Publications by authors named "Jianrong Wu"

234 Publications

Self-synergistic effect of Prussian blue nanoparticles for cancer therapy: driving photothermal therapy and reducing hyperthermia-induced side effects.

J Nanobiotechnology 2021 May 4;19(1):126. Epub 2021 May 4.

Shanghai Institute of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, People's Republic of China.

Background: Photothermal therapy (PTT), involving application of localized hyperthermia to kill cancer cells, has attracted wide attention in cancer therapy. The production of reactive oxygen species (ROS) during PTT may cause irreversible damage to healthy tissues around the tumor. Simultaneously, hyperthermia can stimulate inflammatory response, thus promoting tumor recurrence and metastasis. Therefore, it is of paramount importance to reduce the undesired side effects for further development of PTT.

Results: Using a hydrothermal method, spherical Prussian blue nanoparticles (PBs) with uniform size were prepared. The PBs exhibited good dispersion and stability in saline with an average hydrodynamic size of 110 nm. The prepared PBs had a high photothermal conversion efficiency and photothermal stability. The PBs showed intrinsic ROS scavenging properties in vitro. Antioxidant and anti-inflammatory effects of PBs were also observed in vivo. Assessment of toxicity and endoplasmic reticulum stress-inducing ability showed that PBs did not induce an inflammatory response. Tissues of major organs of mice stained with hematoxylin-eosin showed no significant damage, indicating good biocompatibility and safety of PBs.

Conclusion: The designed single-component PBs with intrinsic ROS scavenging and anti-inflammatory properties could avoid inflammatory response and heat stress-induced ROS during PTT. Thus, further research on PBs is worthwhile to achieve their clinical translation and promote the development of PTT.
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http://dx.doi.org/10.1186/s12951-021-00819-2DOI Listing
May 2021

Metabolic profiles of oligosaccharides derived from four microbial polysaccharides by faecal inocula from type 2 diabetes patients.

Int J Food Sci Nutr 2021 Apr 17:1-12. Epub 2021 Apr 17.

The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, China.

digestion of curdlan oligosaccharides (COSs), pullulan oligosaccharides (POSs), xanthan gum oligosaccharides (XGOSs) and gellan gum oligosaccharides (GGOSs) was investigated. These four oligosaccharides showed resistance to simulated saliva and gastric and small intestinal fluid. In further fermentation with faecal microbiota from healthy subjects and type 2 diabetes (T2D) patients, COS fermentation significantly increased the abundance of spp. and spp. and the production of short-chain fatty acids in healthy and T2D groups. Digestion of XGOS enhanced the growth of the subgroup and significantly increased butyric acid production in healthy and T2D groups. Sole fermentation with COS, POS, XGOS and GGOS exhibited different metabolic profiles between healthy and T2D groups, and more small molecule polyols were produced in the T2D group than in the healthy group. This study provides a novel perspective on the reconstruction of gut microbiota and metabolism by POS, COS, GGOS and XGOS intervention.
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http://dx.doi.org/10.1080/09637486.2021.1908964DOI Listing
April 2021

Impact of Patient Load on the Quality of Electronic Medical Record Documentation.

J Med Educ Curric Dev 2021 Jan-Dec;8:2382120520988597. Epub 2021 Jan 20.

Department of Internal Medicine, Monmouth Medical Center, Long Branch, NJ, USA.

Objective: American College of Graduate Medical Education (ACGME) recommends ongoing care of 10 patients per resident however its implication is unclear. We hypothesized EMR quality to vary based on patient load and call status.

Methods: We conducted a double-blind, single-center, retrospective observational study between 2017 and 2019 to investigate the quality and accuracy of resident documentation using the Responsible Electronic Documentation (RED) Checklist, a validated scoring system.

Results: A total of 234 independent charts were analyzed and 80 met scoring criteria. Average patients per residents was 4, 9.1, 7.2, and 5.5 on "call" day (D0), "post-call" day (D1), "mid-call" day (D2), and "pre-call" day (D3), respectively. Mean RED checklist scores were 68.1%, 57%, 68.6%, and 72.1% on the above call status. The difference in score between D3 and D1 was statistically significant ( = .00042). There was a negative correlation between score and number of patients per resident ( = -0.286,  = .010).

Conclusion: EMR documentation quality is directly impacted by patient load and resident call status with the lowest documentation quality on post-call day, correlating with patient load.
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http://dx.doi.org/10.1177/2382120520988597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940739PMC
January 2021

Hollow Mesoporous Silica Nanoparticles Gated by Chitosan-Copper Sulfide Composites as Theranostic Agents for the Treatment of Breast Cancer.

Acta Biomater 2021 May 14;126:408-420. Epub 2021 Mar 14.

College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, P.R. China. Electronic address:

The combination of chemotherapy and photothermal therapy (PTT) into a single formulation has attracted increasing attention as a strategy for enhancing cancer treatment. Here, hollow mesoporous silica nanoparticles (HMSNs) were used as a base carrier material, loaded with the anti-cancer drug doxorubicin (DOX), and surface functionalized with chitosan (CS) and copper sulfide (CuS) nanodots to give HMSNs-CS-DOX@CuS. In this formulation, the CuS dots act as gatekeepers to seal the surface pores of the HMSNs, preventing a burst release of DOX into the systemic circulation. S-S bonds connect the CuS dots to the HMSNs; these are selectively cleaved under the reducing microenvironment of the tumor, permitting targeted drug release. This, coupled with the PTT properties of CuS, results in a potent chemo/PTT platform. The HMSNs-CS-DOX@CuS nanoparticles have a uniform size (150 ± 13 nm), potent photothermal properties (η = 36.4 %), and tumor-targeted and near infrared (NIR) laser irradiation-triggered DOX release. In vitro and in vivo experimental results confirmed that the material has good biocompatibility, but is effectively taken up by cancer cells. Moreover, the CuS nanodots permit simultaneous thermal/photoacoustic dual-modality imaging. Treatment with HMSNs-CS-DOX@CuS and NIR irradiation caused extensive apoptosis in cancer cells both in vitro and in vivo, and could dramatically extend the lifetimes of animals in a murine breast cancer model. The system developed in this work therefore merits further investigation as a potential nanotheranostic platform for cancer treatment. STATEMENT OF SIGNIFICANCE: Conventional cancer chemotherapy is accompanied by unavoidable off-target toxicity. Combination therapies, which can ameliorate these issues, are attracting significant attention. Here, the anticancer drug doxorubicin (DOX) was encapsulated in the central cavity of chitosan (CS)-modified hollow mesoporous silica nanoparticles (HMSNs). The prepared system can target drug release to the tumor microenvironment. When exposed to near infrared laser (NIR) irradiation, CuS nanodots located at the surface pores of the HMSNs generate energy, accelerating drug release. In addition, a systematic in vitro and in vivo evaluation confirmed the HMSNs-CS-DOX@CuS platform to give highly effective synergistic chemotherapeutic-photothermal therapy and have effective thermal/photoacoustic dual-imaging properties. This work may open up a new avenue for NIR-enhanced synergistic therapy with simultaneous thermal/photoacoustic dual imaging.
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http://dx.doi.org/10.1016/j.actbio.2021.03.024DOI Listing
May 2021

