Publications by authors named "Sara Nizzero"

17 Publications

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Dedifferentiation-mediated stem cell niche maintenance in early-stage ductal carcinoma in situ progression: insights from a multiscale modeling study.

Cell Death Dis 2022 May 21;13(5):485. Epub 2022 May 21.

Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX, 77030, USA.

We present a multiscale agent-based model of ductal carcinoma in situ (DCIS) to study how key phenotypic and signaling pathways are involved in the early stages of disease progression. The model includes a phenotypic hierarchy, and key endocrine and paracrine signaling pathways, and simulates cancer ductal growth in a 3D lattice-free domain. In particular, by considering stochastic cell dedifferentiation plasticity, the model allows for study of how dedifferentiation to a more stem-like phenotype plays key roles in the maintenance of cancer stem cell populations and disease progression. Through extensive parameter perturbation studies, we have quantified and ranked how DCIS is sensitive to perturbations in several key mechanisms that are instrumental to early disease development. Our studies reveal that long-term maintenance of multipotent stem-like cell niches within the tumor are dependent on cell dedifferentiation plasticity, and that disease progression will become arrested due to dilution of the multipotent stem-like population in the absence of dedifferentiation. We have identified dedifferentiation rates necessary to maintain biologically relevant multipotent cell populations, and also explored quantitative relationships between dedifferentiation rates and disease progression rates, which may potentially help to optimize the efficacy of emerging anti-cancer stem cell therapeutics.
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http://dx.doi.org/10.1038/s41419-022-04939-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9124196PMC
May 2022

A Mathematical Model to Estimate Chemotherapy Concentration at the Tumor-Site and Predict Therapy Response in Colorectal Cancer Patients with Liver Metastases.

Cancers (Basel) 2021 Jan 25;13(3). Epub 2021 Jan 25.

Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX 77030, USA.

Chemotherapy remains a primary treatment for metastatic cancer, with tumor response being the benchmark outcome marker. However, therapeutic response in cancer is unpredictable due to heterogeneity in drug delivery from systemic circulation to solid tumors. In this proof-of-concept study, we evaluated chemotherapy concentration at the tumor-site and its association with therapy response by applying a mathematical model. By using pre-treatment imaging, clinical and biologic variables, and chemotherapy regimen to inform the model, we estimated tumor-site chemotherapy concentration in patients with colorectal cancer liver metastases, who received treatment prior to surgical hepatic resection with curative-intent. The differential response to therapy in resected specimens, measured with the gold-standard Tumor Regression Grade (TRG; from 1, complete response to 5, no response) was examined, relative to the model predicted systemic and tumor-site chemotherapy concentrations. We found that the average calculated plasma concentration of the cytotoxic drug was essentially equivalent across patients exhibiting different TRGs, while the estimated tumor-site chemotherapeutic concentration (eTSCC) showed a quadratic decline from TRG = 1 to TRG = 5 ( < 0.001). The eTSCC was significantly lower than the observed plasma concentration and dropped by a factor of ~5 between patients with complete response (TRG = 1) and those with no response (TRG = 5), while the plasma concentration remained stable across TRG groups. TRG variations were driven and predicted by differences in tumor perfusion and eTSCC. If confirmed in carefully planned prospective studies, these findings will form the basis of a paradigm shift in the care of patients with potentially curable colorectal cancer and liver metastases.
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http://dx.doi.org/10.3390/cancers13030444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866038PMC
January 2021

A mathematical model for the quantification of a patient's sensitivity to checkpoint inhibitors and long-term tumour burden.

Nat Biomed Eng 2021 04 4;5(4):297-308. Epub 2021 Jan 4.

Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX, USA.

