Publications by authors named "Jinqiang Wang"

63 Publications

Disrupting tumour vasculature and recruitment of aPDL1-loaded platelets control tumour metastasis.

Nat Commun 2021 05 13;12(1):2773. Epub 2021 May 13.

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.

Although therapies of cancer are advancing, it remains challenging for therapeutics to reach the sites of metastasis, which accounts for majority of cancer associated death. In this study, we have developed a strategy that guides an anti-programmed cell death-ligand 1 (aPDL1) antibody to accumulate in metastatic lesions to promote anti-tumour immune responses. Briefly, we have developed a combination in which Vadimezan disrupts tumour blood vessels of tumour metastases and facilitates the recruitment and activation of adoptively transferred aPDL1-conjugated platelets. In situ activated platelets generate aPDL1-decorated platelet-derived microparticles (PMP) that diffuse within the tumour and elicit immune responses. The proposed combination increases 10-fold aPDL1 antibody accumulation in lung metastases as compared to the intravenous administration of the antibody and enhances the magnitude of immune responses leading to improved antitumour effects.
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http://dx.doi.org/10.1038/s41467-021-22674-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119987PMC
May 2021

Bioorthogonal catalytic patch.

Nat Nanotechnol 2021 May 10. Epub 2021 May 10.

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P. R. China.

Bioorthogonal catalysis mediated by transition metals has inspired a new subfield of artificial chemistry complementary to enzymatic reactions, enabling the selective labelling of biomolecules or in situ synthesis of bioactive agents via non-natural processes. However, the effective deployment of bioorthogonal catalysis in vivo remains challenging, mired by the safety concerns of metal toxicity or complicated procedures to administer catalysts. Here, we describe a bioorthogonal catalytic device comprising a microneedle array patch integrated with Pd nanoparticles deposited on TiO nanosheets. This device is robust and removable, and can mediate the local conversion of caged substrates into their active states in high-level living systems. In particular, we show that such a patch can promote the activation of a prodrug at subcutaneous tumour sites, restoring its parent drug's therapeutic anticancer properties. This in situ applied device potentiates local treatment efficacy and eliminates off-target prodrug activation and dose-dependent side effects in healthy organs or distant tissues.
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http://dx.doi.org/10.1038/s41565-021-00910-7DOI Listing
May 2021

Enhanced tumour penetration and prolonged circulation in blood of polyzwitterion-drug conjugates with cell-membrane affinity.

Nat Biomed Eng 2021 Apr 15. Epub 2021 Apr 15.

Zhejiang Key Laboratory of Smart BioMaterials and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.

Effective anticancer nanomedicines need to exhibit prolonged circulation in blood, to extravasate and accumulate in tumours, and to be taken up by tumour cells. These contrasting criteria for persistent circulation and cell-membrane affinity have often led to complex nanoparticle designs with hampered clinical translatability. Here, we show that conjugates of small-molecule anticancer drugs with the polyzwitterion poly(2-(N-oxide-N,N-diethylamino)ethyl methacrylate) have long blood-circulation half-lives and bind reversibly to cell membranes, owing to the negligible interaction of the polyzwitterion with proteins and its weak interaction with phospholipids. Adsorption of the polyzwitterion-drug conjugates to tumour endothelial cells and then to cancer cells favoured their transcytosis-mediated extravasation into tumour interstitium and infiltration into tumours, and led to the eradication of large tumours and patient-derived tumour xenografts in mice. The simplicity and potency of the polyzwitterion-drug conjugates should facilitate the design of translational anticancer nanomedicines.
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http://dx.doi.org/10.1038/s41551-021-00701-4DOI Listing
April 2021

Analgesic efficacy of imrecoxib for postoperative pain following oral surgery: a prospective randomized, active-controlled, non-inferiority trial.

Ann Transl Med 2021 Mar;9(6):469

Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.

Background: Imrecoxib, a novel cyclooxygenase (COX-2) selective non-steroidal anti-inflammatory drug (NSAID), has been approved in China for more than 9 years. This study aimed to assess the efficacy and safety of imrecoxib compared with celecoxib for patients with moderate or severe acute pain following oral surgery.

Methods: Patients with moderate or severe pain within 6 hours following surgery were enrolled in this randomized, active-control trial. Patients were randomly assigned (1:1) to receive either imrecoxib or celecoxib. Pain assessments on the visual analog scale, verbal rating scale, and pain relief were conducted at 0.5, 1, 2, 4, 6, 9, 12, and 24 hours after the first dose. Adverse events were also recorded.

