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Featured researches published by Ganlin Zhao.


Nature | 2005

Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system.

Shiladitya Sengupta; David Eavarone; Ishan Capila; Ganlin Zhao; Nicki Watson; Tanyel Kiziltepe; Ram Sasisekharan

In the continuing search for effective treatments for cancer, the emerging model is the combination of traditional chemotherapy with anti-angiogenesis agents that inhibit blood vessel growth. However, the implementation of this strategy has faced two major obstacles. First, the long-term shutdown of tumour blood vessels by the anti-angiogenesis agent can prevent the tumour from receiving a therapeutic concentration of the chemotherapy agent. Second, inhibiting blood supply drives the intra-tumoural accumulation of hypoxia-inducible factor-1α (HIF1-α); overexpression of HIF1-α is correlated with increased tumour invasiveness and resistance to chemotherapy. Here we report the disease-driven engineering of a drug delivery system, a ‘nanocell’, which overcomes these barriers unique to solid tumours. The nanocell comprises a nuclear nanoparticle within an extranuclear pegylated-lipid envelope, and is preferentially taken up by the tumour. The nanocell enables a temporal release of two drugs: the outer envelope first releases an anti-angiogenesis agent, causing a vascular shutdown; the inner nanoparticle, which is trapped inside the tumour, then releases a chemotherapy agent. This focal release within a tumour results in improved therapeutic index with reduced toxicity. The technology can be extended to additional agents, so as to target multiple signalling pathways or distinct tumour compartments, enabling the model of an ‘integrative’ approach in cancer therapy.


The New England Journal of Medicine | 2008

Contaminated Heparin Associated with Adverse Clinical Events and Activation of the Contact System

Takashi Kei Kishimoto; Karthik Viswanathan; Tanmoy Ganguly; Subbiah Elankumaran; Sean W. Smith; Kevin D. Pelzer; Jonathan C. Lansing; Nammalwar Sriranganathan; Ganlin Zhao; Zoya Galcheva-Gargova; Ali Al-Hakim; Gregory Scott Bailey; Blair A. Fraser; Sucharita Roy; Thomas Rogers-Cotrone; Lucinda F. Buhse; Mark T. Whary; James G. Fox; Moheb Nasr; Gerald J. Dal Pan; Zachary Shriver; Robert Langer; Ganesh Venkataraman; K. Frank Austen; Janet Woodcock; Ram Sasisekharan

BACKGROUND There is an urgent need to determine whether oversulfated chondroitin sulfate (OSCS), a compound contaminating heparin supplies worldwide, is the cause of the severe anaphylactoid reactions that have occurred after intravenous heparin administration in the United States and Germany. METHODS Heparin procured from the Food and Drug Administration, consisting of suspect lots of heparin associated with the clinical events as well as control lots of heparin, were screened in a blinded fashion both for the presence of OSCS and for any biologic activity that could potentially link the contaminant to the observed clinical adverse events. In vitro assays for the activation of the contact system and the complement cascade were performed. In addition, the ability of OSCS to recapitulate key clinical manifestations in vivo was tested in swine. RESULTS The OSCS found in contaminated lots of unfractionated heparin, as well as a synthetically generated OSCS reference standard, directly activated the kinin-kallikrein pathway in human plasma, which can lead to the generation of bradykinin, a potent vasoactive mediator. In addition, OSCS induced generation of C3a and C5a, potent anaphylatoxins derived from complement proteins. Activation of these two pathways was unexpectedly linked and dependent on fluid-phase activation of factor XII. Screening of plasma samples from various species indicated that swine and humans are sensitive to the effects of OSCS in a similar manner. OSCS-containing heparin and synthetically derived OSCS induced hypotension associated with kallikrein activation when administered by intravenous infusion in swine. CONCLUSIONS Our results provide a scientific rationale for a potential biologic link between the presence of OSCS in suspect lots of heparin and the observed clinical adverse events. An assay to assess the amidolytic activity of kallikrein can supplement analytic tests to protect the heparin supply chain by screening for OSCS and other highly sulfated polysaccharide contaminants of heparin that can activate the contact system.


