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Polymeric Systems for Active Targeted Therapeutics Delivery
(2024-05) Kanjilal, Pintu
The nanomedicine field has advanced significantly and current progress in nanotechnologies has enabled translational research across therapeutic landscape. Recent trends in clinical studies and FDA approvals have demonstrated the potential of using biologics as therapeutic modalities. Ongoing fundamental research across therapeutic modalities have set foundations to treat multiple diseases, including the ones that were hard-to-cure and assures the promising future of nanomedicine. However, the therapeutic expansion from small molecule drug to biologics comes with their unique delivery challenges. It requires strategic designing of delivery platforms to overcome biological barriers associated with each modality and demands fundamental understanding of formulation factors to predetermine the fate of delivered therapeutics. Each formulation requires stability in blood circulation, ability to reach specific organs or tissue types, have enough tissue penetrations and importantly, and have cytosolic accessibility. These different aspects of delivery challenges can be addressed by tuning formulation properties, and understanding these structural and formulation factors are essential in improving therapeutic efficacy. In this dissertation, we have developed polymeric systems focusing on two different aspects of drug delivery viz, targeted tissue accumulation and cellular internalization. An antibody guided polymeric system is established to address the challenges with current antibody drug conjugates (chapter 2). Then we understood the effect of antibody polymer conjugation process towards cell receptor binding activity by varying polymer molecular weights and number of polymers per antibody (chapter 3). We also designed disulfide-based polymeric nanogel to fundamentally understand the effect of disulfide bonds in endosomal escape (chapter 4). Finally, we designed stimuli-responsive self-immolative protein-PEGylation strategy with terminal disulfide functionality to leverage thiol-mediated internalization of biologics.
Plasticity and Adhesion of Nano-Structured Polymeric Materials in High-Strain-Rate Additive Manufacturing
(2024-05) Kim, Ara
In many applications, such as aerospace and additive manufacturing, polymeric materials with nanoscale structures can be subjected to extensive plastic deformations and present nonlinear dynamic responses under high-strain-rate adiabatic conditions due to nanostructure changes and temperature-dependent material properties. Their rate-dependent characteristics are determined not just by volumetric plastic deformation but also by the resultant thermal effects in the excessively deformed region. Hence, the dynamic nonlinearity of model polymeric systems, microparticles of multiphase block copolymers, is systemically investigated using the Laser-Induced Projectile Impact Tests with perpendicular (α-LIPIT) and non-perpendicular (θ-LIPIT) incidence angles in this study. The polystyrene-block-polydimethylsiloxane (PS-b-PDMS) copolymers are the model materials consisting of mechanically distinctive nanoscale domains of PS (glassy-phase) and PDMS (rubbery-phase), and the visco-plasticity during impact is quantified through mechanical and rheological analysis. The α-LIPIT produces precisely controlled high-strain-rate collision conditions, and the kinetic parameters are used to analyze the mechanical behaviors of the block copolymer microparticles in the forms of the coefficient of restitution and adhesion windows. Furthermore, the newly introduced θ-LIPIT results with a non-perpendicular incidence angle demonstrate the effect of tribological nonlinearity on adhesion mechanisms through the rheological analysis representing the collision-induced thermal condition changes such as thermal softening. The glassy domain controls the rheological transition, while the rubber domain enhances interfacial conditions and is favorable for adhesion. The microparticles’ post-impact shape changes are used to optimize material parameters for a computational model. The nanostructure changes are directly analyzed after cross-sectional milling with a focused ion beam to understand the stress flow and the effective thermal softening region during impact. This study offers a comprehensive understanding of nanostructured block copolymers’ plastic and adhesion mechanisms for use in high-strain-rate additive manufacturing, such as cold spray. The verified correlations between adhesion and compositional and tribological properties are expected to be used to investigate the applicability of feedstock materials and optimize the material parameters for cold spray.