Results: Eighty-seven patients were approached from November 2018 to August 2019. Of these, 60 were eligible for randomization. Ultimately, 56 patients (imrecoxib group, n=27; celecoxib group, n=29) were included in the analysis. The difference in total pain relief (TOTPAR) between the imrecoxib and celecoxib groups was 1.03 [95% confidence interval (CI): -1.31-3.77], with the lower bound of the CI above the specified non-inferiority boundary. No perioperative complications were observed in the imrecoxib group during the 24-hour period after the first dose.

Conclusions: Imrecoxib could significantly relieve pain and has a non-inferior analgesic efficacy compared to celecoxib with good tolerance following oral surgery.
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http://dx.doi.org/10.21037/atm-21-264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039693PMC
March 2021

MiR-133b Modulates the Osteoblast Differentiation to Prevent Osteoporosis Via Targeting GNB4.

Biochem Genet 2021 Mar 9. Epub 2021 Mar 9.

Department of Spine Surgery, Weifang Traditional Chinese Medicine Hospital, No. 1055 Weizhou Road, Kuiwen District, Weifang, Shandong, People's Republic of China.

MiR-133b is considered to be lowly expressed in osteoporosis patients. This study aimed to probe the role and in-depth mechanism of miR-133b in modulating osteoblast biological behavior and differentiation. The differential expressions of miR-133b and GNB4 in patients with osteoporosis and healthy control were analyzed based on the GEO database. Osteoblastic differentiation of hFOB 1.19 cells was induced in the culture medium containing 10 mM β-glycerophosphate, 50 nm dexamethasone, and 100 μg/ml ascorbic acid. The level of GNB4 was detected using quantitative real-time PCR (qRT-PCR) and Western blot. Cell viability and apoptosis were measured by Cell Counting Kit-8 (CCK-8) and flow cytometry assays, respectively. Western blot was also utilized to measure the levels of osteoblast-related proteins, including ALP, Runx2, Osterix, and OPN. GNB4 was identified and confirmed as a downstream target gene of miR-133b. The expression of miR-133b was declined while the expression of GNB4 was increased in osteoporosis patients. Importantly, up-regulation of miR-133b caused the increase of cell viability and the decrease of apoptosis, which could be blocked by overexpression of GNB4. Also, up-regulation of miR-133b promoted osteoblasts differentiation, as shown by the increase in the expression of ALP, Runx2, Osterix, and OPN. Similarly, this promoting impact resulted from miR-133b overexpression can be reversed via up-regulation of GNB4. These findings revealed that miR-133b can promote the viability and differentiation of osteoblasts by targeting GNB4, hoping to lay a feasible theoretical foundation for the clinical treatment of osteoporosis.
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http://dx.doi.org/10.1007/s10528-021-10048-9DOI Listing
March 2021

Injectable Biodegradable Polymeric Complex for Glucose-Responsive Insulin Delivery.

ACS Nano 2021 03 8;15(3):4294-4304. Epub 2021 Mar 8.

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.

Insulin therapy is the central component of treatment for type 1 and advanced type 2 diabetes; however, its narrow therapeutic window is associated with a risk of severe hypoglycemia. A glucose-responsive carrier that demonstrates consistent and slow basal insulin release under a normoglycemic condition and accelerated insulin release in response to hyperglycemia in real-time could offer effective blood glucose regulation with reduced risk of hypoglycemia. Here, we describe a poly(l-lysine)-derived biodegradable glucose-responsive cationic polymer for constructing polymer-insulin complexes for glucose-stimulated insulin delivery. The effects of the modification degree of arylboronic acid in the synthesized cationic polymer and polymer-to-insulin ratio on the glucose-dependent equilibrated free insulin level and the associated insulin release kinetics have been studied. In addition, the blood glucose regulation ability of these complexes and the associated glucose challenge-triggered insulin release are evaluated in type 1 diabetic mice.
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http://dx.doi.org/10.1021/acsnano.0c07291DOI Listing
March 2021

The prescription patterns and safety profiles of oral non-steroidal anti-inflammatory drugs in China: an 8-year real-life analysis.

Ann Palliat Med 2021 Feb 30;10(2):2224-2237. Epub 2021 Jan 30.

Jiangsu Hengrui Pharmaceutical Co. Ltd., Lianyungang, China.

Background: This study aimed to evaluate the prescription patterns and safety profiles of oral nonsteroidal anti-inflammatory drugs (NSAIDs) in three Chinese hospitals.

Methods: The study analyzed the data of 50,732 patients who were prescribed oral NSAIDs from July 1, 2012 to August 31, 2019. The characteristics of these patients, the prescription patterns of NSAIDs, and the drug-related safety profiles were evaluated.

