RNAi-Microsponges Form through Self-Assembly of the Organic and Inorganic Products of Transcription

Inorganic nanostructures have been used extensively to package nucleic acids into forms useful for therapeutic applications. Here we report that the two products of transcription, RNA and inorganic pyrophosphate, can self-assemble to form composite microsponge structures composed of nanocrystalline magnesium pyrophosphate sheets (Mg[subscript 2]P[subscript 2]O[subscript 7]•3.5H[subscript 2]O) with RNA adsorbed to their surfaces. The microsponge particles contain high loadings of RNA (15–21 wt.%) that are protected from degradation and can be obtained through a rolling circle mechanism as large concatemers capable of mediating RNAi. The morphology of the RNAi microsponges is influenced by the time-course of the transcription reaction and interactions between RNA and the inorganic phase. Previous work demonstrated that polycations can be used to condense RNAi microsponges into nanoparticles capable of efficient transfection with low toxicity. Our new findings suggest that the formation of these nanoparticles is mediated by the gradual dissolution of magnesium pyrophosphate that occurs in the presence of polycations. The simple one-pot approach for assembling RNAi microsponges along with their unique properties could make them useful for RNA-based therapeutics.National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051)National Cancer Institute (U.S.) (Center for Cancer Nanotechnology Excellence Grant 5 U54 CA151884-02)Natural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship)National Health and Medical Research Council (Australia) (CJ Martin Fellowship)National Science Foundation (U.S.). Graduate Research Fellowshi

A Convergent Synthetic Platform for Single-Nanoparticle Combination Cancer Therapy: Ratiometric Loading and Controlled Release of Cisplatin, Doxorubicin, and Camptothecin

The synthesis of polymer therapeutics capable of controlled loading and synchronized release of multiple therapeutic agents remains a formidable challenge in drug delivery and synthetic polymer chemistry. Herein, we report the synthesis of polymer nanoparticles (NPs) that carry precise molar ratios of doxorubicin, camptothecin, and cisplatin. To our knowledge, this work provides the first example of orthogonally triggered release of three drugs from single NPs. The highly convergent synthetic approach opens the door to new NP-based combination therapies for cancer.MIT Research Support CommitteeLincoln Laboratory. Advanced Concepts CommitteeUnited States. Dept. of Defense (Ovarian Cancer Research Program Teal Innovator Award)National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award 1F32EB017614-01)Natural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship)Natural Sciences and Engineering Research Council of Canada (Graduate Fellowship)National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051

Flexible Photonic Cellulose Nanocrystal Films.

The fabrication of self-assembled cellulose nanocrystal (CNC) films of tunable photonic and mechanical properties using a facile, green approach is demonstrated. The combination of tunable flexibility and iridescence can dramatically expand CNC coating and film barrier capabilities for paints and coating applications, sustainable consumer packaging products, as well as effective templates for photonic and optoelectronic materials and structures.CelluForce Inc., Biotechnology and Biological Sciences Research Council (David Phillips fellowship (Grant ID: BB/K014617/1, 76933), European Research Council (Grant ID: ERC-2014-STG H2020 639088), Engineering and Physical Sciences Research Council (Grant ID: 1525292

Scalable Manufacture of Built-to-Order Nanomedicine: Spray-Assisted Layer-by-Layer Functionalization of PRINT Nanoparticles

Scalable methods, PRINT particle fabrication, and spray-assisted Layer-by-Layer deposition are combined to generate uniform and functional nanotechnologies with precise control over composition, size, shape, and surface functionality. A modular and tunable approach towards design of built-to-order nanoparticle systems, spray coating on PRINT particles is demonstrated to achieve technologies capable of targeted interactions with cancer cells for applications in drug delivery.National Cancer Institute (U.S.) (Center for Cancer Nanotechnology Excellence Grant 5 U54 CA151884-02)National Science Foundation (U.S.). Graduate Research FellowshipNatural Sciences and Engineering Research Council of Canada (Postdoctoral Fellowship

A Nanoparticle-Based Combination Chemotherapy Delivery System for Enhanced Tumor Killing by Dynamic Rewiring of Signaling Pathways

