Santiago (Santi) is interested in the intersection of materials science and immunotherapy, and is working to develop injectable hydrogels to stimulate the immune system to recognize and eliminate cancer. Santi is especially interested in leveraging the unique drug delivery capabilities provided by such materials systems in order to explore combination immunotherapy and the role of release kinetics on therapeutic efficacy and safety.
Honors & Awards
Siebel Scholar, Siebel Foundation (2018)
Sloan UCEM Fellow, Alfred P. Sloan Foundation (2016)
Lemelson Engineering Presidential Fellowship, MIT (2012)
National Science Foundation (NSF) Graduate Research Fellowship, National Science Foundation (2012)
Science, Technology, and Research Scholars Fellowship, Yale (2010)
Doctor of Philosophy, Massachusetts Institute of Technology (2018)
BS, Yale University, Biomedical Engineering (2012)
- Binary Targeting of siRNA to Hematologic Cancer Cells In Vivo Using Layer-by-Layer Nanoparticles ADVANCED FUNCTIONAL MATERIALS 2019; 29 (20)
Solution Conditions Tune and Optimize Loading of Therapeutic Polyelectrolytes into Layer-by-Layer Functionalized Liposomes
2019; 13 (5): 5623–34
Layer-by-layer (LbL) nanoparticles offer great potential to the field of drug delivery, where these nanocomposites have been studied for their ability to deliver chemotherapeutic agents, small molecule inhibitors, and nucleic acids. Most exciting is their ability to encapsulate multiple functional elements, which allow nanocarriers to deliver complex combination therapies with staged release. However, relative to planar LbL constructs, colloidal LbL systems have not undergone extensive systematic studies that outline critical synthetic solution conditions needed for robust and efficient assembly. The multistaged process of adsorbing a series of materials onto a nanoscopic template is inherently complex, and facilitating the self-assembly of these materials depends on identifying proper solution conditions for each synthetic step and adsorbed material. Here, we focus on addressing some of the fundamental questions that must be answered in order to obtain a reliable and robust synthesis of nucleic acid-containing LbL liposomes. This includes a study of solution conditions, such as pH, ionic strength, salt composition, and valency, and their impact on the preparation of LbL nanoparticles. Our results provide insight into the selection of solution conditions to control the degree of ionization and the electrostatic screening length to suit the adsorption of nucleic acids and synthetic polypeptides. The optimization of these parameters led to a roughly 8-fold improvement in nucleic acid loading in LbL liposomes, indicating the importance of optimizing solution conditions in the preparation of therapeutic LbL nanoparticles. These results highlight the benefits of defining principles for constructing highly effective nanoparticle systems.
View details for DOI 10.1021/acsnano.9b00792
View details for Web of Science ID 000469886300069
View details for PubMedID 30986034
RNA-Peptide nanoplexes drug DNA damage pathways in high-grade serous ovarian tumors.
Bioengineering & translational medicine
2018; 3 (1): 26–36
DNA damaging chemotherapy is a cornerstone of current front-line treatments for advanced ovarian cancer (OC). Despite the fact that a majority of these patients initially respond to therapy, most will relapse with chemo-resistant disease; therefore, adjuvant treatments that synergize with DNA-damaging chemotherapy could improve treatment outcomes and survival in patients with this deadly disease. Here, we report the development of a nanoscale peptide-nucleic acid complex that facilitates tumor-specific RNA interference therapy to chemosensitize advanced ovarian tumors to frontline platinum/taxane therapy. We found that the nanoplex-mediated silencing of the protein kinase, MK2, profoundly sensitized mouse models of high-grade serous OC to cytotoxic chemotherapy by blocking p38/MK2-dependent cell cycle checkpoint maintenance. Combined RNAi therapy improved overall survival by 37% compared with platinum/taxane chemotherapy alone and decreased metastatic spread to the lungs without observable toxic side effects. These findings suggest (a) that peptide nanoplexes can serve as safe and effective delivery vectors for siRNA and (b) that combined inhibition of MK2 could improve treatment outcomes in patients currently receiving frontline chemotherapy for advanced OC.
View details for DOI 10.1002/btm2.10086
View details for PubMedID 29376131
View details for PubMedCentralID PMC5773954
Engineering nanolayered particles for modular drug delivery.
Journal of controlled release : official journal of the Controlled Release Society
2016; 240: 364–86
Layer-by-layer (LbL) based self-assembly of nanoparticles is an emerging and powerful method to develop multifunctional and tissue responsive nanomedicines for a broad range of diseases. This unique assembly technique is able to confer a high degree of modularity, versatility, and compositional heterogeneity to nanoparticles via the sequential deposition of alternately charged polyelectrolytes onto a colloidal template. LbL assembly can provide added functionality by directly incorporating a range of functional materials within the multilayers including nucleic acids, synthetic polymers, polypeptides, polysaccharides, and functional proteins. These materials can be used to generate hierarchically complex, heterogeneous thin films on an extensive range of both traditional and novel nanoscale colloidal templates, providing the opportunity to engineer highly precise systems capable of performing the numerous tasks required for systemic drug delivery. In this review, we will discuss the recent advancements towards the development of LbL nanoparticles for drug delivery and diagnostic applications, with a special emphasis on the incorporation of biostability, active targeting, desirable drug release kinetics, and combination therapies into LbL nanomaterials. In addition to these topics, we will touch upon the next steps for the translation of these systems towards the clinic.