Results: Oral NSAIDs were prescribed to patients of all ages. Of the patients, 81.88% were prescribed NSAIDs on only one occasion, and 91.64% were prescribed one type of NSAID only. The combination of different NSAIDs accounted for 2,360 person-times. Orthopedic departments most commonly used selective cyclo-oxygenase-2 (COX-2) inhibitors, while emergency departments most commonly used traditional NSAIDs. The incidences of gastrointestinal (GI) complications, cardiovascular (CV) events, and newonset hypertension were lower in patients treated with selective COX-2 inhibitors than those treated with traditional NSAIDs and NSAID combinations (P<0.05). In relation to selective COX-2 inhibitors, incidences of new-onset hypertension were lower in patients treated with imrecoxib than those treated with other types of selective COX-2 inhibitors (P=0.0102).

Conclusions: In respect of the at-risk patients (i.e., those with related disease, such as GI complications, CV events or other risks), the patterns with which oral NSAIDs were prescribed was not standardized. In terms of adverse effects, selective COX-2 inhibitors represent a better choice than traditional NSAIDs and NSAID combinations.
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http://dx.doi.org/10.21037/apm-20-2356DOI Listing
February 2021

Cryo-shocked cancer cells for targeted drug delivery and vaccination.

Sci Adv 2020 Dec 9;6(50). Epub 2020 Dec 9.

Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA.

Live cells have been vastly engineered into drug delivery vehicles to leverage their targeting capability and cargo release behavior. Here, we describe a simple method to obtain therapeutics-containing "dead cells" by shocking live cancer cells in liquid nitrogen to eliminate pathogenicity while preserving their major structure and chemotaxis toward the lesion site. In an acute myeloid leukemia (AML) mouse model, we demonstrated that the liquid nitrogen-treated AML cells (LNT cells) can augment targeted delivery of doxorubicin (DOX) toward the bone marrow. Moreover, LNT cells serve as a cancer vaccine and promote antitumor immune responses that prolong the survival of tumor-bearing mice. Preimmunization with LNT cells along with an adjuvant also protected healthy mice from AML cell challenge.
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http://dx.doi.org/10.1126/sciadv.abc3013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725453PMC
December 2020

Tumor-Associated Macrophage and Tumor-Cell Dually Transfecting Polyplexes for Efficient Interleukin-12 Cancer Gene Therapy.

Adv Mater 2021 Jan 3;33(2):e2006189. Epub 2020 Dec 3.

Zhejiang Key Laboratory of Smart Biomaterials and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027, P. R. China.

Interleukin 12 (IL12) is a potent pro-inflammatory chemokine with multifunction, including promoting cytotoxic T-cell-mediated killing of cancer cells. IL12-based cancer gene therapy can overcome IL12's life-threatening adverse effects, but its clinical translation has been limited by the lack of systemic gene-delivery vectors capable of efficiently transfecting tumors to produce sufficient local IL12. Macrophages inherently excrete IL12, and tumor-associated macrophages (TAMs) are the major tumor component taking up a large fraction of the vectors arriving in the tumor. It is thus hypothesized that a gene vector efficiently transfecting both cancer cells and TAMs would make the tumor to produce sufficient IL12; however, gene transfection of TAMs is challenging due to their inherent strong degradation ability. Herein, an IL12 gene-delivery vector is designed that efficiently transfects both cancer cells and TAMs to make them as a factory for IL12 production, which efficiently activates anticancer immune responses and remodels the tumor microenvironment, for instance, increasing the M1/M2 ratio by more than fourfold. Therefore, the intravenously administered vector retards tumor growth and doubles survival in three animal models' with negligible systemic toxicities. This work reports the first nonviral IL12 gene delivery system that effectively makes use of both macrophages and tumor cells.
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http://dx.doi.org/10.1002/adma.202006189DOI Listing
January 2021

Developing Insulin Delivery Devices with Glucose Responsiveness.

Trends Pharmacol Sci 2021 01 26;42(1):31-44. Epub 2020 Nov 26.

Department of Bioengineering, University of California, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA; College of Pharmaceutical Sciences, Zhejiang University, 310058 Hangzhou, China; California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA. Electronic address:

Individuals with type 1 and advanced type 2 diabetes require daily insulin therapy to maintain blood glucose levels in normoglycemic ranges to prevent associated morbidity and mortality. Optimal insulin delivery should offer both precise dosing in response to real-time blood glucose levels as well as a feasible and low-burden administration route to promote long-term adherence. A series of glucose-responsive insulin delivery mechanisms and devices have been reported to increase patient compliance while mitigating the risk of hypoglycemia. This review discusses currently available insulin delivery devices, overviews recent developments towards the generation of glucose-responsive delivery systems, and provides commentary on the opportunities and barriers ahead regarding the integration and translation of current glucose-responsive insulin delivery designs.
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http://dx.doi.org/10.1016/j.tips.2020.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758938PMC
January 2021

Dual self-regulated delivery of insulin and glucagon by a hybrid patch.

Proc Natl Acad Sci U S A 2020 11 11;117(47):29512-29517. Epub 2020 Nov 11.