Tumor Growth and Spontaneous Metastasis Assays Using A549 Lung Cancer Cells.

Bio Protoc 2020 Apr 5;10(7):e3579. Epub 2020 Apr 5.

Markey Cancer Center, University of Kentucky, Lexington, 40536-0679, USA.

Metastasis accounts for the majority of cancer related deaths. The genetically engineered mouse (GEM) models and cell line-based subcutaneous and orthotopic mouse xenografts have been developed to study the metastatic process. By using lung cancer cell line A549 as an example, we present a modified protocol to establish the cell line-based xenograft. Our protocol ensures sufficient establishment of the mouse xenografts and allows us to monitor tumor growth and spontaneous metastasis. This protocol could be adapted to other types of established cancer cell lines or primary cancer cells to study the mechanism of metastatic process as well as to test the effect of the potential anti-cancer agents on tumor growth and metastatic capacity.
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http://dx.doi.org/10.21769/BioProtoc.3579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842773PMC
April 2020

Real world clinicopathologic observations of patients with metastatic solid tumors receiving immune checkpoint inhibitor therapy: Analysis from Kentucky Cancer Registry.

Cancer Med 2021 Mar 22;10(6):2054-2062. Epub 2021 Feb 22.

Department of Internal Medicine, University of Kentucky, Lexington, KY, USA.

The state of Kentucky has the highest cancer incidence and mortality in the United States. High-risk populations such as this are often underrepresented in clinical trials. The study aims to do a comprehensive analysis of molecular landscape of metastatic cancers among these patients with detailed evaluation of factors affecting response and outcomes to immune checkpoint inhibitor (ICI) therapy. We performed a retrospective analysis of metastatic solid tumor patients who received ICI and underwent molecular profiling at our institution. Sixty nine patients with metastatic solid tumors who received ICI were included in the study. Prevalence of smoking and secondhand tobacco exposure was 78.3% and 14.5%, respectively. TP53 (62.3%), CDKN1B/2A (40.5%), NOTCH and PIK3 (33.3%) were the most common alterations in tumors. 67.4% were PDL1 positive and 59.4% had intermediate-high tumor mutational burden (TMB). Median TMB (12.6) was twofold to fourfold compared to clinical trials. The prevalence of mutations associated with smoking, homologous recombinant repair and PIK3/AKT/mTOR pathway mutations was higher compared to historic cohorts. PDL1 expression had no significant effect on radiologic response, but PFS improvement in patients with tumors expressing PDL1 trended toward statistical significance (median 18 vs. 40 weeks. HR = 1.43. 95%CI 0.93, 4.46). Median PFS was higher in the high-TMB cohort compared to low-intermediate TMB (median not reached vs. 26 weeks; HR = 0.37. 95%CI 0.13, 1.05). A statistically significant improvement in PFS was observed in the PIK3 mutated cohort (median 123 vs. 23 weeks. HR = 2.51. 95%CI 1.23, 5.14). This was independent of tumor mutational burden (TMB) status or PDL1 expression status. PIK3 mutants had a higher overall response rate than the wild type (69.6% vs. 43.5%, OR 0.34; p = 0.045). The results should prompt further evaluation of these potential biomarkers and more widespread real-world data publications which might help determine biomarkers that could benefit specific populations.
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http://dx.doi.org/10.1002/cam4.3802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957185PMC
March 2021

Excavating bioactivities of nanozyme to remodel microenvironment for protecting chondrocytes and delaying osteoarthritis.

Bioact Mater 2021 Aug 29;6(8):2439-2451. Epub 2021 Jan 29.

Shanghai Institute of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, PR China.

Osteoarthritis (OA) is the main cause of disability in the elderly. Effective intervention in the early and middle stage of osteoarthritis can greatly prevent or slow down the development of the disease, and reduce the probability of joint replacement. However, there is to date no effective intervention for early and middle-stage OA. OA microenvironment mainly destroys the balance of oxidative stress, extracellular matrix synthesis and degradation of chondrocytes under the joint action of biological and mechanical factors. Herein, hollow Prussian blue nanozymes (HPBzymes) were designed via a modified hydrothermal template-free method. The aim of this study was to investigate the effects of HPBzymes on chondrocytes and the progression of OA. The intrinsic bioactivities of HPBzymes were excavated and , remodeling microenvironment for significantly protecting chondrocytes and delaying the progression of traumatic OA by inhibiting reactive oxygen species (ROS) and Rac1/nuclear factor kappa-B (NF-κB) signaling in a rat model. HPBzyme significantly diminished interleukin (IL)-1β-stimulated inflammation, extracellular matrix degradation, and apoptosis of human chondrocytes. HPBzyme attenuated the expression of Rac1 and the ROS levels and prevented the release and nuclear translocation of NF-κB. Deeply digging the intrinsic bioactivities of nanozyme with single component to remodel microenvironment is an effective strategy for ROS-associated chronic diseases. This study reveals that excavating the bioactivities of nanomedicine deserves attention for diagnosis and treatment of severe diseases.
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http://dx.doi.org/10.1016/j.bioactmat.2021.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848724PMC
August 2021

Development and validation of an artificial intelligence system for grading colposcopic impressions and guiding biopsies.

BMC Med 2020 12 22;18(1):406. Epub 2020 Dec 22.

Department of Cancer Epidemiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.

