Nanomaterials for Theranostics and Tissue Engineering

Techniques, Trends and Applications

Filippo Rossi, Alberto Rainer

• Publisher: Elsevier
• Year: 2020
• Print ISBN: 9780128178386
• eBook ISBN: 9780128178393
• Topic: Technology & Engineering
• Subtopic: Materials Science
• Index: Technology & Engineering

Nanomaterials for Theranostics and Tissue Engineering: Techniques, Trends and Applications provides information on the major methodologies for the application of nanomaterials in the medical field. In recent years, nanotechnology for medicine, commonly known as bionanotechnology, or nanomedicine, has revolutionized various types of medical treatment. This book is intended for practicing engineers and scientists, and includes detailed, readily applicable protocols. It focuses on 4 major themes, including the synthesis of nanosystems for controlled drug delivery, nanotechnology-enhanced sensing systems, the application of nanotechnologies to the synthesis of novel biomaterials, and safety issues related to the application of medicinal nanotechnology.- Provides a comprehensive overview on how nanotechnology is being used to create new tissue engineering techniques- Covers, in detail, the physicochemical fundamentals of bionanotechnologies- Explores major applications in the fields of theranostics and tissue engineering- Assesses important challenges and safety issues related to the implementation of nanotechnology in medicine

1

Polymeric nanoparticles for controlled drug delivery

Mattia Sponchioni, Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”, Politecnico di Milano, Milano, Italy

Abstract

While liposomes are the main representatives of the first generation of nanotherapeutics, that is to say nanosized vectors for the encapsulation and controlled release of therapeutics, polymer NPs are rapidly coming to the fore. This is mainly due to the possibility of finely controlling their physical and chemical properties, taking advantage of the advent of controlled polymerization techniques. Another important factor that justifies this growing interest is the development of stimuli-responsive polymers, which can be exploited for precise drug targeting by exploiting environmental signals. Therefore the necessity of smart drug delivery systems for a second generation of nanotherapeutics, and in particular for the delivery of nucleic acids, proteins, or other biotherapeutics, could be covered by these stimuli-responsive NPs in the near future. However, the long road toward the final clinical application should be carefully considered during the design of a novel nanoformulation. Here, the frontiers in the synthesis of smart polymer NPs to direct a drug to the desired site of action are presented in the context of their implication in biological systems. Finally, the stages for a nanotherapeutic before gaining the approval for clinical applications are discussed in order to understand the current regulatory framework for these systems.

Keywords

Polymer; nanoparticles; drug delivery; targeting; stimuli-responsive; regulation; clinical trials

1.1 General concepts and synthetic strategies

The idea of controlled drug delivery arises from the dream of selectively addressing a bioactive compound to a specific target area in the body, in order to maximize its therapeutic effect while minimizing side effects. In recent years, nanometer-sized drug delivery systems, and specifically nanoparticles (NPs) able to load and mediate the release of therapeutically active compounds, have experienced growing attention due to the several advantages they offer compared to traditional ways of drug administration [1,2]. In particular, NPs can ideally take advantage of all of the possible administration routes, including oral, mucosal, transdermal, subcutaneous, and intravenous. The limitation is represented by the biological barriers that the NPs have to cross before reaching the target, which determines the efficacy of the formulation [3,4]. Following this consideration, the optimal administration route would be the oral one, being the less invasive. However, this is often characterized by poor adsorption by the gastrointestinal mucosa and by a harsh environment for the NPs, especially in terms of pH. This is why parenteral administrations, including subcutaneous, intravenous, and transdermal, are so far the most explored and characterized by the highest drug bioavailability [5]. Following this administration route, drug delivery through NPs ensures the maintenance of the drug concentration in a desired therapeutic window over a prolonged period of time, thus ideally reducing the amount of drug and the number of administrations required [6]. In addition, it reduces the side effects associated with the traditional formulations based on organic solvents and surfactants, with an overall increase in the patient compliance [7].

