A systems approach to engineering cancer nanotechnologies

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, February 2010.Vita. Cataloged from PDF version of thesis.Includes bibliographical references (p. 203-210).therapy. Over the past three decades, advances in nanomaterial synthesis have produced impressive nanostructures with unique electromagnetic and therapeutic properties. These represent a powerful toolkit of building blocks through which multi-component nanosystems could be constructed. Yet, while biological systems produce higher-order functions through coordinated interactions between multiple nanoscale components, biomedical nanotechnologies to date have largely lacked systems-scale complexity. Considering that typical in vivo doses of diagnostic or therapeutic nanoparticles exceed I trillion nanoparticles, there is considerable opportunity to construct multi-component, interactive nanoparticle systems that perform sophisticated new functions in vivo. This thesis takes a systems approach to engineering cancer nanotechnologies, where interactions between multiple nanoparticle populations are designed to generate emergent system properties for enhancing the sensing and targeting of cancer cells. In the first section of this thesis, direct nanoparticle interactions are engineered to produce emergent properties for cancer sensing. Three classes of magnetic particles are developed that respectively enable: MRI detection of single cancer-associated proteases, performance of logical AND/OR operations using two cancer-associated proteases, and reversible sensing of antagonistic kinase/phosphatase enzyme pairs.(cont.) In the second section of this thesis, indirect mechanisms of nanoparticle interaction-where nanoparticles communicate at a distance via intermediates-are engineered to amplify nanoparticle targeting to regions of tumor invasion in vivo. Two nanosystems are synthesized wherein intravenously administered nanoparticles that have successfully targeted tumors broadcast the tumor's location to other nanoparticles in circulation to recruit their amplified local accumulation. In mice, one of these systems intravenously delivers >40-fold higher drug doses to tumors than non-communicating controls, leading to durable repression of tumor growth and significantly improved host survival. Together, these systems highlight the potential for interactive nanoparticle systems to perform highly complex functions in vivo. In contrast to the current strategy of injecting large populations of nanoparticles that carry out identical, often competitive functions in vivo, this work promotes a paradigm of 'systems nanotechnology,' directed toward the construction of nanoparticle systems that produce emergent behaviors for enhancing in vivo diagnostics, regenerative medicines, and therapeutics.by Geoffrey von Maltzahn.Ph.D

Ligand-clustered “patchy” nanoparticles for modulated cellular uptake and in vivo tumor targeting

Author Manuscript: 2012 August 05.A matter of presentation: The manner in which polyvalent ligands are presented to a cell—homogeneously or in spatially defined groupings on a nanoparticle surface—may play an important role in cellular uptake. This aspect is investigated for the first time using a linear dendritic polymer construct to pattern the surfaces of nanoparticles with variable-sized ligand clusters in different spatial arrangements.National Institutes of Health (U.S.) (NIH NIBIB Grant 5R01EB008082-02)MIT-Harvard Center of Cancer Nanotechnology ExcellenceNational Science Foundation (U.S.

Mass-encoded synthetic biomarkers for multiplexed urinary monitoring of disease

Biomarkers are increasingly important in the clinical management of complex diseases, yet our ability to discover new biomarkers remains limited by our dependence on endogenous molecules. Here we describe the development of exogenously administered `synthetic biomarkers' composed of mass-encoded peptides conjugated to nanoparticles that leverage intrinsic features of human disease and physiology for noninvasive urinary monitoring. These protease-sensitive agents perform three functions in vivo: target sites of disease, sample dysregulated protease activities and emit mass-encoded reporters into host urine for multiplexed detection by mass spectrometry. Using mouse models of liver fibrosis and cancer, we show that they can noninvasively monitor liver fibrosis and resolution without the need for invasive core biopsies and can substantially improve early detection of cancer compared with clinically used blood biomarkers. This approach of engineering synthetic biomarkers for multiplexed urinary monitoring should be broadly amenable to additional pathophysiological processes and to point-of-care diagnostics

Nanoparticles that communicate in vivo to amplify tumour targeting

Author Manuscript: 2012 May 29Nanomedicines have enormous potential to improve the precision of cancer therapy, yet our ability to efficiently home these materials to regions of disease in vivo remains very limited. Inspired by the ability of communication to improve targeting in biological systems, such as inflammatory-cell recruitment to sites of disease, we construct systems where synthetic biological and nanotechnological components communicate to amplify disease targeting in vivo. These systems are composed of ‘signalling’ modules (nanoparticles or engineered proteins) that target tumours and then locally activate the coagulation cascade to broadcast tumour location to clot-targeted ‘receiving’ nanoparticles in circulation that carry a diagnostic or therapeutic cargo, thereby amplifying their delivery. We show that communicating nanoparticle systems can be composed of multiple types of signalling and receiving modules, can transmit information through multiple molecular pathways in coagulation, can operate autonomously and can target over 40 times higher doses of chemotherapeutics to tumours than non-communicating controls.National Cancer Institute (U.S.) (SBMRI Cancer Center Support Grant 5 P30 CA30199-28)National Cancer Institute (U.S.) (MIT CCNE Grant U54 CA119349)National Cancer Institute (U.S.) (Bioengineering Research Partnership Grant 5-R01-CA124427)National Cancer Institute (U.S.) (UCSD CCNE Grant U54 CA 119335)National Science Foundation (U.S.) (Whitaker Graduate Fellowship

Mass-encoded synthetic biomarkers for multiplexed urinary monitoring of disease

Biomarkers are becoming increasingly important in the clinical management of complex diseases, yet our ability to discover new biomarkers remains limited by our dependence on endogenous molecules. Here we describe the development of exogenously administered 'synthetic biomarkers' composed of mass-encoded peptides conjugated to nanoparticles that leverage intrinsic features of human disease and physiology for noninvasive urinary monitoring. These protease-sensitive agents perform three functions in vivo: they target sites of disease, sample dysregulated protease activities and emit mass-encoded reporters into host urine for multiplexed detection by mass spectrometry. Using mouse models of liver fibrosis and cancer, we show that these agents can noninvasively monitor liver fibrosis and resolution without the need for invasive core biopsies and substantially improve early detection of cancer compared with current clinically used blood biomarkers. This approach of engineering synthetic biomarkers for multiplexed urinary monitoring should be broadly amenable to additional pathophysiological processes and point-of-care diagnostics.National Institutes of Health (U.S.) (Bioengineering Research Partnership R01 CA124427)Kathy and Curt Marble Cancer Research FundNational Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service Award (F32CA159496-01

Probing nanoantenna-directed photothermal destruction of tumors using noninvasive laser irradiation

Plasmonic nanomaterials have tremendous potential to improve the tumor specificity of traditional cancer ablation practices, yet little effort has been directed toward quantitatively understanding their photothermal energy conversion in tumor tissues. In the present work, we develop a predictive model for plasmonic nanomaterial assisted tumor destruction under extracorporeal laser irradiation. Instead of appealing to heuristically based laser intensification models with tunable, tissue absorption and scattering coefficients, we consider fundamental characteristics of optoelectrothermal energy conversion and heat dissipation for plasmonic nanomaterials within living tumor tissues to construct a simulation tool that accurately reproduces our experimental findings, including aspects of delayed time-temperature characteristics. We believe the comprehensive modeling strategy outlined here provides a groundwork for the development of anticipatory therapeutic planning tools with individually tailored treatment plans, resulting in an ultimate benefit to ailing cancer patients.DST of the Government of Indi