Background: Colposcopy diagnosis and directed biopsy are the key components in cervical cancer screening programs. However, their performance is limited by the requirement for experienced colposcopists. This study aimed to develop and validate a Colposcopic Artificial Intelligence Auxiliary Diagnostic System (CAIADS) for grading colposcopic impressions and guiding biopsies.

Methods: Anonymized digital records of 19,435 patients were obtained from six hospitals across China. These records included colposcopic images, clinical information, and pathological results (gold standard). The data were randomly assigned (7:1:2) to a training and a tuning set for developing CAIADS and to a validation set for evaluating performance.

Results: The agreement between CAIADS-graded colposcopic impressions and pathology findings was higher than that of colposcopies interpreted by colposcopists (82.2% versus 65.9%, kappa 0.750 versus 0.516, p < 0.001). For detecting pathological high-grade squamous intraepithelial lesion or worse (HSIL+), CAIADS showed higher sensitivity than the use of colposcopies interpreted by colposcopists at either biopsy threshold (low-grade or worse 90.5%, 95% CI 88.9-91.4% versus 83.5%, 81.5-85.3%; high-grade or worse 71.9%, 69.5-74.2% versus 60.4%, 57.9-62.9%; all p < 0.001), whereas the specificities were similar (low-grade or worse 51.8%, 49.8-53.8% versus 52.0%, 50.0-54.1%; high-grade or worse 93.9%, 92.9-94.9% versus 94.9%, 93.9-95.7%; all p > 0.05). The CAIADS also demonstrated a superior ability in predicting biopsy sites, with a median mean-intersection-over-union (mIoU) of 0.758.

Conclusions: The CAIADS has potential in assisting beginners and for improving the diagnostic quality of colposcopy and biopsy in the detection of cervical precancer/cancer.
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http://dx.doi.org/10.1186/s12916-020-01860-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754595PMC
December 2020

Cancer immunotherapy trial design with long-term survivors.

Pharm Stat 2021 01 1;20(1):117-128. Epub 2020 Sep 1.

Biostatistics and Bioinformatics Shared Resource Facility Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.

Cancer immunotherapy often reflects the improvement in both short-term risk reduction and long-term survival. In this scenario, a mixture cure model can be used for the trial design. However, the hazard functions based on the mixture cure model between two groups will ultimately crossover. Thus, the conventional assumption of proportional hazards may be violated and study design using standard log-rank test (LRT) could lose power if the main interest is to detect the improvement of long-term survival. In this paper, we propose a change sign weighted LRT for the trial design. We derived a sample size formula for the weighted LRT, which can be used for designing cancer immunotherapy trials to detect both short-term risk reduction and long-term survival. Simulation studies are conducted to compare the efficiency between the standard LRT and the change sign weighted LRT.
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http://dx.doi.org/10.1002/pst.2060DOI Listing
January 2021

Efficient and Effective Training of COVID-19 Classification Networks With Self-Supervised Dual-Track Learning to Rank.

IEEE J Biomed Health Inform 2020 10 20;24(10):2787-2797. Epub 2020 Aug 20.

Coronavirus Disease 2019 (COVID-19) has rapidly spread worldwide since first reported. Timely diagnosis of COVID-19 is crucial both for disease control and patient care. Non-contrast thoracic computed tomography (CT) has been identified as an effective tool for the diagnosis, yet the disease outbreak has placed tremendous pressure on radiologists for reading the exams and may potentially lead to fatigue-related mis-diagnosis. Reliable automatic classification algorithms can be really helpful; however, they usually require a considerable number of COVID-19 cases for training, which is difficult to acquire in a timely manner. Meanwhile, how to effectively utilize the existing archive of non-COVID-19 data (the negative samples) in the presence of severe class imbalance is another challenge. In addition, the sudden disease outbreak necessitates fast algorithm development. In this work, we propose a novel approach for effective and efficient training of COVID-19 classification networks using a small number of COVID-19 CT exams and an archive of negative samples. Concretely, a novel self-supervised learning method is proposed to extract features from the COVID-19 and negative samples. Then, two kinds of soft-labels ('difficulty' and 'diversity') are generated for the negative samples by computing the earth mover's distances between the features of the negative and COVID-19 samples, from which data 'values' of the negative samples can be assessed. A pre-set number of negative samples are selected accordingly and fed to the neural network for training. Experimental results show that our approach can achieve superior performance using about half of the negative samples, substantially reducing model training time.
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http://dx.doi.org/10.1109/JBHI.2020.3018181DOI Listing
October 2020

Functionalized boron nanosheets as an intelligent nanoplatform for synergistic low-temperature photothermal therapy and chemotherapy.

Nanoscale 2020 Jul;12(27):14739-14750

College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, 201620, P.R. China.

In this work, an innovative boron-based multifunctional nanoplatform was developed for synergistic chemotherapy/low temperature photothermal therapy (PTT). This platform is functionalized with a cRGD peptide to allow the targeting of αvβ3 integrin, which is over-expressed in the cells of tumors. The nanoparticles were further loaded with the chemotherapeutic drug doxorubicin (DOX) and a heat shock protein inhibitor (17AAG), and high loading capacities for both DOX (603 mg g-1 B-PEG-cRGD) and 17AAG (417 mg g-1) were obtained. The resultant DOX-17AAG@B-PEG-cRGD system shows both pH-controlled and near-infrared (NIR)-induced DOX and 17AAG release. It also provides significantly enhanced cellular uptake in cancerous cells over healthy cells. The presence of 17AAG allows low-temperature PTT to be combined with chemotherapy with DOX, resulting in highly effective anti-cancer activity. This has been confirmed by both in vitro assays and using an in vivo murine cancer model. It is expected that such a multifunctional nanoplatform can serve as a promising candidate for cancer therapy.
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http://dx.doi.org/10.1039/d0nr02291hDOI Listing
July 2020

Prognostic and predictive factors associated with ipilimumab-related adverse events: a retrospective analysis of 11 NCI-sponsored phase I clinical trials.

Oncotarget 2020 Apr 21;11(16):1427-1434. Epub 2020 Apr 21.

Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA.

Background: We review factors impacting ipilimumab-associated adverse events through the experience from National Cancer Institute (NCI)-sponsored phase I immunotherapy clinical trials.