DESIGN AND FABRICATION OF ANTIBODY-NANOGEL CONJUGATES FOR TARGETED DELIVERY OF THERAPEUTICS
(2024-05) Huynh, Uyen Gia Thuc
The utilization of antibody–drug conjugates (ADCs) represents a promising avenue for achieving precise drug delivery, thereby facilitating the targeted eradication of cancer cells while minimizing the adverse effects on healthy tissues. This approach seeks to ameliorate the side effects typically associated with conventional chemotherapy. Striking examples of ADCs include Kadcyla and Trodelvy, which have exhibited remarkable efficacy in the treatment of HER2-positive and triple-negative breast cancer (TNBC), respectively. Nonetheless, the complete realization of the clinical potential of ADCs faces substantial challenges. The prevailing ADC format exhibits a low drug-to-antibody ratio (DAR), necessitating the deployment of highly potent yet inherently toxic drugs, thereby increasing the risk of off-target toxicity. Additionally, stringent criteria regarding the stability and degradability of the antibody–drug linker introduce intricate design considerations and impose constraints on the selection of drugs compatible with ADC components. To address these challenges, we developed a versatile drug delivery platform known as antibody-nanogel conjugates (ANCs). This nanocarrier platform features (i) an easily functionalized surface for antibody decoration; (ii) simple preparation protocols; (iii) high drug loading capacity for a broad range of drugs thereby, significantly increases the DAR; (iv) low vehicle toxicity; and (v) triggerable on-demand release of cargo at targeted sites. The efficacy of our antibody-nanogel conjugate (ANC) systems was demonstrated through the fabrication of two ANCs containing identical cytotoxic payloads and targeting antibodies, analogous to Kadcyla and Trodelvy. in vitro assessments reveal a substantial increase in efficacy with the ANC system compared to the ADCs with several-folds improvement. Moreover, we have also presented a dual chemo-immunomodulator approach employing the ANC system. This strategy involves the conjugation of an anti-PD-L1 antibody to a nanogel encapsulating a chemotherapeutic agent. The aPDL1 antibody serves as an inhibitor for the PD-1/PD-L1 interaction, thereby activating the immune system's response against cancer cells. Concurrently, the chemotherapeutic drug exerts its effect by impeding cancer cell proliferation and promoting apoptosis in a synergistic fashion.
FEAST AGAINST FAMINE: THE NEGATIVE OFFERINGS OF SACRED ECOLOGY
(2024-05) Huling, Raymond E
Folklore is a way to save the world. Major sustainability problems—climate change,mass extinction, pollution, and more—are driving the global human system into crisis. The physical growth of this human system is the cause of these problems. By shunting the energies that feed this growth into spendthrift pursuits, among which folklore holds an important place, we can evade crisis in a fair way. This study brings this sustainability solution to bear on the folklore of food, for two reasons. First, because folklore is a squandering of energy that builds community. Second, because the Food System is the biggest driver of sustainability problems, the sector these problems threaten most, and the one system we cannot live without. I use the Planetary Boundaries framework to bring these dire sustainability crises on the horizon into sharper view. To justify folklore as a solution, I take up recent scholarship that applies the General Economy of Georges Bataille to sustainability, and I then re-work these ideas through Systems Thinking. I call this approach “Sacred Ecology”. Sacred Ecology seeks to avoid sustainability crises through squandering of wealth, thereby starving the system out of physical growth. Pouring our energies into food-based folklore, under the guidance of sacred ecological principles and within scientific frameworks, is a reasonable means of either dodging onrushing crises fueled by the growth of the global human system, or, if we fail at those sustainability tasks, of readying ourselves for the long, dark years of resilience it will take to ride these crises out.
NANOMATERIALS AT LIQUID INTERFACES: FROM STRUCTURE AND DYNAMICS TO MACROSCOPIC PROPERTIES
(2024-05) Fink, Zachary Marc
Liquid surfaces decorated with nanoparticles (NPs) afford a promising route to materials with unique and technologically important properties and an ideal platform from which to probe particle adsorption, rearrangement, and structure. Probing these two-dimensional (2D) assemblies can reveal the kinetics, dynamics, and ordering of assemblies that possess inherently interesting optical, chemical, or physical properties. This topic has received renewed interest from the condensed matter community, yet directly visualizing the assemblies in-situ and leveraging the unique properties of NPs at these interfaces remains challenging. The thesis work detailed herein connects 2D NP assembly fundamentals to striking plasmonic, photonic, electronic, and reconfiguration properties afforded by the inherent NP properties and the fluid nature of the interface. The real time NP structure and dynamics at an ionic liquid–vacuum interface were revealed by single particle tracking using scanning electron microscopy (SEM). Upon approach to jamming, the dynamics trends were strongly particle size dependent due to the increase in particle lubrication facilitated by the ligand brush layer. Unfortunately extending the in-situ SEM technique to liquid–liquid interfaces was not possible; instead, a suite of complementary techniques including: GISAXS, GIXPCS, UV-Vis reflection spectroscopy, and pendant drop tensiometry, were used to probe the assemblies. The phase separation of plasmonic and non-plasmonic NP mixtures was examined and showed that NP size disparity and non-plasmonic NP number fraction significantly influence the adsorption process and equilibrium packing of gold NPs. Electronic or photonic properties were incorporated into liquid–liquid interfaces by the careful selection of the polymer used. Phytic acid (PA) and sulfonated polyaniline (S-PANI) ink phases showed enhanced electrical performance due to the dense packing of PA/S-PANI complexes at the interface. 3D printed all-liquid circuits could self-repair on demand after the conductive pathway was mechanically broken. Block copolymers were used to generate well-ordered interfacial films, where all colors across the visible spectrum were obtained. Finally, future directions and the design of a liquid cell TEM are discussed. Understanding how collective NP characteristics direct interfacial self-assembly is a promising step in improving current nanotechnologies to confront challenges in renewable and green energy, energy storage, and materials transportation.

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