View details for DOI 10.1016/j.jconrel.2016.01.040
View details for PubMedID 26809005
View details for PubMedCentralID PMC6450096
Highly scalable, closed-loop synthesis of drug-loaded, layer-by-layer nanoparticles.
Advanced functional materials
2016; 26 (7): 991–1003
Layer-by-layer (LbL) self-assembly is a versatile technique from which multicomponent and stimuli-responsive nanoscale drug carriers can be constructed. Despite the benefits of LbL assembly, the conventional synthetic approach for fabricating LbL nanoparticles requires numerous purification steps that limit scale, yield, efficiency, and potential for clinical translation. In this report, we describe a generalizable method for increasing throughput with LbL assembly by using highly scalable, closed-loop diafiltration to manage intermediate purification steps. This method facilitates highly controlled fabrication of diverse nanoscale LbL formulations smaller than 150 nm composed from solid-polymer, mesoporous silica, and liposomal vesicles. The technique allows for the deposition of a broad range of polyelectrolytes that included native polysaccharides, linear polypeptides, and synthetic polymers. We also explore the cytotoxicity, shelf life and long-term storage of LbL nanoparticles produced using this approach. We find that LbL coated systems can be reliably and rapidly produced: specifically, LbL-modified liposomes could be lyophilized, stored at room temperature, and reconstituted without compromising drug encapsulation or particle stability, thereby facilitating large scale applications. Overall, this report describes an accessible approach that significantly improves the throughput of nanoscale LbL drug-carriers that show low toxicity and are amenable to clinically relevant storage conditions.
View details for DOI 10.1002/adfm.201504385
View details for PubMedID 27134622
View details for PubMedCentralID PMC4847955
Layer-by-layer assembled fluorescent probes in the second near-infrared window for systemic delivery and detection of ovarian cancer.
Proceedings of the National Academy of Sciences of the United States of America
2016; 113 (19): 5179–84
Fluorescence imaging in the second near-infrared window (NIR-II, 1,000-1,700 nm) features deep tissue penetration, reduced tissue scattering, and diminishing tissue autofluorescence. Here, NIR-II fluorescent probes, including down-conversion nanoparticles, quantum dots, single-walled carbon nanotubes, and organic dyes, are constructed into biocompatible nanoparticles using the layer-by-layer (LbL) platform due to its modular and versatile nature. The LbL platform has previously been demonstrated to enable incorporation of diagnostic agents, drugs, and nucleic acids such as siRNA while providing enhanced blood plasma half-life and tumor targeting. This work carries out head-to-head comparisons of currently available NIR-II probes with identical LbL coatings with regard to their biodistribution, pharmacokinetics, and toxicities. Overall, rare-earth-based down-conversion nanoparticles demonstrate optimal biological and optical performance and are evaluated as a diagnostic probe for high-grade serous ovarian cancer, typically diagnosed at late stage. Successful detection of orthotopic ovarian tumors is achieved by in vivo NIR-II imaging and confirmed by ex vivo microscopic imaging. Collectively, these results indicate that LbL-based NIR-II probes can serve as a promising theranostic platform to effectively and noninvasively monitor the progression and treatment of serous ovarian cancer.
View details for DOI 10.1073/pnas.1521175113
View details for PubMedID 27114520
View details for PubMedCentralID PMC4868435
Tumor-Targeted Synergistic Blockade of MAPK and PI3K from a Layer-by-Layer Nanoparticle.
Clinical cancer research : an official journal of the American Association for Cancer Research
2015; 21 (19): 4410–19
Cross-talk and feedback between the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR cell signaling pathways is critical for tumor initiation, maintenance, and adaptive resistance to targeted therapy in a variety of solid tumors. Combined blockade of these pathways-horizontal blockade-is a promising therapeutic strategy; however, compounded dose-limiting toxicity of free small molecule inhibitor combinations is a significant barrier to its clinical application.AZD6244 (selumetinib), an allosteric inhibitor of Mek1/2, and PX-866, a covalent inhibitor of PI3K, were co-encapsulated in a tumor-targeting nanoscale drug formulation-layer-by-layer (LbL) nanoparticles. Structure, size, and surface charge of the nanoscale formulations were characterized, in addition to in vitro cell entry, synergistic cell killing, and combined signal blockade. In vivo tumor targeting and therapy was investigated in breast tumor xenograft-bearing NCR nude mice by live animal fluorescence/bioluminescence imaging, Western blotting, serum cytokine analysis, and immunohistochemistry.Combined MAPK and PI3K axis blockade from the nanoscale formulations (160 ± 20 nm, -40 ± 1 mV) was synergistically toxic toward triple-negative breast (MDA-MB-231) and RAS-mutant lung tumor cells (KP7B) in vitro, effects that were further enhanced upon encapsulation. In vivo, systemically administered LbL nanoparticles preferentially targeted subcutaneous MDA-MB-231 tumor xenografts, simultaneously blocked tumor-specific phosphorylation of the terminal kinases Erk and Akt, and elicited significant disease stabilization in the absence of dose-limiting hepatotoxic effects observed from the free drug combination. Mice receiving untargeted, but dual drug-loaded nanoparticles exhibited progressive disease.Tumor-targeting nanoscale drug formulations could provide a more safe and effective means to synergistically block MAPK and PI3K in the clinic.
View details for DOI 10.1158/1078-0432.CCR-15-0013
View details for PubMedID 26034127
View details for PubMedCentralID PMC4624301