Materials And Methods: Attributable ipilimumab-related adverse events from NCI-sponsored phase I immunotherapy clinical trials were queried retrospectively by anonymized patient experience reports for observed adverse events like decreased hematological cell counts, blood electrolytes or proteins, or reduced patient performance status. The prevalence of ipilimumab-related toxicity was associated by patient to the duration of ipilimumab exposure, radiographic responses, progression-free survival, and overall survival.

Results: 373 patients from 11 phase 1 ipilimumab clinical trials were analyzed. Patients experiencing at least one grade 3 or 4 adverse event associated with observed radiographic response were included. The average number of grade 3/4 adverse events in responders was 1.167 versus 0.645 in non-responders ( = 0.001). Patient performance status did not significantly impact observed toxicity grade. Pretherapy lymphocyte count or chemistries were not associated with ipilimumab-associated toxicity. The number of agents combined with ipilimumab on trial was associated with average number of grade 3/4 toxicities-ipilimumab monotherapy (0.631) versus ipilimumab + 1 agent (0.877) versus ipilimumab + 2 agents (1.408) ( = 0.014). Number of low grade (grade 1/2) toxicities was associated with duration of treatment, Pearson correlation coefficient = 0.456 ( < 0.0001); whereas the number of high grade (grade 3/4) toxicities was not, = 0.032 ( = 0.546).

Conclusions: Ipilimumab-attributed grade 3/4 toxicity was associated with therapeutic response. The number of co-administered agents added to ipilimumab significantly raised the likelihood of toxicity. Extended duration of treatment increased the incidence of low but not high-grade toxicity.
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http://dx.doi.org/10.18632/oncotarget.27537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185063PMC
April 2020

Phase I expansion cohort to evaluate the combination of bevacizumab, sorafenib and low-dose cyclophosphamide in children and young adults with refractory or recurrent solid tumours.

Eur J Cancer 2020 06 20;132:35-42. Epub 2020 Apr 20.

Department of Pediatrics, Children's Hospital Los Angeles, University of Southern California, Keck School of Medicine, Los Angeles, CA 90027, USA.

Background: Angiogenesis is critical for tumour growth and metastasis. Dual inhibition of vascular endothelial growth factors and platelet-derived growth factor receptors suppresses angiogenesis. This expansion cohort of a phase I study targeted angiogenesis with sorafenib, bevacizumab and low-dose cyclophosphamide in children and young adults with recurrent solid tumours.

Methods: An expansion cohort including patients with refractory or recurrent solid tumours was enrolled and received bevacizumab (15 mg/kg IV, day 1), sorafenib (90 mg/m po twice daily, days 1-21) and low-dose cyclophosphamide (50 mg/m po daily, days 1-21). Each course was 21 days. Toxicities were assessed using Common Terminology Criteria for Adverse Events, v3.0, and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. Serial bevacizumab pharmacokinetic (PK) studies were performed during course 1.

Results: Twenty-four patients (15 males; median age 14.5 yrs; range 1-22 yr) received a median of 6 courses (range 1-18). Twelve patients had a bone or soft tissue sarcoma. The most common grade III/IV non-haematologic toxicities were hypertension (N = 4), hand/foot rash (N = 3) and elevated lipase (N = 3). The most common grade III/IV haematologic toxicities were neutropenia (N = 7) and lymphopenia (N = 17). Three patients (2 synovial sarcoma, 1 rhabdoid tumour) achieved a partial response and 18 had stable disease. The progression-free survival at 3 and 6 months were 78.1% (95% confidence interval [CI] 60.6-95.6%) and 54% (95% CI 30.2-78.2%), respectively. Bevacizumab PKs in 15 patients was similar to published adult PK results.

Conclusions: Intravenous bevacizumab combined with oral sorafenib and low-dose cyclophosphamide was tolerated and demonstrated promising activity in a subset of childhood solid tumours.
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http://dx.doi.org/10.1016/j.ejca.2020.03.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958650PMC
June 2020

Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant Mutant Ovarian Cells.

Diagnostics (Basel) 2020 Feb 22;10(2). Epub 2020 Feb 22.

Markey Cancer Center, University of Kentucky, 789 South Limestone Street, 526 Todd Building, Lexington, KY 40536, USA.

Objective: Despite the promise of PARP inhibitors (PARPi) for treating mutated ovarian cancer (OC), drug resistance invariably develops. We hypothesized rationale drug combinations, targeting key molecules in DNA repair pathways and the cell cycle may be synergistic and overcome acquired PARPi resistance.

Methods: Drug sensitivity to PARPi alone and in combination with inhibitors of key DNA repair and cell cycle proteins, including ATR (VE-821), Chk1 (MK-8776), Wee1 (MK-1775), RAD51 (RI-1) was assessed in PARPi-sensitive (UWB1) and -resistant (UWB1-R) mutant OC cell lines using a cell proliferation assay. The Bliss synergy model was used to estimate the two-drug combination effect and pharmacologic synergy (Bliss score ≥ 0) or antagonistic (Bliss score ≥ 0) response of the PARPi in combination with the inhibitors.

Results: IC for olaparib alone was 1.6 ± 0.9 µM compared to 3.4 ± 0.6 µM ( = 0.05) for UWB1 and UWB1-R cells, respectively. UWB1-R demonstrated increased sensitivity to ATRi ( = 0.04) compared to UWB1. Olaparib (0.3-1.25 µM) and ATRi (0.8-2.5 µM) were synergistic with Bliss scores of 17.2 ± 0.2, 11.9 ± 0.6 for UWB1 and UWB1-R cells, respectively. Olaparib (0.3-1.25 µM) and Chk1i(0.05-1.25 µM) were synergistic with Bliss scores of 8.3 ± 1.6, 5.7 ± 2.9 for UWB1 and UWB1-R cells, respectively.

Conclusions: Combining an ATRi or Chk1i with olaparib is synergistic in both PARPi-sensitive and -resistant mutated OC cell models, and are rationale combinations for further clinical development.
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http://dx.doi.org/10.3390/diagnostics10020121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168282PMC
February 2020

Designing cancer immunotherapy trials with delayed treatment effect using maximin efficiency robust statistics.

Pharm Stat 2020 07 24;19(4):424-435. Epub 2020 Feb 24.

Biostatistics and Bioinformatics Shared Resource Facility, Markey Cancer Center, University of Kentucky, Lexington, KY, USA.