Exposure to the EGFR (epidermal growth factor receptor) inhibitor erlotinib promotes the dynamic rewiring of apoptotic pathways, which sensitizes cells within a specific period to subsequent exposure to the DNA-damaging agent doxorubicin. A critical challenge for translating this therapeutic network rewiring into clinical practice is the design of optimal drug delivery systems. We report the generation of a nanoparticle delivery vehicle that contained more than one therapeutic agent and produced a controlled sequence of drug release. Liposomes, representing the first clinically approved nanomedicine systems, are well-characterized, simple, and versatile platforms for the manufacture of functional and tunable drug carriers. Using the hydrophobic and hydrophilic compartments of liposomes, we effectively incorporated both hydrophobic (erlotinib) and hydrophilic (doxorubicin) small molecules, through which we achieved the desired time sequence of drug release. We also coated the liposomes with folate to facilitate targeting to cancer cells. When compared to the time-staggered application of individual drugs, staggered release from tumor-targeted single liposomal particles enhanced dynamic rewiring of apoptotic signaling pathways, resulting in improved tumor cell killing in culture and tumor shrinkage in animal models.National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. P30-CA14051)National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. U54-CA151884)National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. U54-CA112967)National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. R01-ES015339)National Institutes of Health (U.S.) (NIH and Center for Cancer Nanotechnology Excellence, grant no. R21-ES020466)Breast Cancer Alliance (Exceptional Project Grant)National Science Foundation (U.S.) (Graduate Research Fellowship)National Health and Medical Research Council (Australia) (CJ Martin Fellowship)National Institutes of Health (U.S.) (Kirschstein NRSA 1F32EB017614-01)Natural Sciences and Engineering Research Council of Canada (post-doctoral fellowship)Kathy and Curt Marble Cancer Research FundDavid H. Koch Institute for Integrative Cancer Research at MIT (Koch Institute Frontier Research Program

Tumor-Targeted Synergistic Blockade of MAPK and PI3K from a Layer-by-Layer Nanoparticle

Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: Tumor-targeting nanoscale drug formulations could provide a more safe and effective means to synergistically block MAPK and PI3K in the clinic.United States. Department of Defense (OCRP Teal Innovator Award)National Institutes of Health (U.S.) (Grant NIBIB 1F32EB017614-02)Misrock FoundationNational Science Foundation (U.S.)Swiss National Science FoundationDavid H. Koch Institute for Integrative Cancer Research at MIT (Support Grant P30-CA14051)National Cancer Institute (U.S.)National Science Foundation (U.S.) (Massachusetts Institute of Technology. Materials Research Science and Engineering Center. Shared Experimental Facilities Grant DMR-0819762)Breast Cancer Alliance (Exceptional Project Grant

Structural Color and Iridescence in Transparent Sheared Cellulosic Films

Shear transparent cellulose free-standing thin films can develop iridescence similar to that found in petals of the tulip Queen of the Night. The iridescence of the film arises from the modulation of the surface into bands periodically spread perpendicular to the shear direction. Small amounts of nanocrystalline cellulose (NCC) rods in the precursor liquid-crystalline solutions do not disturb the optical properties of the solutions but enhance the mechanical characteristics of the films and affects their iridescence. Smaller bands periodicity, not affected by the NCC rods, slightly deviated from the shear direction is also observed. NCCs are crucial to tune and understand the film's surface features formation. Our findings could lead to new materials for application in soft reflective screens and devices

RNA-Peptide nanoplexes drug DNA damage pathways in high-grade serous ovarian tumors

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.National Institutes of Health (U.S.) (Grant R01-ES015339)National Institute of Biomedical Imaging and Bioengineering (U.S.) (Grant 1F32EB017614)National Science Foundation (U.S.) (Grant GFRP 1122374)National Cancer Institute (U.S.) (Grant P30-CA14051)National Science Foundation (U.S.) (Grant DMR-0819762

Cholesteric Liquid Crystal Shells as Enabling Material for Information-Rich Design and Architecture.

The responsive and dynamic character of liquid crystals (LCs), arising from their ability to self-organize into long-range ordered structures while maintaining fluidity, has given them a role as key enabling materials in the information technology that surrounds us today. Ongoing research hints at future LC-based technologies of entirely different types, for instance by taking advantage of the peculiar behavior of cholesteric liquid crystals (CLCs) subject to curvature. Spherical shells of CLC reflect light omnidirectionally with specific polarization and wavelength, tunable from the UV to the infrared (IR) range, with complex patterns arising when many of them are brought together. Here, these properties are analyzed and explained, and future application opportunities from an inter- disciplinary standpoint are discussed. By incorporating arrangements of CLC shells in smart facades or vehicle coatings, or in objects of high value subject to counterfeiting, game-changing future uses might arise in fields spanning infor- mation security, design, and architecture. The focus here is on the challenges of a digitized and information-rich future society where humans increasingly rely on technology and share their space with autonomous vehicles, drones, and robots

An Interesting Class of Porous Polymer-Revisiting the Structure of Mesoporous α-d-Polysaccharide Gels

The processes involved in the transformation of non-porous, native polysaccharides to their highly porous equivalents introduce significant molecular complexity and are not yet fully understood. In this paper, we propose that distinct changes in polysaccharide local short-range ordering promotes and directs the formation of meso- and micro-pores, which are investigated here using N2 sorption, FTIR, and solid-state 13CNMR. It is found that an increase in the overall double helical amylose content, and their local association structures, are responsible for formation of the porous polysaccharide gel phase. An exciting consequence of this local ordering change is elegantly revealed using a 19FNMR experiment, which identifies the stereochemistry-dependent diffusion of a fluorinated chiral probe molecule (1-phenyl-2,2,2-trifluoroethanol) from the meso- to the micro-pore region. This finding opens opportunities in the area of polysaccharide-based chiral stationary phases and asymmetric catalyst preparation