A large proportion of patients with cancer are unresponsive to treatment with immune checkpoint blockade and other immunotherapies. Here, we report a mathematical model of the time course of tumour responses to immune checkpoint inhibitors. The model takes into account intrinsic tumour growth rates, the rates of immune activation and of tumour-immune cell interactions, and the efficacy of immune-mediated tumour killing. For 124 patients, four cancer types and two immunotherapy agents, the model reliably described the immune responses and final tumour burden across all different cancers and drug combinations examined. In validation cohorts from four clinical trials of checkpoint inhibitors (with a total of 177 patients), the model accurately stratified the patients according to reduced or increased long-term tumour burden. We also provide model-derived quantitative measures of treatment sensitivity for specific drug-cancer combinations. The model can be used to predict responses to therapy and to quantify specific drug-cancer sensitivities in individual patients.
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http://dx.doi.org/10.1038/s41551-020-00662-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8669771PMC
April 2021

Education and Outreach in Physical Sciences in Oncology.

Trends Cancer 2021 01 7;7(1):3-9. Epub 2020 Nov 7.

Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Jacksonville, FL, USA; Department of Transplantation, Mayo Clinic, Jacksonville, FL, USA; Center for Immunotherapeutic Transport Oncophysics, Houston Methodist Research Institute, Houston, TX, USA. Electronic address:

Physical sciences are often overlooked in the field of cancer research. The Physical Sciences in Oncology Initiative was launched to integrate physics, mathematics, chemistry, and engineering with cancer research and clinical oncology through education, outreach, and collaboration. Here, we provide a framework for education and outreach in emerging transdisciplinary fields.
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http://dx.doi.org/10.1016/j.trecan.2020.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895467PMC
January 2021

Retraction of the Research Article: "Molecular targeting of FATP4 transporter for oral delivery of therapeutic peptide" by Z. Hu, S. Nizzero, S. Goel, L. E. Hinkle, X. Wu, C. Li, M. Ferrari and H. Shen.

Sci Adv 2020 06 26;6(26):eabc9572. Epub 2020 Jun 26.

Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA.

[This retracts the article DOI: 10.1126/sciadv.aba0145.].
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http://dx.doi.org/10.1126/sciadv.abc9752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319764PMC
June 2020

Sequential deconstruction of composite drug transport in metastatic breast cancer.

Sci Adv 2020 06 24;6(26):eaba4498. Epub 2020 Jun 24.

Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA.

It is challenging to design effective drug delivery systems (DDS) that target metastatic breast cancers (MBC) because of lack of competent imaging and image analysis protocols that suitably capture the interactions between DDS and metastatic lesions. Here, we integrate high temporal resolution of in vivo whole-body PET-CT, ex vivo whole-organ optical imaging, high spatial resolution of confocal microscopy, and mathematical modeling, to systematically deconstruct the trafficking of injectable nanoparticle generators encapsulated with polymeric doxorubicin (iNPG-pDox) in pulmonary MBC. iNPG-pDox accumulated substantially in metastatic lungs, compared to healthy lungs. Intratumoral distribution and retention of iNPG-pDox varied with lesion size, possibly induced by locally remodeled microenvironment. We further used multiscale imaging and mathematical simulations to provide improved drug delivery strategies for MBC. Our work presents a multidisciplinary translational toolbox to evaluate transport and interactions of DDS within metastases. This knowledge can be recursively applied to rationally design advanced therapies for metastatic cancers.
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http://dx.doi.org/10.1126/sciadv.aba4498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314527PMC
June 2020

Image-guided mathematical modeling for pharmacological evaluation of nanomaterials and monoclonal antibodies.

Wiley Interdiscip Rev Nanomed Nanobiotechnol 2020 09 21;12(5):e1628. Epub 2020 Apr 21.

Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, Texas, USA.

While plasma concentration kinetics has traditionally been the predictor of drug pharmacological effects, it can occasionally fail to represent kinetics at the site of action, particularly for solid tumors. This is especially true in the case of delivery of therapeutic macromolecules (drug-loaded nanomaterials or monoclonal antibodies), which can experience challenges to effective delivery due to particle size-dependent diffusion barriers at the target site. As a result, disparity between therapeutic plasma kinetics and kinetics at the site of action may exist, highlighting the importance of target site concentration kinetics in determining the pharmacodynamic effects of macromolecular therapeutic agents. Assessment of concentration kinetics at the target site has been facilitated by non-invasive in vivo imaging modalities. This allows for visualization and quantification of the whole-body disposition behavior of therapeutics that is essential for a comprehensive understanding of their pharmacokinetics and pharmacodynamics. Quantitative non-invasive imaging can also help guide the development and parameterization of mathematical models for descriptive and predictive purposes. Here, we present a review of the application of state-of-the-art imaging modalities for quantitative pharmacological evaluation of therapeutic nanoparticles and monoclonal antibodies, with a focus on their integration with mathematical models, and identify challenges and opportunities. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Diagnostic Tools > in vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.
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http://dx.doi.org/10.1002/wnan.1628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507140PMC
September 2020

Molecular targeting of FATP4 transporter for oral delivery of therapeutic peptide.

