Polymer nanoparticles (PNPs) that exhibit selective stimuli-responsive degradation and drug release at tumor sites are promising candidates in the development of smart nanomedicines. In this thesis, we demonstrate a microfluidic approach to manufacturing biological stimuli-responsive PNPs with flow-tunable physicochemical and pharmacological properties. The investigated PNPs contain cleavable disulfide linkages in two different locations (core and interface, DualM PNPs) exhibiting responsivity to elevated levels of glutathione (GSH), such as those found within cancerous cells. First, we conduct a mechanistic study on the microfluidic formation of DualM PNPs without encapsulated drug. We show that physicochemical properties, including size, morphology, and internal structure, of DualM PNPs are tunable with manufacturing flow rate. Microfluidic formation of DualM PNPs is explained by the interplay of shear-induced coalescence, shear-induced breakup, and intraparticle chain rearrangements. In addition, we demonstrate that rates of GSH-triggered changes in size and internal structure are linearly correlated with initial PNP sizes and internal structures, respectively. Next, we expand our study to focus on microfluidic control of pharmacological properties of DualM PNPs containing either an anticancer drug (paclitaxel, PAX-PNPs) or a fluorescent drug surrogate (DiI-PNPs). Microfluidic PAX-PNPs and DiI-PNPs show similar sizes and morphologies with their non-drug-loaded counterparts under the same flow conditions. We then show that pharmacological properties of DualM PNPs, including encapsulation efficiency, GSH-triggered release rate, cell uptake, cytotoxicity against MCF-7 (cancerous) and HaCaT (healthy), and relative difference in MCF-7 and HaCaT cytotoxicity, all increase linearly as flow-directed PNP size decreases, providing remarkably simple process-structure-property relationships. In addition, we show that microfluidic manufacturing improves encapsulation homogeneities within PNPs relative to bulk nanoprecipitation. These results highlight the potential of flow-directed shear processing in microfluidics for providing controlled manufacturing routes to biological stimuli-responsive nanomedicines optimized for specific therapeutic applications. Finally, we summarize various design strategies of biological stimuli-responsive PNPs. We show that the location and density of disulfide linkages within PNPs determines stimulus-triggered degradation mechanism and kinetics. In addition, we show various bottom-up approaches to tune PNP responsivities that involves chemical processing, including formulation chemistry and intramolecular forces. Along with the top-down microfluidic approach that we demonstrate experimentally, this chapter provides a more comprehensive understanding of process-structure-property relations opening up vast possibilities for manufacturing smarter nanomedicines.

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications, Volume One: Types and Triggers discusses, in detail, the recent trends in designing biodegradable and biocompatible single-responsive polymers and nanoparticles for safe drug delivery. Focusing on the most advanced materials and technologies, evaluation methods, and advanced synthesis techniques stimuli-responsive polymers, the book is an essential reference for scientists with an interest in drug delivery vehicles. Sections focus on innovation, development and the increased global demand for biodegradable and biocompatible responsive polymers and nanoparticles for safe drug delivery. - Offers an in-depth look at the basic and fundamental aspects of alternative stimuli-responsive polymers, mechanisms, structure, synthesis and properties - Provides a well-defined categorization for stimuli-responsive polymers for drug delivery based on different triggering mechanisms - Discusses novel approaches and challenges for scaling up and commercialization of stimuli-responsive polymers

Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications: Volume Two: Advanced Nanocarriers for Therapeutics discusses, in detail, the recent trends in designing dual and multi-responsive polymers and nanoparticles for safe drug delivery. Chapters cover dual-responsive polymeric nanocarriers for drug delivery and their different stimuli, multi-responsive polymeric nanocarriers, and the therapeutic applications of stimuli-responsive polymers. With an emphasis on advanced medical applications and synergistic operational and technological methodologies for the improvement of polymers systems for the production of stimuli-responsive polymers, this book is essential reading for materials scientists and researchers working in the drug delivery and pharmaceutical industries. As innovation and development in the area of stimuli responsive polymer-based nanomaterials for drug delivery is moving fast and there is an increased global demand for biodegradable and biocompatible responsive polymers and nanoparticles for safe drug delivery, users will find this to be a timely resource. - Focusses on the most advanced technologies, recent evaluation methods, technical aspects, and advanced synthesis techniques stimuli-responsive polymers - Examines advanced medical applications of stimuli responsive polymers - Analyzes synergistic operational and technological methodologies for the improvement of polymer systems for the production of stimuli-responsive polymers in drug delivery