Proceedings of the National Academy of Sciences of the United States of America | 2003

Rational design of low-molecular weight heparins with improved in vivo activity.

Mallik Sundaram; Yiwei Qi; Zachary Shriver; Dongfang Liu; Ganlin Zhao; Ganesh Venkataraman; Robert Langer; Ram Sasisekharan

Heparin and low-molecular weight heparins (LMWHs), complex, sulfated polysaccharides isolated from endogenous sources, are potent modulators of hemostasis. Heparin and LMWHs interact with multiple components of the coagulation cascade to inhibit the clotting process. Pharmaceutical preparations of these complex polysaccharides, typically isolated from porcine intestinal mucosa, are heterogeneous in length and composition and, hence, highly polydisperse. Because of the structural heterogeneity of heparin and LMWHs, correlating their activity with a particular structure or structural motif has been a challenging task. Herein, we demonstrate a practical analytical method that enables the measurement of a structural correlate to in vivo anticoagulant function. With this understanding we have developed LMWHs with increased anticoagulant activity and decreased polydispersity. In addition to the pronounced anti-Xa and anti-IIa activity of these LMWHs, we also demonstrate that they possess desirable in vivo pharmacokinetic properties, the ability to cause the release of tissue factor pathway inhibitor (TFPI) from the endothelium, complete bioavailability through s.c. delivery, and the ability to inhibit both venous and arterial thromboses. Importantly, from a clinical safety point of view, unlike LMWHs presently used in the clinic, we show that these LMWHs are rapidly and completely neutralized by protamine. Together, the findings presented herein demonstrate a facile approach for the creation of designer LMWHs with optimal activity profiles.


PLOS ONE | 2011

M402, a novel heparan sulfate mimetic, targets multiple pathways implicated in tumor progression and metastasis.

He Zhou; Sucharita Roy; Edward Cochran; Radouane Zouaoui; Chia Lin Chu; Jay Duffner; Ganlin Zhao; Sean W. Smith; Zoya Galcheva-Gargova; Juliane Karlgren; Nancy Dussault; Rain Yq Kwan; Erick Moy; Marishka Barnes; Alison Long; Chris Honan; Yi Wei Qi; Zachary Shriver; Tanmoy Ganguly; Birgit Schultes; Ganesh Venkataraman; Takashi Kishimoto

Heparan sulfate proteoglycans (HSPGs) play a key role in shaping the tumor microenvironment by presenting growth factors, cytokines, and other soluble factors that are critical for host cell recruitment and activation, as well as promoting tumor progression, metastasis, and survival. M402 is a rationally engineered, non-cytotoxic heparan sulfate (HS) mimetic, designed to inhibit multiple factors implicated in tumor-host cell interactions, including VEGF, FGF2, SDF-1α, P-selectin, and heparanase. A single s.c. dose of M402 effectively inhibited seeding of B16F10 murine melanoma cells to the lung in an experimental metastasis model. Fluorescent-labeled M402 demonstrated selective accumulation in the primary tumor. Immunohistological analyses of the primary tumor revealed a decrease in microvessel density in M402 treated animals, suggesting anti-angiogenesis to be one of the mechanisms involved in-vivo. M402 treatment also normalized circulating levels of myeloid derived suppressor cells in tumor bearing mice. Chronic administration of M402, alone or in combination with cisplatin or docetaxel, inhibited spontaneous metastasis and prolonged survival in an orthotopic 4T1 murine mammary carcinoma model. These data demonstrate that modulating HSPG biology represents a novel approach to target multiple factors involved in tumor progression and metastasis.