The indirect mechanism of action of immunotherapy causes a delayed treatment effect, producing delayed separation of survival curves between the treatment groups, and violates the proportional hazards assumption. Therefore using the log-rank test in immunotherapy trial design could result in a severe loss efficiency. Although few statistical methods are available for immunotherapy trial design that incorporates a delayed treatment effect, recently, Ye and Yu proposed the use of a maximin efficiency robust test (MERT) for the trial design. The MERT is a weighted log-rank test that puts less weight on early events and full weight after the delayed period. However, the weight function of the MERT involves an unknown function that has to be estimated from historical data. Here, for simplicity, we propose the use of an approximated maximin test, the V test, which is the sum of the log-rank test for the full data set and the log-rank test for the data beyond the lag time point. The V test fully uses the trial data and is more efficient than the log-rank test when lag exits with relatively little efficiency loss when no lag exists. The sample size formula for the V test is derived. Simulations are conducted to compare the performance of the V test to the existing tests. A real trial is used to illustrate cancer immunotherapy trial design with delayed treatment effect.
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http://dx.doi.org/10.1002/pst.2003DOI Listing
July 2020

MYCN amplification and ATRX mutations are incompatible in neuroblastoma.

Nat Commun 2020 02 14;11(1):913. Epub 2020 Feb 14.

Basic Science Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.

Aggressive cancers often have activating mutations in growth-controlling oncogenes and inactivating mutations in tumor-suppressor genes. In neuroblastoma, amplification of the MYCN oncogene and inactivation of the ATRX tumor-suppressor gene correlate with high-risk disease and poor prognosis. Here we show that ATRX mutations and MYCN amplification are mutually exclusive across all ages and stages in neuroblastoma. Using human cell lines and mouse models, we found that elevated MYCN expression and ATRX mutations are incompatible. Elevated MYCN levels promote metabolic reprogramming, mitochondrial dysfunction, reactive-oxygen species generation, and DNA-replicative stress. The combination of replicative stress caused by defects in the ATRX-histone chaperone complex, and that induced by MYCN-mediated metabolic reprogramming, leads to synthetic lethality. Therefore, ATRX and MYCN represent an unusual example, where inactivation of a tumor-suppressor gene and activation of an oncogene are incompatible. This synthetic lethality may eventually be exploited to improve outcomes for patients with high-risk neuroblastoma.
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http://dx.doi.org/10.1038/s41467-020-14682-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021759PMC
February 2020

Enhancement of Sphingolipid Synthesis Improves Osmotic Tolerance of Saccharomyces cerevisiae.

Appl Environ Microbiol 2020 04 1;86(8). Epub 2020 Apr 1.

Key Laboratory of Industrial Biotechnology, Ministry of Education, Jiangnan University, Wuxi, China

To enhance the growth performance of under osmotic stress, mutant XCG001, which tolerates up to 1.5 M NaCl, was isolated through adaptive laboratory evolution (ALE). Comparisons of the transcriptome data of mutant XCG001 and the wild-type strain identified as being associated with osmotic tolerance. In the overexpression strain (XCG010), the contents of inositol phosphorylceramide (IPC; t18:0/26:0), mannosylinositol phosphorylceramide [MIPC; t18:0/22:0(2OH)], MIPC (d18:0/22:0), MIPC (d20:0/24:0), mannosyldiinositol phosphorylceramide [M(IP)C; d20:0/26:0], M(IP)C [t18:0/26:0(2OH)], and M(IP)C [d20:0/26:0(2OH)] increased by 88.3 times, 167 times, 63.3 times, 23.9 times, 27.9 times, 114 times, and 208 times at 1.0 M NaCl, respectively, compared with the corresponding values of the control strain XCG002. As a result, the membrane integrity, cell growth, and cell survival rate of strain XCG010 increased by 24.4% ± 1.0%, 21.9% ± 1.5%, and 22.1% ± 1.1% at 1.0 M NaCl, respectively, compared with the corresponding values of the control strain XCG002 (wild-type strain with a control plasmid). These findings provided a novel strategy for engineering complex sphingolipids to enhance osmotic tolerance. This study demonstrated a novel strategy for the manipulation of membrane complex sphingolipids to enhance tolerance to osmotic stress. Elo2, a sphingolipid acyl chain elongase, was related to osmotic tolerance through transcriptome analysis of the wild-type strain and an osmosis-tolerant strain generated from ALE. Overexpression of increased the content of complex sphingolipid with longer acyl chain; thus, membrane integrity and osmotic tolerance improved.
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http://dx.doi.org/10.1128/AEM.02911-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117927PMC
April 2020

Efficacy and Safety of Limited-Margin Conformal Radiation Therapy for Pediatric Rhabdomyosarcoma: Long-Term Results of a Phase 2 Study.

Int J Radiat Oncol Biol Phys 2020 05 25;107(1):172-180. Epub 2020 Jan 25.

Department of Radiation Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee. Electronic address:

Purpose: Our purpose was to assess disease outcomes and late toxicities in pediatric patients with rhabdomyosarcoma treated with conformal photon radiation therapy (RT).

Methods And Materials: Sixty-eight patients (median age, 6.9 years) were treated with conformal photon RT to the primary site on a prospective clinical trial. Target volumes included a 1-cm expansion encompassing microscopic disease. Prescribed doses were 36 Gy to this target volume and 50.4 Gy to gross residual disease. Chemotherapy consisted of vincristine/dactinomycin (n = 6), vincristine/dactinomycin/cyclophosphamide (n = 37), or vincristine/dactinomycin/cyclophosphamide-based combinations (n = 25). Patients were evaluated with primary-site magnetic resonance imaging, whole-body [F]fluorodeoxyglucose positron emission tomography, and chest computed tomography for 5 years after treatment.

Results: Five-year disease-free survival was 88% for low-risk (n = 8), 76% for intermediate-risk (n = 37), and 36% for high-risk (n = 23) patients (P ≤ .01 for low risk/intermediate risk vs high risk). The cumulative incidence of local failure (LF) at 5 years for the entire cohort was 10.4%. Tumor size at diagnosis was a significant predictor of LF (P < .01). Patients with head and neck primary tumors (n = 31) had a 35% cumulative incidence of cataracts; the risk correlated with lens dose (P = .0025). Jaw dysfunction was more severe when the pterygoid and masseter muscles received a mean dose of >20 Gy (P = .013). Orbital hypoplasia developed more frequently after a mean bony orbit dose of >30 Gy (P = .041). Late toxicity in patients with genitourinary tumors included microscopic hematuria (9 of 14), bladder-wall thickening (10 of 14), and vaginal stenosis (2 of 5).

