Stimuli-Responsive Nanomedicine

Lin Zhu

• Publisher: Jenny Stanford Publishing
• Year: 2021
• Print ISBN: 9789814800709
• eBook ISBN: 9781000733365
• Topic: Medicina
• Subtopic: Biotecnologia in medicina

The response to environmental and internal stimuli is one of the basic characteristics of living organisms. Inspired by this natural strategy and fast-developing nanotechnology and materials science, stimuli-responsive nanomedicine has emerged as an active and important field of nanomedicine.

This book offers a fundamental and comprehensive overview of stimuli-responsive nanomedicine and compiles and details the recent cutting-edge findings and most impressive achievements in biomedical applications, from a pharmaceutical science perspective, making it the first book of its kind in this field. By providing readers a broad and in-depth coverage of endogenous and exogenous stimuli as well as their applicable nanomedicines, this book is valuable for students, researchers, and educators in biomedical sciences or anyone interested in this burgeoning field.

Chapter 1
Overview of Stimuli-Responsive Nanomedicine

Qing Zhou,^* Qing Yao,^* Jiao Wang,^* and Lin Zhu

^*These authors contributed equally.

Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University Health Science Center, Kingsville, Texas 78363, USA

[email protected]

1.1 Introduction

Nanoscale systems have recently received tremendous attention, particularly in the field of biomedical research [1, 2]. Although drug molecules can be manipulated to improve their properties at drug discovery stage, the compatible drug delivery strategies have to be applied to facilitate the clinical applications and achieve the desirable therapeutic outcomes. In this regard, the drugs are formulated into various dosage forms or drug delivery systems. Among them, the nanoparticle-based medicine or nanomedicine is the most important one.

Therapeutic or imaging agents can be encapsulated into the inner layer or core of nanoparticles or absorbed on the surface of nanoparticles via various mechanisms. Once loaded, these molecules can be masked by the nanomaterials and drugs’ physicochemical properties as well as some other properties, such as pharmacokinetic and biodistribution profiles, are expected to be improved [3]. The most commonly used nanoparticles/nanocarriers include liposomes [4], micelles [5], dendrimers [6], lipid or polymeric nanoparticles [7, 8], emerging inorganic nanoparticles, like quantum dots, gold nanoparticles, carbon nanotubes, etc. [9–11], and macromolecule-based conjugates, such as antibody-drug conjugates (ADC) and drug-polymer conjugates (e.g., polyethylene glycol (PEG)-protein conjugates and PEG-siRNA conjugates) [12–14]. These particles typically range from 10 to 100 nm, which is considered safe and effective for most administration routes, including oral, systemic (e.g., intravenous), inhalation, ocular, and transdermal/transmucosal routes.

Thanks to the advances achieved in materials science and engineering, a broad range of nanoparticles with various sizes, morphologies, architectures, and surface properties have been developed. Moreover, the chemical or physical engineering on the surface or backbone of the nanomaterials provides additional opportunities for controlling the performance of nanomedicine. One of the most successful modification technologies is PEGylation. Due to the “stealth” property, the PEG-modified nanoparticles are able to escape the capture by the mononuclear phagocyte system (MPS) [15], leading to the prolonged blood circulation and the enhanced permeability and retention (EPR) effect-mediated “passive” tumor targeting [15, 16]. This is extremely useful for the tumor-targeted delivery of drugs and imaging agents. The nanoparticles, such as polymeric micelles, are able to extravasate into the tumors through the gaps between endothelial cells and accumulate there due to poor lymphatic drainage.

To achieve site- or cell-specific drug delivery, the nanoparticles need to be further engineered by the targeting ligands (such as monoclonal antibodies), “on-demand” drug release/delivery moieties (such as stimuli-sensitive moieties), and the intracellular delivery moieties (such as tissue or cell-penetrating proteins or peptides).

The idea of the stimuli-responsive drug delivery comes from the fact of abnormalities in the diseased tissues or cells. For example, in the tumor microenvironment, the abnormalities include acidic pH, altered redox potential, and upregulated proteins. As shown in Fig. 1.1, these internal conditions as well as external stimuli such as hyperthermia, magnetic field, light, and ultrasound, can be employed to design a stimuli-responsive drug delivery system for on-demand and/or targeted drug delivery [17].

Figure 1.1 Schematic illustration of stimuli-responsive nanomedicine.