This thesis covers the general scope of stimuli-responsive polymers and the concept of controlled drug delivery, with special focus on controlled/triggered release applications of temperature-responsive poly (N-isopropylacrylamide) (pNIPAm)-based hydrogels, microgels, their assemblies, and composites. Chapter 2 focuses on investigating the methodology and mechanism of a controlled release system, i.e., a pNIPAm-based microgel-based assembly. Surface modification was utilized to build a chemical barrier to control the molecular interchange between the inside and the outside of the device. The small-molecule diffusion behaviors of the device were studied, and mathematical models were used to describe the behaviors. Chapter 3 focuses on the development of a small-molecule controlled release system, based on the stimuli-responsive hydrogel-microgel composite (HMC). In this work, the small hydrophilic molecule release kinetics were tuned by changing the chemical composition of the material, and the mechanism of the controlled release was investigated based on the interactions between the small molecules and the polymer materials. As a further study of the HMC in controlled drug delivery applications, Chapter 4 discusses the idea of applying the HMC to a multi-drug controlled release system. In addition, four appendices, A, B, C, and D have been added to the end of this dissertation. They contain supporting information for the main chapters, previous related work done before my PhD program, and preliminary experimental results on related research projects.

This volume serves as a valuable handbook for the development of nanomedicines made of polymer nanoparticles because it provides researchers, students, and entrepreneurs with all the material necessary to begin their own projects in this field. Readers will find protocols to prepare polymer nanoparticles using different methods, since these are based on the variety of experiences that experts encounter in the field. In addition, complex topics such as, the optimal characterization of polymer nanoparticles is discussed, as well as practical guidelines on how to formulate polymer nanoparticles into nanomedicines, and how to modify the properties of nanoparticles to give them the different functionalities required to become an efficient nanomedicine for different clinical applications. The book also discusses the translation of technology from research to practice, considering aspects related to industrialization of preparation and aspects of regulatory and clinical development.

Stimuli-responsive polymeric nanoparticles have recently gained tremendous attention, in particular in the field of controlled drug delivery as a result of offering prolonged circulation times and on demand delivery. The tailor-made design of stimuli-responsive nanoparticles mostly relies on the incorporation of desired stimuli-responsive motifs into the polymers. However, the challenge is to synthesize the corresponding polymers in a well-defined and reproducible way. In the context of the synthesis of stimuli-responsive polymers, the reversible addition fragmentation chain transfer (RAFT) polymerization process is advantageous compared to other techniques due to its high tolerance to various functional groups and polymerization conditions. After the synthesis of the stimuli responsive polymers, it is also crucial to formulate the resulting stimuli-responsive nanoparticles in a controlled way. Nanoprecipitation represents a facile and reliable way to produce polymeric nanoparticles. As a result, the RAFT polymerization process and the nanoprecipitation technique were selected as the methods of choice within this thesis for the synthesis of (multi)functional polymers and the formation of the corresponding nanoparticles. The presented thesis represents an overview of (i) the synthesis of various new stimuli-responsive polymers with tailor-made functionalities and polymer structures, (ii) the formulation of stimuli-responsive nanoparticles via nanoprecipitation, (iii) the investigation of stimuli-responsive behavior of the nanoparticles, as well as (iv) the evaluation of synthesized nanoparticles for drug delivery applications.

Smart drug delivery at both the micro- and nanoscale is an evolving field with numerous potential applications. It has the potential to revolutionize drug therapy by making treatments more effective, reducing side effects, and improving patient outcomes. This book presents a comprehensive review of the most recent studies on smart micro- and nanomaterials with a focus on their “smart” activity for formation of targeted and responsive drug-delivery carriers. This volume: Introduces readers to the fundamentals of these the micro- and nanoscale materials as well as approaches to smart drug delivery and drug delivery systems. Covers polymers, metals, and composite materials as well as quantum dots and carbon nanotubes. Describes of all possible stimulated systems for drug delivery such as enzyme-responsive, small molecules-responsive, thermo-responsive, pH-responsive, electric field-responsive, magnetic field-responsive, light-responsive, ultrasound-responsive, and reductive environment responsive. Offers a critical perspective on the future scope of smart drug delivery systems. This reference work is written to support researchers in the fields of materials engineering and biotechnology with the goal of improving the diagnosis and treatment of disease and patient quality of life.