Conclusions: Long-term LF rates were low, and higher rates correlated with larger tumors. Treatment-related toxicities resulting in measurable functional deficits were not infrequent, despite the conformal RT approach.
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http://dx.doi.org/10.1016/j.ijrobp.2020.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668436PMC
May 2020

Biomineralized Bimetallic Oxide Nanotheranostics for Multimodal Imaging-Guided Combination Therapy.

Theranostics 2020 1;10(2):841-855. Epub 2020 Jan 1.

College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, P.R. China.

The hypoxia of the tumor microenvironment (TME) often hinders the effectiveness of cancer treatments, especially O-dependent photodynamic therapy (PDT). An integrated iridium oxide (IrO)-manganese dioxide (MnO) nanotheranostic agent was fabricated through bovine serum albumin (BSA)-based biomineralization of Ir and Mn. BSA was first covalently modified with chlorin e6 (Ce6), and used to fabricate multifunctional BSA-Ce6@IrO/MnO nanoparticles (NPs) for computed X-ray tomography (CT) and photoacoustic (PA) imaging-guided PDT and photothermal (PTT) therapy of cancer. Extensive and studies were performed. The theranostic agent produced can relieve tumor hypoxia by the decomposition of endogenous HO in cancer cells to oxygen. The oxygen generated can be exploited for improved PDT. Paramagnetic Mn released from the NPs in the acidic TME permits magnetic resonance imaging (MRI) to be performed. The exceptional photothermal conversion efficiency (65.3%) and high X-ray absorption coefficient of IrO further endow the NPs with the ability to be used in computed CT and PA imaging. Extensive antitumor studies demonstrated that the BSA-Ce6@IrO/MnO nanoplatform inhibits cancer cell growth, particularly after combined PTT and PDT. Systematic biosafety evaluations confirmed the high biocompatibility of the nanoplatform. This work not only provides a novel strategy for designing albumin-based nanohybrids for theranostic applications but also provides a facile approach for extending the biomedical applications of iridium-based materials.
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http://dx.doi.org/10.7150/thno.40715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929990PMC
April 2021

A Tumor Microenvironment-Responsive Biodegradable Mesoporous Nanosystem for Anti-Inflammation and Cancer Theranostics.

Adv Healthc Mater 2020 01 9;9(2):e1901307. Epub 2019 Dec 9.

College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, 201620, P. R. China.

A nanoplatform that integrates diagnostic and therapeutic functions with intrinsic tumor microenvironment-responsive biodegradability is highly desired. Herein, a biodegradable nanotheranostic agent based on hollow mesoporous organosilica nanoparticles (HMONs), followed by encapsulating of heat shock protein 90 (Hsp 90) inhibitor is described. Then, the pore-engineering including gating with bovine serum albumin-iridium oxide nanoparticles (BSA-IrO ) and conjugation of polyethylene glycol (PEG) is conducted to yield 17AAG@HMONs-BSA-IrO -PEG (AHBIP) nanotheranostics for multimode computed tomography (CT)/photoacoustic (PA) imaging-guided photodynamic therapy (PDT) and low-temperature photothermal therapy (PTT). Such nanoplatforms show extraordinary photothermal conversion efficiency, high cargo loading (35.4% for 17AAG), and stimuli-responsive release of 17AAG for inhibition of Hsp90, which induces cell apoptosis at low-temperatures (≈41 °C). Also, the IrO simultaneously endows the nanotheranostics with catalytic activity in triggering the decomposition of H O into O and thus reducing the tumor hypoxia, as well as protecting normal tissues against H O -induced inflammation. AHBIP shows good photocatalysis activity for PDT as a result of the generation of superoxide anion by laser irradiation. The resulting AHBIP-mediated synergistic PTT/PDT offers an outstanding therapeutic outcome both in vitro and in vivo. Overall, the incorporation of the BSA-IrO and biodegradable HMONs into one nanoplatform has great potential for clinical applications.
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http://dx.doi.org/10.1002/adhm.201901307DOI Listing
January 2020

Cancer immunotherapy trial design with cure rate and delayed treatment effect.

Stat Med 2020 03 26;39(6):698-708. Epub 2019 Nov 26.

Biostatistics and Bioinformatics Shared Resource Facility Markey Cancer Center, University of Kentucky, Lexington, Kentucky.

Cancer immunotherapy trials have two special features: a delayed treatment effect and a cure rate. Both features violate the proportional hazard model assumption and ignoring either one of the two features in an immunotherapy trial design will result in substantial loss of statistical power. To properly design immunotherapy trials, we proposed a piecewise proportional hazard cure rate model to incorporate both delayed treatment effect and cure rate into the trial design consideration. A sample size formula is derived for a weighted log-rank test under a fixed alternative hypothesis. The accuracy of sample size calculation using the new formula is assessed and compared with the existing methods via simulation studies. A real immunotherapy trial is used to illustrate the study design along with practical consideration of balance between sample size and follow-up time.
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http://dx.doi.org/10.1002/sim.8440DOI Listing
March 2020

Two-stage phase II survival trial design.

Pharm Stat 2020 05 21;19(3):214-229. Epub 2019 Nov 21.

Department of Internal Medicine, Division of Medical Oncology, University of Kentucky, Lexington, Kentucky, USA.

Recently, molecularly targeted agents and immunotherapy have been advanced for the treatment of relapse or refractory cancer patients, where disease progression-free survival or event-free survival is often a primary endpoint for the trial design. However, methods to evaluate two-stage single-arm phase II trials with a time-to-event endpoint are currently processed under an exponential distribution, which limits application of real trial designs. In this paper, we developed an optimal two-stage design, which is applied to the four commonly used parametric survival distributions. The proposed method has advantages compared with existing methods in that the choice of underlying survival model is more flexible and the power of the study is more adequately addressed. Therefore, the proposed two-stage design can be routinely used for single-arm phase II trial designs with a time-to-event endpoint as a complement to the commonly used Simon's two-stage design for the binary outcome.
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http://dx.doi.org/10.1002/pst.1983DOI Listing
May 2020

Preparation and property of a biantenna macromolecule based on polysialic acid.