Department of Bioengineering, University of California, Los Angeles, CA 90095;

Reduced β-cell function and insulin deficiency are hallmarks of diabetes mellitus, which is often accompanied by the malfunction of glucagon-secreting α-cells. While insulin therapy has been developed to treat insulin deficiency, the on-demand supplementation of glucagon for acute hypoglycemia treatment remains inadequate. Here, we describe a transdermal patch that mimics the inherent counterregulatory effects of β-cells and α-cells for blood glucose management by dynamically releasing insulin or glucagon. The two modules share a copolymerized matrix but comprise different ratios of the key monomers to be "dually responsive" to both hyper- and hypoglycemic conditions. In a type 1 diabetic mouse model, the hybrid patch effectively controls hyperglycemia while minimizing the occurrence of hypoglycemia in the setting of insulin therapy with simulated delayed meal or insulin overdose.
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http://dx.doi.org/10.1073/pnas.2011099117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703584PMC
November 2020

Tumor-specific fluorescence activation of rhodamine isothiocyanate derivatives.

J Control Release 2021 Feb 31;330:842-850. Epub 2020 Oct 31.

Key Laboratory of Biomass Chemical Engineering of Ministry of Education and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China; Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311215, China. Electronic address:

Fluorescence is routinely used for in vivo tracking and imaging of molecules and nanostructures with assuming that the fluorescence intensity is proportional to the dye concentration. Herein, we report the unique tumor-specific fluorescence character of rhodamine B isothiocyanate derivatives (RBITCs), which emits fluorescence selectively in cancerous tissues, including small metastatic tumors, but is quenched in blood and healthy tissues. A preliminary mechanism study shows that binding of the thiourea group in the RBITCs on hemoglobin quenches their fluorescence, but the oxidation of the thiourea by the elevated reactive oxygen species in tumor activates the fluorescence. Thus, the fluorescent intensity of RBITCs is associated with the microenvironment of tissues and positively correlates with the cancer stages. These findings suggest that the RBITCs are not suitable for tracking of cargos in the presence of red blood cells but may be useful for cancer imaging and early diagnosis, and probing the tumor microenvironment.
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http://dx.doi.org/10.1016/j.jconrel.2020.10.057DOI Listing
February 2021

Bounded neural adaptive formation control of multiple underactuated AUVs under uncertain dynamics.

ISA Trans 2020 Oct 5;105:111-119. Epub 2020 Jun 5.

Harbin Institute of Technology, Harbin, China. Electronic address:

This paper studies the leader-following formation control problem of multiple underactuated autonomous underwater vehicles (AUVs) under uncertain dynamics and limited control torques. A multi-layer neural network-based estimation model is designed to handle the unknown follower dynamics. The backstepping approach, a neural estimation model, as well as a saturation function, are employed to propose a bounded formation control law. Then, a Lyapunov-based stability analysis ensures a maximum bound for all the closed-loop system variables and guarantees that the formation errors between vehicles ultimately converge to a bounded compact set. The outstanding properties of the designed controller are highlighted as follows. First, only the leader position and given formation are required without any leader velocity information requirement. Second, update laws of the neural network weight are extracted using the estimation errors instead of tracking ones, which can effectively enhance the transient characteristics of the control system. Third, the control torques are bounded within predefined bounds. At the end, extensive simulations are given for a number of AUVs to verify the efficiency of the presented formation control scheme.
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http://dx.doi.org/10.1016/j.isatra.2020.06.002DOI Listing
October 2020

CRISPR-Cas12a delivery by DNA-mediated bioresponsive editing for cholesterol regulation.

Sci Adv 2020 May 20;6(21):eaba2983. Epub 2020 May 20.

Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA.

CRISPR-Cas12a represents an efficient tool for genome editing in addition to the extensively investigated CRISPR-Cas9. However, development of efficient nonviral delivery system for CRISPR-Cas12a remains challenging. Here, we demonstrate a DNA nanoclew (NC)-based carrier for delivery of Cas12a/CRISPR RNA (crRNA) ribonucleoprotein (RNP) toward regulating serum cholesterol levels. The DNA NC could efficiently load the Cas12a/crRNA RNP through complementation between the DNA NC and the crRNA. Addition of a cationic polymer layer condensed the DNA-templated core and allowed further coating of a charge reversal polymer layer, which makes the assembly negatively charged under a physiological pH but reverts to positive charge under an acidic environment. When was selected as the target gene because of its important role in regulating the level of serum cholesterol, efficient disruption was observed in vivo (~48%), significantly reducing the expression of PCSK9 and gaining the therapeutic benefit of cholesterol control (~45% of cholesterol reduction).
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http://dx.doi.org/10.1126/sciadv.aba2983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239642PMC
May 2020

Engineered PD-L1-Expressing Platelets Reverse New-Onset Type 1 Diabetes.