Circulation | 2003

Targeting of Mitogen-Activated Protein Kinases and Phosphatidylinositol 3 Kinase Inhibits Hepatocyte Growth Factor/Scatter Factor–Induced Angiogenesis

Shiladitya Sengupta; Lynda A. Sellers; Rung Chi Li; Ermanno Gherardi; Ganlin Zhao; Nicki Watson; Ram Sasisekharan; Tai-Ping Fan

Background Hepatocyte growth factor/scatter factor (HGF/SF) can sufficiently and independently induce pathophysiological angiogenesis. However, the treatment strategies have mostly been unsuccessful. The present study is the first to evaluate the possible targeting of downstream signals for the inhibition of HGF/SF‐induced angiogenesis. Methods and Results In a multichannel scratch assay with human endothelial cells (ECs), HGF/SF induced a strong and prolonged activation of MAPK and cell proliferation that was inhibited by PD98059 and LY294002/wortmannin, selective inhibitors of MAPK and PI3K signaling modules, respectively. Western blotting demonstrated a temporal relation between the activation of the two pathways. Chemical inhibition of the PI3K and MAPK signals inhibited HGF/SF‐induced chemoinvasion of ECs in vitro and blocked the HGF/SF‐induced neovascularization into a polymer scaffold in vivo, as quantified by vessel counts and the clearance of radioactive 133Xe. Conclusions These data indicate that MEK and PI3K inhibitors represent a promising approach to the clinical management of pathological conditions characterized by overt HGF/SF‐induced angiogenesis. (Circulation. 2003;107: 2955‐2961.)


Glycobiology | 2011

Bioactivity screening of partially desulfated low-molecular-weight heparins: A structure/activity relationship study

Sucharita Roy; Hsuanchi Lai; Radouane Zouaoui; Jay Duffner; He Zhou; Lakshmi Priya Jayaraman; Ganlin Zhao; Tanmoy Ganguly; Takashi Kishimoto; Ganesh Venkataraman

A series of size-defined low-molecular-weight heparins were generated by regioselective chemical modifications and profiled for their in vitro and in vivo activities. The compounds displayed reduced anti-coagulant activity, demonstrated varying affinities toward angiogenic growth factors (fibroblast growth factor-2, vascular endothelial growth factor and stromal cell-derived factor-1α), inhibited the P-selectin/P-selectin glycoprotein ligand-1 interaction and, notably, exhibited anti-tumor efficacy in a murine melanoma experimental metastasis model. Our results demonstrate that modulating specific sequences, especially the N-domains (-NS or -NH(2) or -NHCOCH(3)) in these polysaccharide sequences, has a major impact on the participation in a diverse range of biological activities. These results also suggest that the 6-O-sulfates, but not the 2-O-sulfates, critically affect the binding of a desulfated derivative to certain angiogenic proteins as well as its ability to inhibit P-selectin-mediated B16F10 melanoma metastases. Furthermore, N-desulfation followed by N-acetylation regenerates the affinity/inhibition properties to different extents in all the compounds tested in the in vitro assays. This systematic study lays a conceptual foundation for detailed structure function elucidation and will facilitate the rational design of targeted heparan sulfate proteoglycan-based anti-metastatic therapeutic candidates.


Cns & Neurological Disorders-drug Targets | 2017

Demonstration of Biological and Immunological Equivalence of a Generic Glatiramer Acetate

Josephine D D`Alessandro; Kevin Garofalo; Ganlin Zhao; Christopher M. Honan; Jay Duffner; Ishan Capila; Ian Fier; Ganesh Kaundinya; Daniel Kantor; Tanmoy Ganguly