Int J Biol Macromol 2020 Jul 13;155:1342-1349. Epub 2019 Nov 13.

Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, China. Electronic address:

Polysialic acid (PSA), an acidic polysaccharide usually exists as a double-chain structure on cell adhesion molecules in vertebrates. The available PSA produced from Escherichia coli fermentation, however, is monochain PSA. In this work, a biomimetic biantenna type PSA (biPSA) was synthesized in vitro under mild conditions, and the terminal nonreducing ends of sialic acid residue were retained. The structure of biPSA was characterized through infrared spectroscopy, and NMR, and the double-chain structure of biPSA was confirmed by the doubled molecular weight and particle size of biPSA. Analysis through circular dichroism, isothermal titration calorimetry, and thermostability experiments revealed that the obtained biPSA was more stable in aqueous solution than PSA, especially after complexation with Ca, which increased the variation in enthalpy and entropy. However, the addition of Cu had a negligible effect on configuration of PSA and biPSA. The addition of Ca promoted cell proliferation in a culture of microglia BV-2 cells with biPSA in medium. By contrast, the addition of Cu had toxic effects. Supplementation with biPSA can maintain cell viability for a longer period than supplementation with monochain PSA. This work indicates that biPSA is a potential substitute for monochain PSA in practical applications.
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http://dx.doi.org/10.1016/j.ijbiomac.2019.11.107DOI Listing
July 2020

Cancer immunotherapy trial design with delayed treatment effect.

Pharm Stat 2020 05 15;19(3):202-213. Epub 2019 Nov 15.

Department of Statistics, University of Kentucky, Lexington, Kentucky.

A challenge arising in cancer immunotherapy trial design is the presence of a delayed treatment effect wherein the proportional hazard assumption no longer holds true. As a result, a traditional survival trial design based on the standard log-rank test, which ignores the delayed treatment effect, will lead to substantial loss of statistical power. Recently, a piecewise weighted log-rank test is proposed to incorporate the delayed treatment effect into consideration of the trial design. However, because the sample size formula was derived under a sequence of local alternative hypotheses, it results in an underestimated sample size when the hazard ratio is relatively small for a balanced trial design and an inaccurate sample size estimation for an unbalanced design. In this article, we derived a new sample size formula under a fixed alternative hypothesis for the delayed treatment effect model. Simulation results show that the new formula provides accurate sample size estimation for both balanced and unbalanced designs.
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http://dx.doi.org/10.1002/pst.1982DOI Listing
May 2020

Group sequential design for historical control trials using error spending functions.

J Biopharm Stat 2020 03 12;30(2):351-363. Epub 2019 Nov 12.

Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.

Group sequential designs using Lan-DeMets error spending functions are proposed for historical control trials with time-to-event endpoints. Both O'Brien-Fleming and Gamma family types of sequential decision boundaries are derived based on sequential log-rank tests, which follow a Brownian motion in a transformed information time. Simulation results show that the proposed group sequential designs using historical controls preserve the overall type I error and power.
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http://dx.doi.org/10.1080/10543406.2019.1684305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737423PMC
March 2020

A multifunctional nanoplatform based on MoS-nanosheets for targeted drug delivery and chemo-photothermal therapy.

Colloids Surf B Biointerfaces 2020 Jan 17;185:110585. Epub 2019 Oct 17.

College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, 201620, China. Electronic address:

Synergistic tumor treatment has recently attracted more and more attention due to its remarkable therapeutic effect. Herein, a multifunctional drug delivery system based on hyaluronic acid (HA) targeted dual stimulation responsive MoS nanosheets (HA-PEI-LA-MoS-PEG, HPMP) for active interaction with CD44 receptor positive MCF-7 cells is reported. Melanin (Mel), a new type of photothermal agent and doxorubicin (DOX) are both loaded onto the HPMP nanocomposite and can be released by mild acid or hyperthermia. The prepared HPMP nanocomposite has a uniform hydrodynamic diameter (104 nm), a high drug loading (944.3 mg.g HPMP), a remarkable photothermal effect (photothermal conversion efficiency: 55.3%) and excellent biocompatibility. The DOX release from HPMP@(DOX/Mel) can be precisely controlled by the dual stimuli of utilizing the acidic environment in the tumor cells and external laser irradiation. Meanwhile, loading of Mel onto the surface can enhance the photothermal effect of the MoS nanosheets. In vitro experiments showed that the HPMP@(DOX/Mel) nanoplatform could efficiently deliver DOX into MCF-7 cells and demonstrated enhanced cytotoxicity compared to that of the non-targeted nanoplatform. In vivo experiments in a breast cancer model of nude mice further confirmed that the HPMP@(DOX/Mel) significantly inhibited tumor growth under near infrared (NIR) laser irradiation, which is superior to any single therapy. In summary, this flexible nanoplatform, based on multi-faceted loaded MoS nanosheets, exhibits considerable potential for efficient pH/NIR-responsive targeted drug delivery and chemo-photothermal synergistic tumor therapy.
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http://dx.doi.org/10.1016/j.colsurfb.2019.110585DOI Listing
January 2020

A Phase II Trial of Hu14.18K322A in Combination with Induction Chemotherapy in Children with Newly Diagnosed High-Risk Neuroblastoma.

Clin Cancer Res 2019 11 10;25(21):6320-6328. Epub 2019 Oct 10.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Purpose: We sought to evaluate whether combining a humanized antidisialoganglioside mAb (hu14.18K322A) with induction chemotherapy improves early responses and outcomes in children with newly diagnosed high-risk neuroblastoma.

Patients And Methods: We conducted a prospective nonrandomized, single-arm, two-stage, phase II clinical trial. Six courses of induction chemotherapy were coadministered with hu14.18K322A and followed with granulocyte-macrophage colony-stimulating factor (GM-CSF) and low-dose IL2. Consolidation was performed with a busulfan/melphalan preparative regimen. An additional course of hu14.18K322A was administered with parent-derived natural killer cells, when available, during consolidation. Hu14.18K322A, GM-CSF, IL2, and isotretinoin were then administered. Secondary outcomes included reduced tumor volume and semiquantitative I-metaiodobenzylguanidine scoring [i.e., Curie scores (CS)] at the end of induction.