Adv Mater 2020 Jul 25;32(26):e1907692. Epub 2020 May 25.

Department of Bioengineering, University of California, Los Angeles, CA, 90095, USA.

The pathogenesis of Type 1 diabetes (T1D) arises from the destruction of insulin-producing β-cells by islet-specific autoreactive T cells. Inhibition of islet-specific autoreactive T cells to rescue β-cells is a promising approach to treat new-onset T1D. The immune checkpoint signal axis programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) can effectively regulate the activity of T cells and prevent autoimmune attack. Here, megakaryocyte progenitor cells are genetically engineered to overexpress PD-L1 to produce immunosuppressive platelets. The PD-L1-overexpressing platelets (designated PD-L1 platelets) accumulate in the inflamed pancreas and may suppress the activity of pancreas autoreactive T cells in newly hyperglycemic non-obese diabetic (NOD) mice, protecting the insulin-producing β-cells from destruction. Moreover, PD-L1 platelet treatment also increases the percentage of the regulatory T cells (Tregs) and maintains immune tolerance in the pancreas. It is demonstrated that the rescue of β-cells by PD-L1 platelets can effectively maintain normoglycemia and reverse diabetes in newly hyperglycemic NOD mice.
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http://dx.doi.org/10.1002/adma.201907692DOI Listing
July 2020

Assemblies of indocyanine green and chemotherapeutic drug to cure established tumors by synergistic chemo-photo therapy.

J Control Release 2020 08 16;324:250-259. Epub 2020 May 16.

State Key Laboratory of Chemical Engineering and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China. Electronic address:

Indocyanine green (ICG), a safe and clinically approved near-infrared (NIR) dye, was recently explored as a potential photosensitizer due to its excellent photophysical properties. However, ICG tends to form aggregations in physiological solution, causing fluorescence quenching, fast blood clearance and thereby inefficient tumor accumulation. Herein, we report ICG-based nanodrug delivery systems formed by self-assembly of ICG and chemotherapeutic drugs without any excipients for combined chemo- and photo-therapy. Taking advantage of the amphiphilic aromatic structure, ICG readily bounded with hydrophobic aromatic drugs such as SN38 and formed well-dispersible nanoparticles, which reduced its aggregation-induced quenching and thus greatly improved its photodynamic efficiency. The loaded hydrophobic drugs elicited chemotherapy synergizing the photodynamic therapy, giving rise to much enhanced antitumor activity in vitro and in vivo against human glioblastoma cells and breast cancer cells upon NIR irradiation. The work demonstrates the fabrication of readily translational nanoformulations of hydrophobic drugs using amphiphilic drugs.
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http://dx.doi.org/10.1016/j.jconrel.2020.05.018DOI Listing
August 2020

Design of 3D Printed Programmable Horseshoe Lattice Structures Based on a Phase-Evolution Model.

ACS Appl Mater Interfaces 2020 May 4;12(19):22146-22156. Epub 2020 May 4.

Robotics Institute and State Key Laboratory of Mechanical System and Vibration, School of Mechanical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China.

By 3D printing lattice structure with active materials, the structures can exhibit shape and functional changes under external stimulus. However, the programmable shape changes of the 3D printed lattice structures are limited due to the complex geometries, nonlinear behaviors of the active materials, and the diverse external stimuli. In this work, we propose a design framework combining experiments, theoretical modeling, and finite element simulations for the controllable shape changes of the 3D printed horseshoe under thermal stimulus. The theoretical model is based on a phase evolution model that combines the geometrical nonlinearity and the material nonlinearity. Results show that the shapes with positive or negative Poisson's ratio and bending intermediate shapes can be programmed by tuning the geometrical parameters and the temperature distribution. This work provides a method to aid the design of 3D printed functional lattice structures and have potential applications in soft robotics, biomedicine, and energy absorbing fields.
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http://dx.doi.org/10.1021/acsami.0c04097DOI Listing
May 2020

Transdermal colorimetric patch for hyperglycemia sensing in diabetic mice.

Biomaterials 2020 04 13;237:119782. Epub 2020 Jan 13.