Background: In April 2015, the US Food and Drug Administration approved the first generic glatiramer acetate, Glatopa® (M356), as fully substitutable for Copaxone® 20 mg/mL for relapsing forms of multiple sclerosis (MS). This approval was accomplished through an Abbreviated New Drug Applica-tion that demonstrated equivalence to Copaxone. Method: This article will provide an overview of the methods used to establish the biological and immu-nological equivalence of the two glatiramer acetate products, including methods evaluating antigen-presenting cell (APC) biology, T-cell biology, and other immunomodulatory effects. Results: In vitro and in vivo experiments from multiple redundant orthogonal assays within four biologi-cal processes (aggregate biology, APC biology, T-cell biology, and B-cell biology) modulated by glati-ramer acetate in MS established the biological and immunological equivalence of Glatopa and Copaxone and are described. The following were observed when comparing Glatopa and Copaxone in these exper-iments: equivalent delays in symptom onset and reductions in “disease” intensity in experimental autoim-mune encephalomyelitis; equivalent dose-dependent increases in Glatopa- and Copaxone-induced mono-kine-induced interferon-gamma release from THP-1 cells; a shift to a T helper 2 phenotype resulting in the secretion of interleukin (IL)-4 and downregulation of IL-17 release; no differences in immunogenicity and the presence of equivalent “immunofingerprints” between both versions of glatiramer acetate; and no stimulation of histamine release with either glatiramer acetate in basophilic leukemia 2H3 cell lines. Conclusion: In summary, this comprehensive approach across different biological and immunological pathways modulated by glatiramer acetate consistently supported the biological and immunological equiv-alence of Glatopa and Copaxone.


Cancer Research | 2010

Abstract 2269: M402 - A novel heparan sulfate proteoglycan mimetic targeting tumor-host interactions

He Zhou; Sucharita Roy; Edward Cochran; Radouane Zouaoui; Juliane Karlgren; Nancy Dussault; Rain Yq Kwan; Jay Duffner; Ganlin Zhao; Sean W. Smith; Zoya Galcheva-Gargova; Erick Moy; Marishka Barnes; Chris Honan; Chia Lin Chu; Yi Wei Qi; Tanmoy Ganguly; Birgit Schultes; Ganesh Venkataraman; Takashi Kishimoto

Heparan sulfate proteoglycans (HSPGs) play important roles in tumorigenesis by mediating tumor-stromal interactions through the presentation of growth factors, cytokines, and chemokines critical for tumor progression, survival and metastasis. M402 is a rationally engineered, non-cytotoxic HSPG mimetic, designed to disrupt tumor-host interactions. M402 binds and inhibits multiple factors including VEGF, FGF2, SDF-1α, and P-selectin. A single 20 mg/kg subcutaneous (s.c.) dose of M402 effectively reduced seeding of B16F10 murine melanoma cells to the lung in a syngeneic experimental metastasis model. Chronic administration of M402, alone or in combination with cisplatin or docetaxel, inhibited spontaneous metastasis of orthotopically implanted 4T1 murine mammary carcinoma in this model. M402 treatment also normalized circulating levels of GR1 + immature myeloid cells and platelet counts in 4T1 metastatic tumor bearing mice. Fluorescently-labeled M402 exhibited selective accumulation in the primary tumor. Immunohistological analyses of primary tumor presented a decrease in microvessel density in M402-treated animals, suggesting anti-angiogenesis may be one of the mechanisms involved in vivo. Importantly, M402, as monotherapy or in combination with chemotherapeutics, also revealed significant survival benefits in this aggressive tumor model. These data demonstrate that targeting HSPG biology may provide a useful approach to attenuate multiple pathways involved in tumor progression and metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2269.


Archive | 2005

Nanocell drug delivery system

Shiladitya Sengupta; Ganlin Zhao; Ishan Capila; David Eavarone; Ram Sasisekharan


Archive | 2005

Methods and compositions related to the modulation of intercellular junctions

Aarthi Chandrasekaran; Shiladitya Sengupta; David Berry; Kristine Holley; Ganlin Zhao; Ram Sasisekharan

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Ram Sasisekharan

Washington University in St. Louis

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Ganesh Venkataraman

Massachusetts Institute of Technology

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Tanmoy Ganguly

Massachusetts Institute of Technology

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Sucharita Roy

Massachusetts Institute of Technology

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Zachary Shriver

Massachusetts Institute of Technology

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He Zhou

University of Massachusetts Boston

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Ishan Capila

Massachusetts Institute of Technology

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Robert Langer

Massachusetts Institute of Technology

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Sean W. Smith

Massachusetts Institute of Technology

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