Different kinds of NPs have been designed over the years as drug delivery systems. In general, a distinction between inorganic and organic NPs is important. Among the former, iron oxide [8,9] and silica [10,11] NPs represent the golden standard. However, organic NPs and in particular polymeric NPs play a key role. The latter offer several advantages including the possibility of tuning their physicochemical properties as well as of introducing specific functionalization, which makes them suitable for loading and controlling the release of different active principles. The NP efficacy in the controlled drug delivery is indeed strongly affected by their properties, and in particular by the size. Nanovectors aimed at systemic administration, for example, should be in the range 30–300 nm in size. Indeed, NPs smaller than 10 nm are below the renal threshold for direct excretion, and hence would be eliminated soon after the injection. This brings about a reduced circulation time and hence a limited possibility of reaching the target site of action [12–14]. On the other hand, NPs bigger than 300 nm introduce the severe risk of thrombosis, since the smallest capillaries in the body have a diameter in the order of few hundreds of nanometers. In addition, such nanovectors are more likely amenable for opsonization operated by the macrophages of the reticuloendothelial system or by hepatic Kupffer cells, leading again to reduced circulation time [15,16]. The NP circulation time in the bloodstream is also strongly affected by their surface composition. It is known that nanovectors in a biological environment undergo the so-called protein corona effect soon after their infusion, being covered by a layer of adsorbed proteins that facilitates their recognition by the macrophages [17,18]. Today, the most commonly adopted strategy to avoid this recognition is the surface modification with polyethylene glycol (PEG), an uncharged and hydrophilic polymer. In fact, PEG creates a hydration layer over the NP surface that hides them from macrophage recognition. This strategy, commonly referred to as PEGylation, is therefore largely employed not only in the realization of “stealth” nanovectors, but also to increase the water stability of lipophilic compounds, proteins and antibodies, thus improving their efficacy [19,20]. However, several drawbacks have only recently been discovered when using PEG in the stabilization of polymer NPs. In particular, the immune system increases the production of antibodies able to specifically bind to PEG after repeated treatments with PEGylated compounds. This process gives rise to the so-called accelerated blood clearance of such functionalized therapeutics [19,21–23]. In addition, recent clinical trials have highlighted allergic reactions and/or hypersensitivity to PEG for a significant number of patients [24–26], thus pushing the research to an extensive effort to find valuable substitutes to PEG [27–30]. So far, zwitterionic polymers represent the most promising alternative to PEG in the stabilization of polymer NPs in water [31–33]. Indeed, the strong electrostatic interactions among the charged groups in these polymers determine the formation of a hydration layer, over the NP surface, able to prevent the nonspecific adsorption of biological macromolecules [34–36]. This determines not only high stability in the biological environment but also the nonspecific elimination of the vector.

It is evident from these considerations that the proper design of the polymer NPs represents a crucial point in determining the circulation time, target selectivity, and drug delivery efficacy [37,38]. The synthesis of these nanocolloids is usually obtained through either physical methods from preformed polymers or chemical methods. Among the physical methods, it is worth citing the emulsion-evaporation process and the nanoprecipitation. The former relies on the polymer dissolution in a water-immiscible organic solvent (e.g., chloroform, ethyl acetate, toluene), followed by the emulsification of this organic phase in water with surfactants. Finally, the NP latex is obtained following the evaporation of the organic solvent. On the other hand, in the nanoprecipitation method, the polymer is dissolved in a water-miscible organic solvent (e.g., ethanol, dimethylformamide, and dimethylsulfoxide). The organic phase is added to a water suspension of surfactant micelles under turbulent mixing conditions. Finally, the organic solvent is removed through dialysis. It is evident that both processes rely on the use of organic solvents as well as of surfactants, which may be harmful when injected into the body. In addition, the physical processes suffer the limitation of a poor solid content in the final NP suspension and the use of complex mixing devices to achieve proper turbulent conditions. Despite these drawbacks, the physical methods are necessary in few occasions. This is the case, for example, for the synthesis of biodegradable NPs. Biodegradable NPs, mainly obtained from aliphatic polyesters, are of paramount importance for drug delivery. In fact, the polyester chains they are made up of can undergo hydrolytic degradation in aqueous environments, thus ensuring the avoidance of any polymer accumulation in the body [39]. Industrially, high-molecular-weight polyesters are produced via the ring opening polymerization (ROP) of cyclic monomers (e.g., lactide, glycolide, ε-caprolactone) and are obtained as bulk materials. Therefore a common strategy to formulate the bulky material in NPs is based on either the emulsion-evaporation or the nanoprecipitation process.

To obtain polymer NPs with a size range suitable for systemic administration, it is also possible to resort to the chemical methods, and in particular to emulsion polymerization. This is actually a well-established technique to obtain PEGylated NPs. In fact, PEG-methacrylate derivatives (i.e., PEGMA) can be used as reactive surfactants, also known as surfmers [40,41], in the emulsion polymerization of lipophilic monomers. In this way, the particle surface is covered with PEG tethers that are functional in increasing its circulation time into the bloodstream. In addition, the surfmer is chemically bound to the NP core, and hence its desorption, which may cause latex aggregation, is prevented. A step forward to obtain biodegradable NPs via chemical methods is the combination of ROP and radical chemistry in the so-called “macromonomer method”. In particular, short oligoester macromonomers can be obtained via ROP initiated by a vinyl group bearing alcohol (e.g., 2-hydroxyethyl methacrylate, HEMA), as shown in Fig. 1.1A. The produced macromonomer can be further reacted via free radical emulsion polymerization to obtain NPs that are structurally composed of polymer chains with a peculiar comb-like structure, comprising a polyHEMA backbone and biodegradable oligoester lateral chains [42,43]. This architect...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of contributors
• Introduction
• 1. Polymeric nanoparticles for controlled drug delivery
• 2. Extracellular vesicles in regenerative medicine
• 3. Novel strategies to improve delivery performances
• 4. HR-MAS NMR Spectroscopy: novel technologies to measure delivery performance
• 5. The role of first principles mathematical modeling in the nanomedicine field
• 6. Nanostrucured substrates for surface-enhanced Raman scattering spectroscopy
• 7. Electro- and nonelectro-assisted spinning technologies for in vitro and in vivo models
• 8. Nanocarbon for drug delivery
• 9. Bioactive nanoceramics
• 10. Guidelines as a starting point to address the needs of small and medium enterprises regarding the Safe-by-Design of polymeric nanobiomaterials for drug delivery
• 11. Regulatory perspectives on medical nanotechnologies
• Conclusion
• Index