Department of Bioengineering, University of California, Los Angeles, CA, 90095, United States; California NanoSystems Institute, University of California, Los Angeles, CA, 90095, United States; Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, 90095, United States; Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA, 90095, United States. Electronic address:

The integration of sampling and instant metabolite readout can fundamentally elevate patient compliance. To circumvent the need for complex in-lab apparatus, here, an all-in-one sampling and display transdermal colorimetric microneedle patch was developed for sensing hyperglycemia in mice. The coloration of 3,3',5,5'-tetramethylbenzidine (TMB) is triggered by the cascade enzymatic reactions of glucose oxidase (GOx) and horseradish peroxidase (HRP) at abnormally high glucose levels. The HRP in the upper layer is biomineralized with calcium phosphate (CaP) shell to add a pH responsive feature for increased sensitivity as well as protection from nonspecific reactions. This colorimetric sensor achieved minimally invasive extraction of the interstitial fluid from mice and converted glucose level to a visible color change promptly. Quantitative red green and blue (RGB) information could be obtained through a scanned image of the microneedle. This costless, portable colorimetric sensor could potentially detect daily glucose levels without blood drawing procedures.
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http://dx.doi.org/10.1016/j.biomaterials.2020.119782DOI Listing
April 2020

Glucose-responsive insulin patch for the regulation of blood glucose in mice and minipigs.

Nat Biomed Eng 2020 05 3;4(5):499-506. Epub 2020 Feb 3.

Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, USA.

Glucose-responsive insulin delivery systems that mimic pancreatic endocrine function could enhance health and improve quality of life for people with type 1 and type 2 diabetes with reduced β-cell function. However, insulin delivery systems with rapid in vivo glucose-responsive behaviour typically have limited insulin-loading capacities and cannot be manufactured easily. Here, we show that a single removable transdermal patch, bearing microneedles loaded with insulin and a non-degradable glucose-responsive polymeric matrix, and fabricated via in situ photopolymerization, regulated blood glucose in insulin-deficient diabetic mice and minipigs (for minipigs >25 kg, glucose regulation lasted >20 h with patches of ~5 cm). Under hyperglycaemic conditions, phenylboronic acid units within the polymeric matrix reversibly form glucose-boronate complexes that-owing to their increased negative charge-induce the swelling of the polymeric matrix and weaken the electrostatic interactions between the negatively charged insulin and polymers, promoting the rapid release of insulin. This proof-of-concept demonstration may aid the development of other translational stimuli-responsive microneedle patches for drug delivery.
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http://dx.doi.org/10.1038/s41551-019-0508-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231631PMC
May 2020

Engineering Biomaterials with Micro/Nanotechnologies for Cell Reprogramming.

ACS Nano 2020 02 3;14(2):1296-1318. Epub 2020 Feb 3.

Department of Bioengineering , University of California, Los Angeles , Los Angeles , California 90095 , United States.

Cell reprogramming is a revolutionized biotechnology that offers a powerful tool to engineer cell fate and function for regenerative medicine, disease modeling, drug discovery, and beyond. Leveraging advances in biomaterials and micro/nanotechnologies can enhance the reprogramming performance and through the development of delivery strategies and the control of biophysical and biochemical cues. In this review, we present an overview of the state-of-the-art technologies for cell reprogramming and highlight the recent breakthroughs in engineering biomaterials with micro/nanotechnologies to improve reprogramming efficiency and quality. Finally, we discuss future directions and challenges for reprogramming technologies and clinical translation.
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http://dx.doi.org/10.1021/acsnano.9b04837DOI Listing
February 2020

Advances in Engineering Cells for Cancer Immunotherapy.

Theranostics 2019 16;9(25):7889-7905. Epub 2019 Oct 16.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, China.

Cancer immunotherapy aims to utilize the host immune system to kill cancer cells. Recent representative immunotherapies include T-cell transfer therapies, such as chimeric antigen receptor T cell therapy, antibody-based immunomodulator therapies, such as immune checkpoint blockade therapy, and cytokine therapies. Recently developed therapies leveraging engineered cells for immunotherapy against cancers have been reported to enhance antitumor efficacy while reducing side effects. Such therapies range from biologically, chemically and physically -engineered cells to bioinspired and biomimetic nanomedicines. In this review, advances of engineering cells for cancer immunotherapy are summarized, and prospects of this field are discussed.
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http://dx.doi.org/10.7150/thno.38583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831467PMC
September 2020

A forskolin-conjugated insulin analog targeting endogenous glucose-transporter for glucose-responsive insulin delivery.

Biomater Sci 2019 Nov 14;7(11):4508-4513. Epub 2019 Oct 14.

Department of Bioengineering, University of California, Los Angeles, CA 90095, USA. and California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90024, USA and Center for Minimally Invasive Therapeutics, University of California, Los Angeles, CA 90095, USA.

Insulin administration for the management of diabetes is accompanied by hypoglycemia, which is expected to be mitigated by glucose-responsive smart insulin that has self-regulation ability in response to blood glucose level (BGL) fluctuation. Here, we have prepared a new insulin analog by modifying insulin with forskolin (designated as insulin-F), a glucose-transporter (Glut) inhibitor. In vitro, insulin-F is capable of binding to Glut on erythrocyte ghosts, which can be inhibited by glucose and cytochalasin B. Upon subcutaneous injection in type 1 diabetic mice, insulin-F maintains BGLs below 200 mg mL for up to 10 h, and achieves 20 h with two sequential injections. Moreover, insulin-F also binds to endogenous Gluts. Upon a glucose challenge, the elevated level of glucose competitively replaces and liberates insulin-F that binds to Glut, rapidly restoring BGLs to the normal range.
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http://dx.doi.org/10.1039/c9bm01283dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148115PMC
November 2019

Glucose-Responsive Insulin and Delivery Systems: Innovation and Translation.

