Smart Nanoparticles for Biomedicine

Gianni Ciofani

• Publisher: Elsevier
• Year: 2018
• Print ISBN: 9780128141564
• eBook ISBN: 9780128141571
• Topic: Tecnologia e ingegneria
• Subtopic: Scienza dei materiali

Smart Nanoparticles for Biomedicine explores smart nanoparticles that change their structural or functional properties in response to specific external stimuli (electric or magnetic fields, electromagnetic radiation, ultrasound, etc.). Particular attention is given to multifunctional nanostructured materials that are pharmacologically active and that can be actuated by virtue of their magnetic, dielectric, optically-active, redox-active, or piezoelectric properties. This important reference resource will be of great value to readers who want to learn more on how smart nanoparticles can be used to create more effective treatment solutions.Nanotechnology has enabled unprecedented control of the interactions between materials and biological entities, from the microscale, to the molecular level. Nanosurfaces and nanostructures have been used to mimic or interact with biological microenvironments, to support specific biological functions, such as cell adhesion, mobility and differentiation, and in tissue healing. Recently, a new paradigm has been proposed for nanomedicine to exploit the intrinsic properties of nanomaterials as active devices rather than as passive structural units or carriers for medications.- Discusses the synthesis, characterization and applications of a new generation of smart nanoparticles for nanomedicine applications- Explores the problems relating to the biocompatibility of a range of nanoparticles, outlining potential solutions- Describes techniques for manipulating specific classes of nanoparticles for a variety of treatment types

1

Introduction: Smart Materials in Biomedicine

Elisa Mele Loughborough University, Materials Department, Loughborough, United Kingdom

Abstract

This chapter introduces diverse classes of smart nanomaterials that elicit a therapeutic action in response to chemical and physical cues. Extracellular and intracellular microenvironments as well as healthy and diseased tissues exhibit differences in temperature, pH, redox potentials, proteins, and enzymes concentrations. Those naturally occurring conditions have been exploited as endogenous stimuli for designing and synthesizing responsive nanomaterials that are able to release drugs with spatiotemporal control. Moreover, nanocarriers sensitive to exogenous stimuli, such as electromagnetic fields, light, and ultrasounds, have been proposed as theranostic tools for their ability of simultaneously detecting and treating diseases. Nanomaterials sensitive to a single stimulus or multiple combinations of them have demonstrated their efficacy not only for cancer therapy, but also for the treatment of inflammations and infections.

Keywords

Drug delivery; Endogenous stimuli; Exogenous stimuli; Hyperthermia; Stimuli-responsive nanomaterials

1.1. Historical Evolution of Smart Nanomaterials

Over the last decade, advances in material science and nanotechnology have led to the development of highly engineered materials that are able to cleverly modify and adapt their physicochemical properties in response to external stimuli. They are often referred to as “smart materials” [1].

For biomedical applications, smart materials with bespoke functionalities and responsiveness have been manufactured into a multitude of nanostructures, including nanoparticles (NPs), nanorods, nanogels, and micelles (Fig. 1.1A) [2–4]. They have been designed to respond to a wide variety of physical and chemical stimuli such as temperature, light, electromagnetic fields, mechanical stresses, pH, enzymatic activity, sugar concentration, and oxidative reactions (Fig. 1.1B) [2]. Those diverse classes of smart nanomaterials are the result of an evolutionary process, which has been initiated and strongly driven by studies on how biological systems interact with nanostructures [5]. Structures with sub-100 nm size are indeed prone to penetrate across in vivo barriers and to be internalized by cells.

Fig. 1.1 Schematic of (A) the diverse classes of stimuli-responsive nanomaterials and of (B) the variety of triggering mechanisms. Reproduced with permission from Ref. [2]; copyright (2017) Elsevier.

Initially, biocompatibility and cell uptake tests were conducted on water-stable quantum dots, gold, and iron oxide NPs, in order to verify their potential for biomedicine [5]. However, in vivo tests revealed a rapid renal clearance of this first generation of NPs due to the lack of suitable surface functionalization. Surface chemical treatments were then implemented in order to prolong blood circulation half-life and to achieve targeted delivery. The second generation of NPs relied mostly on poly(ethylene glycol) (PEG) and other ligands for anchoring themselves to cellular receptors. They passively accumulated inside target organs and tissues due to the enhanced permeation and retention effect [1]. Limitations associated with this passive and transient retention, and with the inability of the functionalized NPs to progress beyond the first few layers of cells in a tissue, moved the research toward stimuli-responsive nanomaterials.

Smart nanomaterials have received great attention in recent years because they are able to overcome passive retention mechanisms and nonspecific cellular uptake. In fact, they exploit the physiological conditions of the target site or artificial environmental cues to trigger therapeutic actions. They have been widely used in diverse biomedical fields, including drug, gene, and protein delivery, tissue engineering, biological imaging, and sensing.

As case of study, this introductive chapter discusses one of the most promising biomedical applications of stimuli-responsive nanomaterials, which is the triggered release of drugs, proteins, and genes [6,7]. Smart nanocarriers offer the advantage of site-specific release of therapeutic agents, and they also provide temporal and dosage control. Chemical composition, size, and shape of the nanocarriers, as well as preparation procedures and interactions with bioactive compounds, can be precisely modified in order to tailor cargo capacity, entrapment efficiency, and release profile [8]. Thanks to those properties, stimuli-responsive nanocarriers are nowadays regarded as potential candidates for the fabrication of high-efficient drug delivery systems (DDSs) that can respond to endogenous or exogenous stimuli or to multiple combinations of those. Here, an overview of the recent progress in the design and synthesis of nanocarriers of therapeutic molecules that respond to endogenous and exogenous stimuli will be provided.