Sci Adv 2020 04 1;6(14):eaba0145. Epub 2020 Apr 1.

Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA.

Low oral bioavailability of peptide drugs has limited their application to parenteral administration, which suffers from poor patient compliance. Here, we show that molecular targeting of the FATP4 transporter is an effective approach to specifically transport long-chain fatty acid (LCFA)-conjugated peptides across the enterocytic membrane and, thus, enables oral delivery of drug peptides. We packaged LCFA-conjugated exendin-4 (LCFA-Ex4) into liposomes and coated with chitosan nanoparticles to form an orally deliverable Ex4 (OraEx4). OraEx4 protected LCFA-Ex4 from damage by the gastric fluid and released LCFA-Ex4 in the intestinal cavity, where LCFA-Ex4 was transported across the enterocyte membrane by the FAPT4 transporter. OraEx4 had a high bioavailability of 24.8% with respect to subcutaneous injection and exhibited a substantial hypoglycemic effect in murine models of diabetes mellitus. Thus, molecular targeting of the FATP4 transporter enhances oral absorption of therapeutic peptides and provides a platform for oral peptide drug development.
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http://dx.doi.org/10.1126/sciadv.aba0145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7112756PMC
April 2020

Immunotherapeutic Transport Oncophysics: Space, Time, and Immune Activation in Cancer.

Trends Cancer 2020 01 30;6(1):40-48. Epub 2019 Dec 30.

Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA; Swansea University Medical School, Singleton Park, Swansea, Wales, UK. Electronic address:

Immuno-oncology has gained momentum thanks to the success of strategies aimed at enhancing immune-mediated antitumor response. The field of immunotherapeutic transport oncophysics investigates the physical processes that drive cancer immunotherapies. This review discusses three main aspects that determine the outcome of an immunotherapy-based treatment from a physical point of view; (i) space, the distribution of cancer and immune cells within tumor masses, (ii) time, the temporal dynamic of immune response against tumors, and (iii) activity, the ability of immune cell populations to suppress cancer. Upon introducing these topics with examples from the literature, we investigate in detail two cases where the interplay between space, time, and activation variables determines immune response: nanodendritic cell vaccines and immunosuppression in ovarian cancer.
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http://dx.doi.org/10.1016/j.trecan.2019.11.008DOI Listing
January 2020

Smeared Multiscale Finite Element Models for Mass Transport and Electrophysiology Coupled to Muscle Mechanics.

Front Bioeng Biotechnol 2019 10;7:381. Epub 2019 Dec 10.

Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, United States.

Mass transport represents the most fundamental process in living organisms. It includes delivery of nutrients, oxygen, drugs, and other substances from the vascular system to tissue and transport of waste and other products from cells back to vascular and lymphatic network and organs. Furthermore, movement is achieved by mechanical forces generated by muscles in coordination with the nervous system. The signals coming from the brain, which have the character of electrical waves, produce activation within muscle cells. Therefore, from a physics perspective, there exist a number of physical fields within the body, such as velocities of transport, pressures, concentrations of substances, and electrical potential, which is directly coupled to biochemical processes of transforming the chemical into mechanical energy and further internal forces for motion. The overall problems of mass transport and electrophysiology coupled to mechanics can be investigated theoretically by developing appropriate computational models. Due to the enormous complexity of the biological system, it would be almost impossible to establish a detailed computational model for the physical fields related to mass transport, electrophysiology, and coupled fields. To make computational models feasible for applications, we here summarize a concept of smeared physical fields, with coupling among them, and muscle mechanics, which includes dependence on the electrical potential. Accuracy of the smeared computational models, also with coupling to muscle mechanics, is illustrated with simple example, while their applicability is demonstrated on a liver model with tumors present. The last example shows that the introduced methodology is applicable to large biological systems.
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http://dx.doi.org/10.3389/fbioe.2019.00381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914730PMC
December 2019

Systematic comparison of methods for determining the in vivo biodistribution of porous nanostructured injectable inorganic particles.