Adv Mater 2020 Apr 18;32(13):e1902004. Epub 2019 Aug 18.

Department of Bioengineering, University of California, Los Angeles, CA, 90095, USA.

Type 1 and advanced type 2 diabetes treatment involves daily injections or continuous infusion of exogenous insulin aimed at regulating blood glucose levels in the normoglycemic range. However, current options for insulin therapy are limited by the risk of hypoglycemia and are associated with suboptimal glycemic control outcomes. Therefore, a range of glucose-responsive components that can undergo changes in conformation or show alterations in intermolecular binding capability in response to glucose stimulation has been studied for ultimate integration into closed-loop insulin delivery or "smart insulin" systems. Here, an overview of the evolution and recent progress in the development of molecular approaches for glucose-responsive insulin delivery systems, a rapidly growing subfield of precision medicine, is presented. Three central glucose-responsive moieties, including glucose oxidase, phenylboronic acid, and glucose-binding molecules are examined in detail. Future opportunities and challenges regarding translation are also discussed.
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http://dx.doi.org/10.1002/adma.201902004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141789PMC
April 2020

Charge-switchable polymeric complex for glucose-responsive insulin delivery in mice and pigs.

Sci Adv 2019 07 10;5(7):eaaw4357. Epub 2019 Jul 10.

Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.

Glucose-responsive insulin delivery systems with robust responsiveness that has been validated in animal models, especially in large animal models, remain elusive. Here, we exploit a new strategy to form a micro-sized complex between a charge-switchable polymer with a glucose-sensing moiety and insulin driven by electrostatic interaction. Both high insulin loading efficiency (95%) and loading capacity (49%) can be achieved. In the presence of a hyperglycemic state, the glucose-responsive phenylboronic acid (PBA) binds glucose instantly and converts the charge of the polymeric moiety from positive to negative, thereby enabling the release of insulin from the complex. Adjusting the ratio of the positively charged group to PBA achieves inhibited insulin release from the complex under normoglycemic conditions and promoted release under hyperglycemic conditions. Through chemically induced type 1 diabetic mouse and swine models, in vivo hyperglycemia-triggered insulin release with fast response is demonstrated after the complex is administrated by either subcutaneous injection or transdermal microneedle array patch.
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http://dx.doi.org/10.1126/sciadv.aaw4357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620100PMC
July 2019

Bioresponsive Protein Complex of aPD1 and aCD47 Antibodies for Enhanced Immunotherapy.

Nano Lett 2019 08 11;19(8):4879-4889. Epub 2019 Jul 11.

Joint Department of Biomedical Engineering , University of North Carolina at Chapel Hill and North Carolina State University , Raleigh , North Carolina 27695 , United States.

Despite the promising efficacy of immune checkpoint blockade (ICB) in treating many types of cancers, the clinical benefits have often been restricted by the low objective response rates and systemic immune-related adverse events. Here, a bioresponsive ICB treatment is developed based on the reactive oxygen species (ROS)-sensitive protein complex for controlled sequential release of anti- "don't eat me" signal antibody (aCD47) and antiprogrammed cell death protein 1 (aPD1), by leveraging the abundant ROS in the tumor microenvironment (TME). These protein complexes can also act as scavengers of ROS in the TME to reverse the immunosuppressive responses, thereby enhancing antitumor efficacy in vivo. In a melanoma cancer model, the synergistic antitumor efficacy was achieved, which was accompanied by enhanced T cell immune responses together with reduced immunosuppressive responses.
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http://dx.doi.org/10.1021/acs.nanolett.9b00584DOI Listing
August 2019

Enzyme-activatable polymer-drug conjugate augments tumour penetration and treatment efficacy.

Nat Nanotechnol 2019 08 1;14(8):799-809. Epub 2019 Jul 1.

Center for Bionanoengineering and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.