Results: Forty-two patients received hu14.18K322A and induction chemotherapy. This regimen was well tolerated, with continuous-infusion narcotics adjusted to patient tolerance. Partial responses (PR) or better after the first two chemoimmunotherapy courses occurred in 32 patients [76.2%; 95% confidence interval (CI), 60.6-88.0]. This was accompanied by primary tumor volume reductions (median, -76%; range, -100% to 5%). Of 35 patients with stage IV disease who completed induction, 31 had end-of-induction CSs of 2 or less. No patients experienced progression during induction. Two-year event-free survival (EFS) was 85.7% (95% CI, 70.9-93.3).

Conclusions: Adding hu14.18K322A to induction chemotherapy produced early PR or better in most patients, reduced tumor volumes, improved CSs at the end of induction, and yielded an encouraging 2-year EFS. These results, if validated in a larger study, may change the standard of care for children with high-risk neuroblastoma.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825564PMC
November 2019

Biodegradable nanotheranostics with hyperthermia-induced bubble ability for ultrasound imaging-guided chemo-photothermal therapy.

Int J Nanomedicine 2019 3;14:7141-7153. Epub 2019 Sep 3.

Department of Ultrasound, Shanghai General Hospital of Nanjing Medical University, Shanghai 201600, People's Republic of China.

Background: Theranostics, elaborately integrating both therapeutic and diagnostic functions into a nanoplatform holds great potential for precision cancer medicine.

Methods: Herein, a biodegradable theranostic nanoplatform with hyperthermia-induced bubble ability for highly efficient ultrasound (US) imaging-guided chemo-photothermal therapy of breast tumors was developed. The prepared nanoparticles consisted of polydopamine (PDA)-modified hollow mesoporous organosilica nanoparticles (HMONs) with approximately 75 nm in diameter for doxorubicin (DOX) loading and perfluoropentane (PFP) filling. In addition, the pH-sensitive PDA coating served as both gatekeeper controlling DOX release and photothermal agent for inducing hyperthermia.

Results: Such nanoplatform (PDA@HMONs-DOX/PFP, PHDP) provides efficient loading (328 mg/g) and controllable stimuli-responsive release of DOX for chemotherapy. The incorporated disulfide bonds in the framework of HMONs endowed nanoparticles with intrinsic glutathione-responsive biodegradability and improved biocompatibility. Benefiting from the hyperthermia upon an 808-nm laser irradiation of PDA, the liquid-gas phase transition of the loaded PFP was induced, resulting in the generation of the nanobubbles, followed by the coalescence into microbubbles. This conversation could enhance the tumor cell uptake of nanoparticles, as well as intensify the US imaging signals. In addition, a synergistic therapeutic effect of our fabricated nanoplatform on cells/tumor growth effect has been systematically evaluated both in vitro and in vivo.

Conclusion: Therefore, such "all-in-one" PHDP nanoparticles with satisfactory biocompatibility and biodegradability, hyperthermia-induced bubble ability and simultaneous US imaging performance hold great potential for cancer nanotheranostics.
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http://dx.doi.org/10.2147/IJN.S213518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731980PMC
November 2019

Biodegradable, pH-Sensitive Hollow Mesoporous Organosilica Nanoparticle (HMON) with Controlled Release of Pirfenidone and Ultrasound-Target-Microbubble-Destruction (UTMD) for Pancreatic Cancer Treatment.

Theranostics 2019 14;9(20):6002-6018. Epub 2019 Aug 14.

Department of Ultrasound, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201600, P.R. China.

The dense extracellular matrix (ECM) and hypovascular networks were often found in solid pancreatic tumors form an impenetrable barrier, leading to limited uptake of chemotherapeutics and thus undesirable treatment outcomes. : A biodegradable nanoplatform based on hollow mesoporous organosilica nanoparticle (HMON) was designed as an effective delivery system for pirfenidone (PFD) to overcome the challenges in pancreatic tumor treatment. By varying pH producing a mildly acidic environment to emulate tumor cells, results in cleavage of the acetal bond between HMON nanoparticle and gating molecular, gemcitabine (Gem), enabling its controlled release. : The and immunocytochemistry evaluations demonstrated an excellent ECM regulation efficacy of the nanoplatform and therefore the improved penetration of drug into the cells. The technique employed was especially enhanced when mediated with ultrasound target microbubble destruction (UTMD). Evaluations culminated with pancreatic cancer bearing mice and demonstrated therapeutic efficacy, good biodegradability, and negligible systemic toxicity. : the designed Gem gated biodegradable nanosystem is expected to provide an alternative way of improving antitumor efficacy by down-regulation of ECM levels and offers a passive-targeted therapy for pancreatic cancer treatment.
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http://dx.doi.org/10.7150/thno.36135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735371PMC
August 2020

A chitosan-based cascade-responsive drug delivery system for triple-negative breast cancer therapy.

J Nanobiotechnology 2019 Sep 10;17(1):95. Epub 2019 Sep 10.

College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai, 201620, People's Republic of China.

Background: It is extremely difficult to develop targeted treatments for triple-negative breast (TNB) cancer, because these cells do not express any of the key biomarkers usually exploited for this goal.

Results: In this work, we develop a solution in the form of a cascade responsive nanoplatform based on thermo-sensitive poly(N-vinylcaprolactam) (PNVCL)-chitosan (CS) nanoparticles (NPs). These are further modified with the cell penetrating peptide (CPP) and loaded with the chemotherapeutic drug doxorubicin (DOX). The base copolymer was optimized to undergo a phase change at the elevated temperatures of the tumor microenvironment. The acid-responsive properties of CS provide a second trigger for drug release, and the inclusion of CPP should ensure the formulations accumulate in cancerous tissue. The resultant CPP-CS-co-PNVCL NPs could self-assemble in aqueous media into spherical NPs of size < 200 nm and with low polydispersity. They are able to accommodate a high DOX loading (14.8% w/w). The NPs are found to be selectively taken up by cancerous cells both in vitro and in vivo, and result in less off-target cytotoxicity than treatment with DOX alone. In vivo experiments employing a TNB xenograft mouse model demonstrated a significant reduction in tumor volume and prolonging of life span, with no obvious systemic toxicity.

Conclusions: The system developed in this work has the potential to provide new therapies for hard-to-treat cancers.
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http://dx.doi.org/10.1186/s12951-019-0529-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737697PMC
September 2019