1.2. Endogenous Stimuli

Differently from healthy tissues, diseased tissues (tumor, inflamed and infected tissues, etc.) present changes in angiogenesis and in the structure of proteins and enzymes, abnormalities in pH conditions (acidic environment) and metabolic states, increased temperature, enhanced production of reactive oxygen species (ROS), and hypoxic response (inadequate oxygen supply) [1,6]. Those naturally occurring conditions, in particular gradients of pH and temperature and redox processes, have been exploited as endogenous stimuli for triggering the release of drugs from nanocarriers.

1.2.1. pH Gradients

pH-sensitive nanocarriers, which are stable at physiological pH (7.4) but undergo modifications when exposed to pH imbalances, utilize acidic microenvironments within the human body to enable drug release and to enhance the bioavailability of therapeutic payloads, as shown in Fig. 1.2 [7,9]. The triggering mechanism can be based on protonation/deprotonation of functional groups or on the cleavage of acid bonds [10].

Fig. 1.2 Schematic representation of pH variation in the body at organ, tissue, and cellular level and representative classes of pH-responsive DDSs. Reproduced with permission from Ref. [9]; copyright (2017) Elsevier.

Nanocarriers that respond to pH gradients along the gastrointestinal (GI) tract, from pH 1–3 in the stomach to pH 6–8 in the intestine [11], have been reported for oral drug delivery applications [12]. For example, pH-sensitive and biodegradable NPs of methoxy PEG-block-(poly(caprolactone)-graft-poly(methacrylic acid)) (mPEG-b-(PCL-g-PMAA)) have been synthesized for the release of hydrophobic drugs such as ibuprofen (IBU, an antiinflammatory drug) [13]. The block copolymer was designed to contain PMAA blocks, whose carboxylic groups accept protons at low pH and loose protons at neutral and high pH. In the stomach (low pH), PMAA chains form a protective layer around the core of NPs (containing the drug), limiting the release of ibuprofen (Fig. 1.3A). Once the NPs reach the intestine (neutral pH), the PMAA chains stretch and the drug is released. The release profile of IBU from mPEG-b-(PCL-g-PMAA) NPs was studied in vitro at 37°C for pH 3.0 and pH 7.4 (Fig. 1.3B). It was observed that about 55% of IBU was released at pH 3.0 and about 85% at pH 7.4, within 12 h. Importantly, the pH sensitivity of the NPs was tailored by modifying the MAA ratio in the block copolymer. When the number of MAA monomers increased, IBU release of 40% and 95% were achieved at pH 3.0 and 7.4, respectively, within 12 h. The ability of PMAA to respond to pH changes has also been exploited to control the oral release of other drugs [15,16], such as insulin for the treatment of diabetes [17], doxorubicin (DOX) for chemotherapy [18,19], and antibiotics such as metronidazole [20] and amoxicillin [21].

Fig. 1.3 (A) Scheme of the formation of mPEG-b-(PCL-g-PMAA) NPs in water and of the release of ibuprofen at pH 3.0 and 7.4; (B) in vitro release profile of ibuprofen from mPEG₁₁₃-b-(PCL_92.5-g-PMAA₈₁) (black symbols) and mPEG₁₁₃-b-(PCL₉₁-g-PMAA₁₅₅) (red symbols) NPs at 37°C, at pH 3.0 (square symbols), and 7.4 (triangular symbols). (C) Schematic representation of the pH-triggered release of DOX from Au-P(LA-DOX)-b-PEG-OH/FA NPs, and (D) release profile of DOX at 37°C, at pH 5.3 (circles), 6.6 (triangles), and 7.4 (squares). (A, B) Reproduced with permission from Ref. [13]; copyright (2013) The Royal Society of Chemistry. (C, D) Reproduced with permission from Ref. [14]; copyright (2009) Elsevier.

Together with PMAA, pH-responsive materials for oral drug delivery include Eudragit® (poly(methacrylic acid-co-methyl acrylate)), modified chitosan, and porous silica [12]. This class of smart NPs helps to protect the active therapeutic compounds from low-pH environments in the GI tract and to achieve organ-spec...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Foreword
• 1: Introduction: Smart Materials in Biomedicine
• 2: Smart Polymeric Nanoparticles
• 3: Smart Liposomes for Drug Delivery
• 4: Pharmacologically Active Plant-Derived Natural Products
• 5: Nanostructured Cyanoacrylates: Biomedical Applications
• 6: Applications of Carbon Nanotubes in the Biomedical Field
• 7: Carbon Nanomaterials for Nanomedicine
• 8: Silica Nanoparticle Applications in the Biomedical Field
• 9: Magnetic Nanoparticles and Their Bioapplications
• 10: TiO2 Nanotube Arrays as Smart Platforms for Biomedical Applications
• 11: Antioxidant Inorganic Nanoparticles and Their Potential Applications in Biomedicine
• 12: Zinc Oxide Nanostructures in Biomedicine
• 13: Smart Inorganic Nanoparticles for Wireless Cell Stimulation
• 14: Nanosized Optical Thermometers
• 15: Advanced Optical Microscopy Techniques for the Investigation of Cell-Nanoparticle Interactions
• Index