Elamprakash N. Savariar

University of California, San Diego

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Roger Y. Tsien

University of California, San Diego

Jessica L. Crisp

University of California, San Diego

Quyen T. Nguyen

University of California, San Diego

Sunil J. Advani

University of California, San Diego

S. Thayumanavan

University of Massachusetts Amherst

Karra A. Jones

Duke University

Andrew M. Lowy

UC San Diego Health System

Lisa Buckel

University of California, San Diego

Angel M. Hicks

Roswell Park Comprehensive Cancer Center

Daniel J. Scanderbeg

University of California, San Diego

Cooperative Institutions

University of California, San Diego

University of Massachusetts Amherst

Moores Cancer Center

Howard Hughes Medical Institute

UC San Diego Health System

University of California San Diego Medical Center

La Jolla Alcohol Research

University of Washington

VA San Diego Healthcare System

AntiCancer (United States)

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Temperature-Sensitive Dendritic Micelles

Journal of the American Chemical Society (2005)

Sivakumar V. Aathimanikandan Elamprakash N. Savariar S. Thayumanavan

Syntheses up to three generations have been achieved of biaryl-based amphiphilic dendrons with a charge-neutral pentaethylene glycol as the hydrophilic part and a decyl chain as the hydrophobic part. Studies on the temperature-dependent characteristics revealed that these dendrons exhibit a generation-dependent lower critical solution temperature (LCST). This behavior is attributed to the combination of the amphipathic nature of the hydrophilic pentaethylene glycol side chain and dendritic effect. Interestingly, this biaryl-based scaffold also maintains the ability to form a micelle-like assembly in polar solvents and an inverted micelle-like assembly in apolar solvents. Polarity of the dendritic interior was investigated using dye-based microenvironment studies. The aggregation behavior of these micelles was analyzed by fluorescence spectroscopy and dynamic light scattering. Critical micelle concentrations (CMC) of these assemblies were investigated using fluorescence excitation spectra of the sequestered guest molecule, pyrene.

Aggregation number

10.1021/ja054542y

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Supplemental Figure 3 from Tumor Radiosensitization by Monomethyl Auristatin E: Mechanism of Action and Targeted Delivery

Lisa Buckel Elamprakash N. Savariar Jessica L. Crisp Karra A. Jones Angel M. Hicks

HCT-116 tumor xenografts have b3 integrin expression.

Mechanism of Action

10.1158/0008-5472.22407374

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Supplementary Methods, Figures 1 - 10, Table 1 from Dual Targeting of Integrin αvβ3 and Matrix Metalloproteinase-2 for Optical Imaging of Tumors and Chemotherapeutic Delivery

Jessica L. Crisp Elamprakash N. Savariar Heather L. Glasgow Lesley G. Ellies Michael Whitney

PDF file - 5319K, Supplementary Materials and Methods. Supplemental Table 1: List of peptides and synthetic intermediates with corresponding molecular weights. Supplemental Figure 1: Chemical Structure of dual targeted peptides. Supplemental Figure 2: Gel images for MMP-2 cleavage assay. Supplemental Figure 3: Peptide SUVs (MDA-MB-231 tumors). Supplemental Figure 4: Injection of cyclic-RGD-PLGC(Me)AG-ACPP with excess of unlabeled cyclic-RGD. Supplemental Figure 5: Dual targeting of PLGC(Me)AG-ACPP with folate does not improve tumor uptake in SK-OV-3 tumors. Supplemental Figure 6: No primary antibody control for IHC. Supplemental Figure 7: Plasma stability and blood clearance of cyclic-RGDPLGC(Me)AG-ACPP. Supplemental Figure 8: Tumor growth curve corresponding to Figure 5B and animal body weights corresponding to Figure 5 B&C. Supplemental Figure 9: Animal body weight and tumor growth curves for therapy studies at 1.2mg/kg (~40nmol) and 0.6mg/kg (~20nmol). Supplemental Figure 10: Targeting of MMAE in Py230 syngeneic tumor model.

10.1158/1535-7163.22500130

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Supplemental Figure 3 from Tumor Radiosensitization by Monomethyl Auristatin E: Mechanism of Action and Targeted Delivery

Lisa Buckel Elamprakash N. Savariar Jessica L. Crisp Karra A. Jones Angel M. Hicks

HCT-116 tumor xenografts have b3 integrin expression.

Mechanism of Action

Delivery system

10.1158/0008-5472.22407374.v1

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Supplemental Figure 2 from Tumor Radiosensitization by Monomethyl Auristatin E: Mechanism of Action and Targeted Delivery

Lisa Buckel Elamprakash N. Savariar Jessica L. Crisp Karra A. Jones Angel M. Hicks

MMAE enhances γH2Ax foci formation following irradiation.

