which was established by covalently conjugating indocyanine green (ICG) and TNYL peptide onto the surface of hollow gold nanospheres (HAuNS). Our nanosystem (TNYL-ICG-HAuNS) was proved to possess significantly increased light stability, reactive oxygen species (ROS) production and photothermal effect under NIR light irradiation, thus presenting a remarkably enhanced antitumor efficacy. The up-regulation of nuclear factor erythroid 2-related factor 2 (NFE2L2, Nrf2) in cancer cells during PDT induced a significant increase of ABCG2, NQO-1 and HIF-1α expression, causing PDT resistance of the cells. Interestingly, ABCG2 expression could almost keep a normal level in the whole PDT process mediated by TNYL-ICG-HAuNS. After repeated irradiations, TNYL-ICG-HAuNS could still produce almost constant ROS in cells while the Nrf2 expression reduced significantly. Furthermore, PDT resistance induced an obvious decrease of the internalization of free ICG, but didn't influence the cell uptake of TNYL-ICG-HAuNS. Our data explained that TNYL-ICG-HAuNS could overcome the photodynamic resistance of cancer cells, acting as a promising modality for simultaneous photothermal and photodynamic cancer therapy.
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http://dx.doi.org/10.1016/j.jconrel.2017.05.015DOI Listing
July 2017

External Magnetic Field-Enhanced Chemo-Photothermal Combination Tumor Therapy via Iron Oxide Nanoparticles.

ACS Appl Mater Interfaces 2017 May 3;9(19):16581-16593. Epub 2017 May 3.

College of Pharmaceutical Sciences, Zhejiang University , 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China.

The development of multifunctional nanoplatforms based on magnetic nanoparticles (MNPs) has attracted increasing attention. MNPs especially exhibit excellent responsiveness under the guidance of an external magnetic field (MF), resulting in tumor-specific, targeted delivery. The behavior and magnetic-targeting efficiency of MNPs largely depend on their physiochemical properties, especially the particle size; however, the optimal size range may vary across the multiple bioapplications associated with multifunctional nanoparticles. The optimal size range of nanoparticles for external MF-mediated targeted delivery has rarely been reported. In this work, we synthesized a series of monodisperse FeO nanoparticles with identical surface properties ranging in size from 10 to 310 nm, and we systematically investigated their behavior and MF-assisted antitumor efficacy. Our data indicated that smaller FeO nanoparticles exhibited greater cellular internalization, while larger FeO nanoparticles showed greater tumor accumulation. Larger FeO nanoparticles exhibited stronger magnetic responsiveness both in vitro and in vivo, which could be used to further induce increased accumulation of nanoparticles and their payload (e.g., doxorubicin) into the tumor site under the guidance of an external MF. Our work demonstrated that larger FeO nanoparticles, with a diameter of up to 310 nm, exhibited the best magnetic-targeting efficiency mediated by an external MF and the strongest antitumor efficacy from combination photothermal-chemotherapy. Our results could serve as a valuable reference for the future design of MNPs and their targeted delivery via the modulation of an external MF.
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http://dx.doi.org/10.1021/acsami.6b16513DOI Listing
May 2017

Specific Photothermal Ablation Therapy of Endometriosis by Targeting Delivery of Gold Nanospheres.

Small 2017 04 1;13(15). Epub 2017 Feb 1.

College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang, 310058, P. R. China.

Endometriosis is difficult to treat since the side effects of the current therapeutic method and the high recurrence rate; thus, newer and safer therapeutic approaches are urgently needed. This work investigates the enhanced permeability and retention effect of CdTe quantum dots (QDs) and hollow gold nanospheres (HAuNS) in endometriosis to increase the delivery of HAuNS into lesion cells. The surface of HAuNS is successfully conjugated with a TNYL peptide that has specific affinity for the EphB4 receptor, which is a member of the Eph family of receptor tyrosine kinases. It is found that the EphB4 receptor is overexpressed in endometriosis lesions. The data indicate that both QDs and HAuNS can efficiently accumulate in endometriotic lesions through permeable vessels and the TNYL-conjugated HAuNS (TNYL-HAuNS) accumulate more via the interaction with EphB4. The specific photothermal ablation therapy based on TNYL-HAuNS significantly inhibits the growth of the endometriotic volume and induces the atrophy and degeneration of ectopic endometrium with no detectable toxicity to the normal organs. The level of TNF-α and estradiol also significantly decreases in the endometriotic lesions, indicating that the treatment enables a recovery from hormonal imbalance and inflammatory injury. This work can be a valuable reference for future endometriosis therapy.
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http://dx.doi.org/10.1002/smll.201603270DOI Listing
April 2017

Gold Nanospheres-Stabilized Indocyanine Green as a Synchronous Photodynamic-Photothermal Therapy Platform That Inhibits Tumor Growth and Metastasis.

ACS Appl Mater Interfaces 2017 Feb 20;9(4):3354-3367. Epub 2017 Jan 20.

College of Pharmaceutical Sciences, Zhejiang University , 866 Yuhangtang Road, Hangzhou 310058, People's Republic of China.