Generally, to construct a stimuli-responsive nanomedicine, first, we have to understand the pathological abnormalities/local stimuli or external stimuli and desirable clinical outcomes; and second, the biocompatible nanomaterials should be available for use, which may undergo conformational change, hydrolytic/enzymatic cleavage/degradation, or changes in their physico-chemical properties in response to corresponding stimuli. These physical and chemical alterations allow for the destabilization or rearrangement of the nanoparticles or “activation” of the blocked functions, resulting in the drug accumulation, on-demand drug release, and/or drug uptake at the disease site and/or diseased cells. A great deal of work has been dedicated to devising stimuli-sensitive polymers, biomacromolecules, and other nanomaterials. Using these “intelligent” materials, a wide variety of stimuli-responsive nanomedicines have been developed. Here, we will overview the recent progress, highlight the important applications, and predict the future trends of stimuli-responsive nanomedicine.

1.2 Typical Stimuli and Stimuli-Responsive Nanomedicines

The stimuli-responsive nanomedicine can employ the internal abnormalities in the specific tissues, cells, or even intracellular compartments, such as the abnormal pH [18], specific proteins/enzymes [19], redox potential [20], or hypoxia [21, 22]; and the physical stimuli that can be artificially applied from outside of the body, such as temperature [23], light [24], magnetic field [25], or ultrasound [26] (Fig. 1.1).

1.2.1 Internal Stimuli and Stimuli-Responsive Nanomedicines

Significant alterations in the physiological condition are often the vital hallmarks for certain diseases, such as cancer and inflammatory diseases, rendering them attractive targets for designing stimuli-responsive systems. Here, we discuss the stimuli-responsive nanosystems that take advantages of the internal stimuli, including pH, enzymes, redox potential, and oxygen. The typical internal stimuli-responsive nanomedicines are summarized in Table 1.1.

Table 1.1 Examples of typical internal stimuli and stimuli-responsive nanomedicines

Acting stimuli	Characteristics of stimuli	Responsive nanomaterials	Cargoes	Applications	Refs
pH	Gastric pH: 1.0-3.5; Small-intestinal pH: 7.5-8.0; Large-intestinal pH: 5.5-7.0.	Polysaccharide nanoparticles	Insulin	Oral delivery of insulin	[27]
	Inflamed tissues (infarcted myocardium): pH6-7	Hydrogel: p(NIPAAm-co-PAA-co-BA)	bFGF	Injection to the infarct zone	[28]
	Tumor extracellular pH: 6.5-7.2	iNPG-pDOX	DOX		[29]
		Liposomes: DSPE-KLA-DMA	PTX	Cancer chemotherapy	[30]
Enzyme	Upregulated tumoral MMPs	Liposomes: PEG-peptide-DOPE	Rh-PE		[31]
		Silica nanoparticles: MSN-SS-CD-peptide-PASP	DOX	Tumor-targeted drug delivery	[32]
	Elevated proteolytic enzymes in inflamed tissues	Hydrogel: TGMS-TAC	Tacrolimus	Local injection of immunosuppressants	[33]
Redox	In the tumor:
	Intracellular redox: 10 mM;	HA-ss-DOCA	PTX	Tumor targeting	[34]
	Extracellular redox: 2-10 μM	PAMAM-S-S-NAC	NAC		[35]
	High ROS	PATK polyplexes	Plasmid DNA		[36]
Hypoxia	Low blood oxygen level in ischemic tissues	Water-soluble lipopolymer	pEpo-SV-VEGF plasmid	Ischemic myocardium targeting	[37]
	Hypoxia in the solid tumor	Azobenzene nanoparticles	GFP siRNA	Tumor-targeted gene and drug delivery	[38]
		2-nitroimidazole derivative	DOX		[22]

Abbreviations: bFGF, basic fibroblast growth factor; DOX, doxorubicin; PTX, Paclitaxel; NAC, N-acetylcysteine; HA-ss-DOCA, hyaluronic acid-deoxycholic acid; PAMAM-S-S-NAC, poly(amidoamine) (PAMAM) dendrimer-NAC; PMNT, poly[4-(2,2,6,6-tetramethylpiperidine-N-oxyl)aminometh ylstyrene].

1.2.1.1 pH-responsive nanomedicines

Under the normal physiolog...

Table of contents

• Cover
• Half Title
• Series Page
• Title Page
• Copyright Page
• Contents
• Preface
• 1. Overview of Stimuli-Responsive Nanomedicine
• 2. pH-Responsive Nanomedicine for Image-Guided Drug Delivery
• 3. Enzyme-Responsive Nanomedicine
• 4. Redox-Responsive Nanomedicine
• 5. Hypoxia-Responsive Nanomedicines
• 6. Thermosensitive Nanomedicine
• 7. Magnetically Responsive Nanomedicine
• 8. Ultrasound-Responsive Nanomedicine
• 9. Light-Triggered Drug and Gene Delivery
• 10. Stimuli-Responsive Liposomes for Cancer
• 11. Stimuli-Responsive Nanomedicine for Treating Non-Cancer Diseases
• Index