Mechanism of Action

10.1158/0008-5472.22407377.v1

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Abstract IA1: Building molecules to guide anticancer therapy

Cancer Research (2011)

Emilia S. Olson Roger Y. Tsien Elamprakash N. Savariar Jessica L. Crisp Tao Jiang

Abstract For clinical imaging, we need synthetic molecules with novel amplifying mechanisms for homing to diseased tissues. Activatable cell penetrating peptides (ACPPs) are polycationic cell penetrating peptides (CPPs) whose cellular uptake is minimized by a polyanionic inhibitory domain and then restored upon proteolysis of the peptide linker connecting the polyanionic and polycationic domains. Local activity of proteases able to cut the linker causes amplified retention in tissues and uptake into cells. ACPPs on dendrimers labeled with Cy5 and Gd-DOTA enable whole body magnetic resonance imaging (Olson et al (2010) PNAS 107: 4311–4316) followed by fluorescenceguided surgery. Such fluorescence guidance improves tumor-free survival in two animal models (Nguyen et al (2010) PNAS 107: 4317–4322). Contrast for tumor over normal tissues is amplified and accelerated when the polyanionic domain includes an acceptor of fluorescence resonance energy transfer (FRET), because loss of FRET (monitored either by multispectral emission or donor excited-state lifetime) instantly signals proteolysis without waiting for uncleaved substrate to wash out of normal tissues. Thrombin-cleavable ACPPs accumulate in atherosclerotic plaques, and their labeling intensity seems to correlate with progression towards rupture. Separately, we have developed fluorescent peptides that light up peripheral nerves to show surgeons where not to cut (Whitney et al (2011) Nature Biotech. 29: 352–356). Thus we believe that basic tumor biology and molecular design can help improve early detection and surgical resection, not just chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA1.

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Proteolysis

10.1158/1538-7445.fbcr11-ia1

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Real-time In Vivo Molecular Detection of Primary Tumors and Metastases with Ratiometric Activatable Cell-Penetrating Peptides

Cancer Research (2012)

Elamprakash N. Savariar Csilla N. Felsen Nadia Nashi Tao Jiang Lesley G. Ellies

Management of metastatic disease is integral to cancer treatment. Evaluation of metastases often requires surgical removal of all anatomically susceptible lymph nodes for ex vivo pathologic examination. We report a family of novel ratiometric activatable cell-penetrating peptides, which contain Cy5 as far red fluorescent donor and Cy7 as near-infrared fluorescent acceptor. Cy5 is quenched in favor of Cy7 re-emission until the intervening linker is cut by tumor-associated matrix metalloproteinases-2 and 9 (MMP2,9) or elastases. Such cleavage increases the Cy5:Cy7 emission ratio 40-fold and triggers tissue retention of the Cy5-containing fragment. This ratiometric increase provides an accelerated and quantifiable metric to identify primary tumors and metastases to liver and lymph nodes with increased sensitivity and specificity. This technique represents a significant advance over existing nonratiometric protease sensors and sentinel lymph node detection methods, which give no information about cancer invasion.

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Ex vivo

Primary tumor

10.1158/0008-5472.can-12-2969

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Data from Real-time In Vivo Molecular Detection of Primary Tumors and Metastases with Ratiometric Activatable Cell-Penetrating Peptides

Elamprakash N. Savariar Csilla N. Felsen Nadia Nashi Tao Jiang Lesley G. Ellies

<div>AbstractManagement of metastatic disease is integral to cancer treatment. Evaluation of metastases often requires surgical removal of all anatomically susceptible lymph nodes for ex vivo pathologic examination. We report a family of novel ratiometric activatable cell-penetrating peptides, which contain Cy5 as far red fluorescent donor and Cy7 as near-infrared fluorescent acceptor. Cy5 is quenched in favor of Cy7 re-emission until the intervening linker is cut by tumor-associated matrix metalloproteinases-2 and 9 (MMP2,9) or elastases. Such cleavage increases the Cy5:Cy7 emission ratio 40-fold and triggers tissue retention of the Cy5-containing fragment. This ratiometric increase provides an accelerated and quantifiable metric to identify primary tumors and metastases to liver and lymph nodes with increased sensitivity and specificity. This technique represents a significant advance over existing nonratiometric protease sensors and sentinel lymph node detection methods, which give no information about cancer invasion. Cancer Res; 73(2); 855–64. ©2012 AACR.</div>

10.1158/0008-5472.c.6505353

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Supramolecular Assemblies from Amphiphilic Homopolymers: Testing the Scope

Journal of the American Chemical Society (2006)

Elamprakash N. Savariar Sivakumar V. Aathimanikandan S. Thayumanavan

It has been shown by us in a recent communication that homopolymers, in which each repeat unit contains a hydrophilic and a hydrophobic head group, are capable of forming environment-dependent micellar or inverse micellar assemblies. A systematic structure-property relationship study is carried out here to test the scope of the design. We show here that the molecular design is indeed broadly applicable and that there is a significant gain in the critical aggregation concentrations of these polymers, as compared to the small molecule counterparts. We also show that the design can be tuned to achieve vesicle-type assemblies, which further expands the repertoire of amphiphilic homopolymers in a variety of areas. Characterizations of these assemblies have been carried out using transmission electron microscopy, dynamic light scattering, static light scattering, and dye incorporation experiments.

Scope (computer science)

10.1021/ja065213o

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Citations (205)

Supplemental Figure 5 from Tumor Radiosensitization by Monomethyl Auristatin E: Mechanism of Action and Targeted Delivery

Lisa Buckel Elamprakash N. Savariar Jessica L. Crisp Karra A. Jones Angel M. Hicks

Polycation conjugated MMAE is cytotoxic to tumor cells.

Mechanism of Action

10.1158/0008-5472.22407368

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