Both photothermal therapy (PTT) and photodynamic therapy (PDT) are phototherapeutic approaches, which have been widely investigated for cancer therapy mediated by an external light source. Here, a nanosystem presenting the synchronous PTT and PDT effect realized through one-step near-infrared (NIR) light irradiation is reported. This system was fabricated by conjugating indocyanine green (ICG) on hollow gold nanospheres (HAuNS) using branched-polyethylenimine (PEI, MW = 10 kDa) as optimal linker, which provided a high ICG payload as well as a covering layer with suitable thickness on HAuNS to maintain ICG fluorescence and reactive oxygen species (ROS) productivity. The resulting system (ICG-PEI-HAuNS) had the molar ratio of ICG:PEI:Au = 3:0.33:5. Compared with free ICG, ICG-PEI-HAuNS exhibited dramatically enhanced stability of ICG molecules and greater intratumoral accumulation. The conjugation of ICG caused significantly higher plasmon absorption of ICG-PEI-HAuNS in the NIR region compared with HAuNS alone, inducing remarkably enhanced photothermal conversion efficiency and synchronous photodynamic effect under NIR light irradiation. Interestingly, compared with PTT or PDT alone, synchronous PTT and PDT produced by ICG-PEI-HAuNS upon NIR light irradiation induced significantly stronger antitumor and metastasis inhibition effects both in vitro and in vivo, which might be a promising strategy for cancer treatment.
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http://dx.doi.org/10.1021/acsami.6b13351DOI Listing
February 2017

Smart Carbon Nanotubes with Laser-Controlled Behavior in Gene Delivery and Therapy through a Non-Digestive Trafficking Pathway.

Small 2016 Dec 28;12(48):6753-6766. Epub 2016 Sep 28.

College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang, 310058, P. R. China.

Near-infrared (NIR) laser-controlled gene delivery presents some benefits in gene therapy, inducing enhanced gene transfection efficiency. In this study, a "photothermal transfection" agent is obtained by wrapping poly(ethylenimine)-cholesterol derivatives (PEI-Chol) around single-walled carbon nanotubes (SWNTs). The PEI-Chol modified SWNTs (PCS) are effective in compressing DNA molecules and protecting them from DNaseI degradation. Compared to the complexes formed by PEI with DNA (PEI/DNA), complexes of PCS and DNA that are formed (PCS/DNA) exhibit a little lower toxicity to HEK293 and HeLa cells under the same PEI molecule weight and weight ratios. Notably, caveolae-mediated cellular uptake of PCS/DNA occurs, which results in a safer intracellular transport of the gene due to the decreased lysosomal degradation in comparison with that of PEI/DNA whose internalization mainly depends on clathrin rather than caveolae. Furthermore, unlike PEI/DNA, PCS/DNA exhibits a photothermal conversion ability, which promotes DNA release from PCS under NIR laser irradiation. The NIR laser-mediated photothermal transfection of PCS /plasmid TP53 (pTP53) results in more apoptosis and necrosis of HeLa cells in vitro than other groups, and achieves a higher tumor-growth inhibition in vivo than naked pTP53, PEI /pTP53, and PCS /pTP53 alone. The enhanced transfection efficiency of PCS/DNA can be attributed to more efficient DNA internalization into the tumor cells, promotes detachment of DNA from PCS under the mediation of NIR laser and higher DNA stability in the cells due to caveolae-mediated cellular uptake of the complexes.
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http://dx.doi.org/10.1002/smll.201601092DOI Listing
December 2016

Appropriate Size of Magnetic Nanoparticles for Various Bioapplications in Cancer Diagnostics and Therapy.

ACS Appl Mater Interfaces 2016 Feb 27;8(5):3092-106. Epub 2016 Jan 27.

College of Pharmaceutical Sciences, Zhejiang University , 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, P. R. China.

The development of multifunctional nanoparticles has attracted increasing attention. The versatility of nanoparticles largely depends on their physiochemical properties (especially size). However, the optimized size range may be different for the bioapplications of each function associated with multifunctional nanoparticles. It is important to investigate every optimized size range to ascertain which size enables the best function of the nanoparticles before deciding their final size. In this work, we synthesized a series of monodisperse Fe3O4 nanoparticles with identical surface properties ranging in size from 60 to 310 nm and systematically investigated their biobehavior and application. Our data indicate that compared to their large counterparts, small Fe3O4 nanoparticles exhibited greater cellular internalization and deeper penetration into multicellular spheroids, thus enabling a higher photothermal ablation efficacy in vitro. Interestingly, larger Fe3O4 nanoparticles showed greater accumulation in tumors, thereby inducing more efficient tumor growth inhibition. In addition, 120 nm may be the optimal diameter of Fe3O4 nanoparticles for magnetic resonance imaging and photoacoustic tomography in vitro. However, more efficient in vivo imaging mediated by Fe3O4 nanoparticles will predominantly depend on their high accumulation. Our work presents a different appropriate size range for each biofunction of Fe3O4 nanoparticles, which could be a valuable reference for future nanoparticle design.
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http://dx.doi.org/10.1021/acsami.5b10352DOI Listing
February 2016

Specific photothermal therapy to the tumors with high EphB4 receptor expression.