Acta Biomater 2019 10 3;97:501-512. Epub 2019 Aug 3.

Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA. Electronic address:

With a wide variety of biodistribution measurement techniques reported in the literature, it is important to perform side-by-side comparisons of results obtained with different methods on the same particle platform, to determine differences across methods, highlight advantages and disadvantages, and inform methods selection according to specific applications. Inorganic nanostructured particles (INPs) have gained a central role in the development of injectable delivery vectors thanks to their controllable design, biocompatibility, and favorable degradation kinetic. Thus, accurate determination of in vivo biodistribution of INPs is a key aspect of developing and optimizing this class of delivery vectors. In this study, a systematic comparison of spectroscopy (inductively coupled plasma optical emission spectroscopy), fluorescence (in vivo imaging system, confocal microscopy, and plate reader), and radiolabeling (gamma counter)-based techniques is performed to assess the accuracy and sensitivity of biodistribution measurements in mice. Each method is evaluated on porous silicon particles, an established and versatile injectable delivery platform. Biodistribution is evaluated in all major organs and compared in terms of absolute results (%ID/g and %ID/organ when possible) and sensitivity (σ). Finally, we discuss how these results can be extended to inform method selection for other platforms and specific applications, with an outlook to potential benefit for pre-clinical and clinical studies. Overall, this study presents a new practical guide for selection of in vivo biodistribution methods that yield quantitative results. STATEMENT OF SIGNIFICANCE: The significance of this work lies in the use of a single platform to test performances of different biodistribution methods in vivo, with a strict quantitative metric. These results, united with the qualitative comparison of advantages and disadvantages of each technique, are aimed at supporting the rational choice of each different method according to the specific application, to improve the quantitative description of biodistribution results that will be published by others in the future.
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http://dx.doi.org/10.1016/j.actbio.2019.08.002DOI Listing
October 2019

Transport Barriers and Oncophysics in Cancer Treatment.

Trends Cancer 2018 04 15;4(4):277-280. Epub 2018 Mar 15.

Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address:

Transport processes in cancer are the focus of transport oncophysics (TOP). In the TOP approach, the sequential negotiation of transport barriers is critical to both drug delivery and metastasis development. New and creative therapeutic opportunities are currently emerging, stimulated by the study of cancer hallmarks with the TOP approach.
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http://dx.doi.org/10.1016/j.trecan.2018.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441955PMC
April 2018

A chloroquine-induced macrophage-preconditioning strategy for improved nanodelivery.

Sci Rep 2017 10 23;7(1):13738. Epub 2017 Oct 23.

Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, 77030, USA.

Site-specific localization is critical for improving the therapeutic efficacy and safety of drugs. Nanoparticles have emerged as promising tools for localized drug delivery. However, over 90% of systemically injected nanocarriers typically accumulate in the liver and spleen due to resident macrophages that form the mononuclear phagocyte system. In this study, the clinically approved antimalarial agent chloroquine was shown to reduce nanoparticle uptake in macrophages by suppressing endocytosis. Pretreatment of mice with a clinically relevant dose of chloroquine substantially decreased the accumulation of liposomes and silicon particles in the mononuclear phagocyte system and improved tumoritropic and organotropic delivery. The novel use of chloroquine as a macrophage-preconditioning agent presents a straightforward approach for addressing a major barrier in nanomedicine. Moreover, this priming strategy has broad applicability for improving the biodistribution and performance of particulate delivery systems. Ultimately, this study defines a paradigm for the combined use of macrophage-modulating agents with nanotherapeutics for improved site-specific delivery.
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http://dx.doi.org/10.1038/s41598-017-14221-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653759PMC
October 2017

Bone-targeting nanoparticle to co-deliver decitabine and arsenic trioxide for effective therapy of myelodysplastic syndrome with low systemic toxicity.