A tumour microenvironment imposes barriers to the passive diffusion of molecules, which renders tumour penetration an unresolved obstacle to an effective anticancer drug delivery. Here, we present a γ-glutamyl transpeptidase-responsive camptothecin-polymer conjugate that actively infiltrates throughout the tumour tissue through transcytosis. When the conjugate passes on the luminal endothelial cells of the tumour blood vessels or extravasates into the tumour interstitium, the overexpressed γ-glutamyl transpeptidase on the cell membrane cleaves the γ-glutamyl moieties of the conjugate to generate positively charged primary amines. The resulting cationic conjugate undergoes caveolae-mediated endocytosis and transcytosis, which enables transendothelial and transcellular transport and a relatively uniform distribution throughout the tumour. The conjugate showed a potent antitumour activity in mouse models that led to the eradication of small solid tumours (~100 mm) and regression of large established tumours with clinically relevant sizes (~500 mm), and significantly extended the survival of orthotopic pancreatic tumour-bearing mice compared to that with the first-line chemotherapeutic drug gemcitabine.
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http://dx.doi.org/10.1038/s41565-019-0485-zDOI Listing
August 2019

Glucose transporter inhibitor-conjugated insulin mitigates hypoglycemia.

Proc Natl Acad Sci U S A 2019 05 16;116(22):10744-10748. Epub 2019 May 16.

Department of Bioengineering, University of California, Los Angeles, CA 90095;

Insulin therapy in the setting of type 1 and advanced type 2 diabetes is complicated by increased risk of hypoglycemia. This potentially fatal complication could be mitigated by a glucose-responsive insulin analog. We report an insulin-facilitated glucose transporter (Glut) inhibitor conjugate, in which the insulin molecule is rendered glucose-responsive via conjugation to an inhibitor of Glut. The binding affinity of this insulin analog to endogenous Glut is modulated by plasma and tissue glucose levels. In hyperglycemic conditions (e.g., uncontrolled diabetes or the postprandial state), the in situ-generated insulin analog-Glut complex is driven to dissociate, freeing the insulin analog and glucose-accessible Glut to restore normoglycemia. Upon overdose, enhanced binding of insulin analog to Glut suppresses the glucose transport activity of Glut to attenuate further uptake of glucose. We demonstrate the ability of this insulin conjugate to regulate blood glucose levels within a normal range while mitigating the risk of hypoglycemia in a type 1 diabetic mouse model.
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http://dx.doi.org/10.1073/pnas.1901967116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561193PMC
May 2019

Personalized Design of Functional Gradient Bone Tissue Engineering Scaffold.

J Biomech Eng 2019 Apr 24. Epub 2019 Apr 24.

College of Mechanical and Electrical Engineering, Nanjing University of Aeronautics and Astronautics, 29 Yudao St., Nanjing 210016, Jiangsu Province, People's Republic of China.

The porous structure of the natural bone not only has the characteristics of lightweight and high strength, but also is conducive to the growth of cells and tissues due to interconnected pores. In this paper, a novel gradient-controlled parametric modeling technology is presented to design bone tissue engineering (BTE) scaffold. First of all, the method functionalizes the pore distribution in the bone tissue, and reconstructs the pore distribution of the bone tissue in combination with the pathological analysis of the bone defect area of the individual patient. Then, based on the reconstructed pore distribution, the Voronoi segmentation algorithm and the contour interface optimization method are used to reconstruct the whole model of the bone tissue. Finally, the mechanical properties of the scaffold are studied by the finite element analysis (FEA) of different density gradient scaffolds. The results show that the method is highly feasible. BTE scaffold can be designed by irregular design methods and adjustment of pore distribution parameters, which is similar with natural bone in structural characteristics and biomechanical properties.
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http://dx.doi.org/10.1115/1.4043559DOI Listing
April 2019

Conjugation of haematopoietic stem cells and platelets decorated with anti-PD-1 antibodies augments anti-leukaemia efficacy.

Nat Biomed Eng 2018 11 29;2(11):831-840. Epub 2018 Oct 29.

Department of Bioengineering, University of California, Los Angeles, CA, USA.

Patients with acute myeloid leukaemia who relapse following therapy have few treatment options and face poor outcomes. Immune checkpoint inhibition, for example, by antibody-mediated programmed death-1 (PD-1) blockade, is a potent therapeutic modality that improves treatment outcomes in acute myeloid leukaemia. Here, we show that systemically delivered blood platelets decorated with anti-PD-1 antibodies (aPD-1) and conjugated to haematopoietic stem cells (HSCs) suppress the growth and recurrence of leukaemia in mice. Following intravenous injection into mice bearing leukaemia cells, the HSC-platelet-aPD-1 conjugate migrated to the bone marrow and locally released aPD-1, significantly enhancing anti-leukaemia immune responses, and increasing the number of active T cells, production of cytokines and chemokines, and survival time of the mice. This cellular conjugate also promoted resistance to re-challenge with leukaemia cells. Taking advantage of the homing capability of HSCs and in situ activation of platelets for the enhanced delivery of a checkpoint inhibitor, this cellular combination-mediated drug delivery strategy can significantly augment the therapeutic efficacy of checkpoint blockade.
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http://dx.doi.org/10.1038/s41551-018-0310-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7032014PMC
November 2018