Biomaterials 2015 Nov 3;68:32-41. Epub 2015 Aug 3.

College of Pharmaceutical Sciences, Zhejiang University, Yuhangtang Road 866, Hangzhou 310058, People's Republic of China. Electronic address:

Photothermal therapy (PTT) employs photo-absorbing agents to generate heat from optical energy, leading to the 'burning' of tumor cells. Real-time imaging of in vivo distribution of photothermal agents and monitoring of post-treatment therapeutic outcomes are very important to design and optimize personalized PTT treatment. In this work, we used chitosan-stearic acid copolymer (CSO-SA) to encapsulate hollow gold nanospheres (HAuNS) and near-infrared (NIR) fluorescent tracer, DiR. Then, the surface of nanoparticles was further conjugated with a peptide (TNYL), which facilitates EphB4-positive tumor targeting delivery. Using a paired tumor mode in vivo and a double tumor-cell co-culture strategy in vitro, we demonstrated the feasibility of increasing the accumulation of our nanoparticles (DiR loaded and TNYL-CSO-SA coated HAuNS (DTCSH)) into EphB4-positive tumors through interaction between TNYL-peptide on the nanoparticles and EpHB4 receptors on tumor cells. When combined with NIR laser irradiation, our nanoparticles induced more EphB4-positive tumor cells death in vitro. We further developed optical imaging to temporally and spatially monitor the biodistribution of DTCSH. Under NIR laser irradiation, PTT exhibited dramatically stronger antitumor effect against EphB4-positive tumors than EphB4-negative tumors. This was attributed to enhanced accumulation of our nanoparticles in EphB4-positive tumors.
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http://dx.doi.org/10.1016/j.biomaterials.2015.07.058DOI Listing
November 2015

The ComP-ComA quorum system is essential for "Trojan horse" like pathogenesis in Bacillus nematocida.

PLoS One 2013 9;8(10):e76920. Epub 2013 Oct 9.

Laboratory for Conservation and Utilization of Bio-Resources and Key Laboratory for Microbial Resources of the Ministry of Education, Yunnan University, Kunming, Yunnan, PR China ; Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, PR China.

Bacillus nematocida B16 has been shown to use "Trojan horse" mechanism in pathogenesis that has characteristics of "social" behavior. The ComP-ComA system, a conserved quorum sensing system in the genus Bacillus, functions in many physiological processes including competence development, lipopeptide antibiotic surfactin production, degradative enzyme production and even some unknown functions. Here we investigated the requirement of ComP-ComA system in B. nematocida B16 for its pathogenicity against nematodes. The ΔcomP mutant displayed deficiencies in attracting and killing nematodes, due to the absence of attractive signal molecules and the decreased expressions of virulence factors, respectively. Contrarily, a complemented comP mutant at least partially resumed its pathogenicity. Our data from transcriptional analysis further confirmed that this signaling system directly or indirectly regulated the expressions of two major virulence proteases in the infection of B. nematocida B16. Bioinformatics analyses from comparative genomics also suggested that the potential target genes of transcription factor ComA were involved in the processes such as the synthesis of attractants, production of extracellular degradative enzymes and sortase, secondary metabolites biosynthesis, regulation of transcription factors, mobility, as well as transporters, most of which were different from a saprophytic relative B. subtilis 168. Therefore, our investigation firstly revealed that the participation and necessity of ComP-ComA signaling system in bacterial pathogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076920PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793909PMC
June 2014

Genetic and physiological diversity of phylogenetically and geographically distinct groups of Arthrobacter isolated from lead-zinc mine tailings.

FEMS Microbiol Ecol 2004 Aug;49(2):333-41

Key Laboratory of Conservation and Utilization for Bio-resources, Yunnan University, Kunming 650091, PR China.

The phylogenetic positions of 60 bacterial strains isolated from three tailing piles were determined by analyzing their partial 16S rRNA gene sequences. These strains were divided into three phylogenetically distinct groups of Arthrobacter and likely represented several non-described species. The physiological diversities of these phylogenetically and geographically distinct populations were evaluated based on their resistance to five heavy metals (Zn, Pb, Cd, Cu and Co) and four antibiotics (Kan, Rif, Str and Amp), and differences in utilization of 49 carbon sources. Genetic differentiations were demonstrated with randomly amplified polymorphic DNA (RAPD) analysis. These biological parameters were significantly different among three phylogenetically distinct groups. Notably, detectable differences were also observed among three geographically distinct subdivisions with similar taxonomic position. These results indicate that mine tailings are an ideal site for investigating the differentiation of natural bacterial populations in response to extreme metal contamination. Additionally, these environments appear to harbor many previously not characterized bacterial species, which are potentially important candidates for application in bioremediation due to their remarkable resistance to multiple metals.
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http://dx.doi.org/10.1016/j.femsec.2004.04.009DOI Listing
August 2004
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