J Control Release 2017 Dec 16;268:92-101. Epub 2017 Oct 16.

Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address:

Myelodysplastic syndromes (MDS) are a diverse group of bone marrow disorders and clonal hematopoietic stem cell disorders characterized by abnormal blood cells, or reduced peripheral blood cell count. Recent clinical studies on combination therapy of decitabine (DAC) and arsenic trioxide (ATO) have demonstrated synergy on MDS treatment, but the treatment can cause significant side effects to patients. In addition, both drugs have to be administered on a daily basis due to their short half-lives. In addressing key issues of reducing toxic side effects and improving pharmacokinetic profiles of the therapeutic agents, we have developed a new formulation by co-packaging DAC and ATO into alendronate-conjugated bone-targeting nanoparticles (BTNPs). Our pharmacokinetic studies revealed that intravenously administered BTNPs increased circulation time up to 3days. Biodistribution analysis showed that the BTNP facilitated DAC and ATO accumulation in the bone, which is 6.7 and 7.9 times more than untargeted NP. Finally, MDS mouse model treated with BTNPs showed better restoration of complete blood count to normal level, and significantly longer median survival as compared to free drugs or untargeted NPs treatment. Our results support bone-targeted co-delivery of DAC and ATO for effective treatment of MDS.
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http://dx.doi.org/10.1016/j.jconrel.2017.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722672PMC
December 2017

A pyruvate decarboxylase-mediated therapeutic strategy for mimicking yeast metabolism in cancer cells.

Pharmacol Res 2016 09 6;111:413-421. Epub 2016 Jul 6.

Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA; CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience & Technology of China, University of Chinese Academy of Sciences, Beijing 100190, China. Electronic address:

Cancer cells have high rates of glycolysis and lactic acid fermentation in order to fuel accelerated rates of cell division (Warburg effect). Here, we present a strategy for merging cancer and yeast metabolism to remove pyruvate, a key intermediate of cancer cell metabolism, and produce the toxic compound acetaldehyde. This approach was achieved by administering the yeast enzyme pyruvate decarboxylase to triple negative breast cancer cells. To overcome the challenges of protein delivery, a nanoparticle-based system consisting of cationic lipids and porous silicon were employed to obtain efficient intracellular uptake. The results demonstrate that the enzyme therapy decreases cancer cell viability through production of acetaldehyde and reduction of lactic acid fermentation.
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http://dx.doi.org/10.1016/j.phrs.2016.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5026593PMC
September 2016

Single-particle absorption spectroscopy by photothermal contrast.

Nano Lett 2015 May 10;15(5):3041-7. Epub 2015 Apr 10.

†Department of Chemistry, ‡Applied Physics Graduate Program, §Department of Electrical and Computer Engineering, Laboratory for Nanophotonics, Rice University, Houston, Texas 77005, United States.

Removing effects of sample heterogeneity through single-molecule and single-particle techniques has advanced many fields. While background free luminescence and scattering spectroscopy is widely used, recording the absorption spectrum only is rather difficult. Here we present an approach capable of recording pure absorption spectra of individual nanostructures. We demonstrate the implementation of single-particle absorption spectroscopy on strongly scattering plasmonic nanoparticles by combining photothermal microscopy with a supercontinuum laser and an innovative calibration procedure that accounts for chromatic aberrations and wavelength-dependent excitation powers. Comparison of the absorption spectra to the scattering spectra of the same individual gold nanoparticles reveals the blueshift of the absorption spectra, as predicted by Mie theory but previously not detectable in extinction measurements that measure the sum of absorption and scattering. By covering a wavelength range of 300 nm, we are furthermore able to record absorption spectra of single gold nanorods with different aspect ratios. We find that the spectral shift between absorption and scattering for the longitudinal plasmon resonance decreases as a function of nanorod aspect ratio, which is in agreement with simulations.
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http://dx.doi.org/10.1021/nl504992hDOI Listing
May 2015
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