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Smart Polymers Classification Essay

What Are Smart Polymers?

How Stimulus-Responsive Polymers Are Used in Biotechnology

Smart polymers, or stimulus-responsive polymers, are materials composed of polymers that respond in a dramatic way to very slight changes in their environment. Scientists studying natural polymers have learned how they behave in biological systems  and are now using that information to develop similar man-made polymeric substances with specific properties. These synthetic polymers are potentially very useful for a variety of applications including some related to biotechnology and biomedicine.

How Smart Polymers Are Used

Smart polymers are becoming increasingly more prevalent as scientists learn about the chemistry and triggers that induce conformational changes in polymer structures and devise ways to take advantage of and control them. New polymeric materials are being chemically formulated that sense specific environmental changes in biological systems, and adjust in a predictable manner, making them useful tools for drug delivery or other metabolic control mechanisms.

In this relatively new area of biotechnology, the potential biomedical applications and environmental uses for smart polymers appear to be limitless. Currently, the most prevalent use o​f smart polymers in biomedicine is for specifically targeted drug delivery. 

Classification and Chemistry of Smart Polymers

Since the advent of timed-release pharmaceuticals, scientists have been faced with the problem of finding ways to deliver drugs to a particular site in the body without having them first degrade in the highly acidic stomach environment.

Prevention of adverse effects to healthy bone and tissue is also an important consideration. Researchers have devised ways to use smart polymers to control the release of drugs until the delivery system has reached the desired target. This release is controlled by either a chemical or physiological trigger.

Linear and matrix smart polymers exist with a variety of properties depending on reactive functional groups and side chains. These groups might be responsive to pH, temperature, ionic strength, electric or magnetic fields, and light. Some polymers are reversibly cross-linked by noncovalent bonds that can break and reform depending on external conditions. Nanotechnology has been fundamental in the development of certain nanoparticle polymers such as dendrimers and fullerenes, that have been applied for drug delivery. Traditional drug encapsulation has been done using lactic acid polymers. More recent developments have seen the formation of lattice-like matrices that hold the drug of interest integrated or entrapped between the polymer strands.

Smart polymer matrices release drugs by a chemical or physiological structure-altering reaction, often a hydrolysis reaction resulting in cleavage of bonds and release of drug as the matrix breaks down into biodegradable components. The use of natural polymers has given way to artificially synthesized polymers such as polyanhydrides, polyesters, polyacrylic acids, poly(methyl methacrylates), and polyurethanes. Hydrophilic, amorphous, low-molecular-weight polymers containing heteroatoms (i.e., atoms other than carbon) have been found to degrade fastest.

Scientists control the rate of drug delivery by varying these properties thus adjusting the rate of degradation.

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Review

A Review of Thermo- and Ultrasound-Responsive Polymeric Systems for Delivery of Chemotherapeutic Agents

Az-Zamakhshariy Zardad 1, Yahya Essop Choonara 1, Lisa Claire du Toit 1, Pradeep Kumar 1, Mostafa Mabrouk 2, Pierre Pavan Demarco Kondiah 1 and Viness Pillay 1,*

1

Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, 7 York Road, Parktown 2193, South Africa

2

Refractories, Ceramics and Building Materials, National Research Centre, 33 El-Bohouth St. (former El-Tahrir St.), Dokki, Giza P.O. 12622, Egypt

Academic Editors: Shiyong Liu, Jinming Hu and Ravin Narain

Received: 24 August 2016 / Accepted: 9 October 2016 / Published: 18 October 2016

Abstract

:

There has been an exponential increase in research into the development of thermal- and ultrasound-activated delivery systems for cancer therapy. The majority of researchers employ polymer technology that responds to environmental stimuli some of which are physiologically induced such as temperature, pH, as well as electrical impulses, which are considered as internal stimuli. External stimuli include ultrasound, light, laser, and magnetic induction. Biodegradable polymers may possess thermoresponsive and/or ultrasound-responsive properties that can complement cancer therapy through sonoporation and hyperthermia by means of High Intensity Focused Ultrasound (HIFU). Thermoresponsive and other stimuli-responsive polymers employed in drug delivery systems can be activated via ultrasound stimulation. Polyethylene oxide/polypropylene oxide co-block or triblock polymers and polymethacrylates are thermal- and pH-responsive polymer groups, respectively but both have proven to have successful activity and contribution in chemotherapy when exposed to ultrasound stimulation. This review focused on collating thermal- and ultrasound-responsive delivery systems, and combined thermo-ultrasonic responsive systems; and elaborating on the advantages, as well as shortcomings, of these systems in cancer chemotherapy. The mechanisms of these systems are explicated through their physical alteration when exposed to the corresponding stimuli. The properties they possess and the modifications that enhance the mechanism of chemotherapeutic drug delivery from systems are discussed, and the concept of pseudo-ultrasound responsive systems is introduced.

*

Correspondence: Tel.: +27-11-717-2274

Keywords:

thermoresponsive; ultrasound-responsive; sonoporation; hyperthermia; thermo-ultrasonic responsive; high-intensity focused ultrasound

1. Introduction

Through the decades of development in cancer treatment, chemotherapy has proven to be the world’s standard management for most cancer conditions [1]. Due to the high cost challenges that arise with new therapeutic approaches, the healthcare fraternity faces difficulty in achieving significant success rates [2]. Escalating efforts are being made by pharmaceutical scientists to advance cancer drug delivery through nanotechnology and the evolution of polymer sciences of biodegradable polymeric nanocarriers. These carriers propose an appropriate approach for transferring chemotherapeutic drugs and proteins in a desirably controlled manner to the target site [3]. Two classes of polymers, namely thermal- and ultrasound-responsive polymers are in many ways associated with advancing cancer therapy [4]. They have also proven to be of value in biomedical applications, ranging from tissue engineering to drug delivery, including gene therapy [5]. Thermoresponsive polymers feature in most copolymeric drug delivery systems [6], with well-known examples including poly(N-isopropyl acrylamide) (P(NIPAM)) [5,7], Pluronic F-127 [8] and chitosan [9]. In most cases these thermoresponsive polymers are used to design hydrogels as 3D networks formed by crosslinking of water-soluble polymers [10]. Thermoresponsive hydrogels have been of much interest for decades in the field of drug delivery [11]. Their properties include phase transitioning, altering drug solubility, and controlling drug release at a desired rate [12]. Internal stimulation of smart polymer delivery systems is ideal for drug delivery from a safety perspective [13]; however careful external control of a temperature stimulus is the standard by which thermoresponsive hydrogels respond to modulate drug release [14]. An example of employment of heat as an external stimulus is Hyperthermia Treatment (HT) where accurate and focused heat at temperatures ≥42 °C is produced at specific radio frequencies. The induced heat alters the morphology of the target tissue which assists in increased blood vessel permeability for enhanced drug delivery or ablation of cancerous tissue [15].

Ultrasound is also applied in advanced medical procedures for tumour therapy through heat production. This has proven to be a potently effective and a safe method of tumoral ablation, as well as promoting tissue generation [16]. Ultrasound-responsive polymers can be classified into biodegradable (polylactides, polyglycolides) and non-biodegradable polymers (ethylene vinyl acetate, poly(lactide-co-glycolide). Zhou and co-workers [17] suggested the forward-thinking approach of nanocarriers in combination with ultrasound for diagnostic and/or therapeutic applications.

In comparison with other polymeric delivery systems e.g., pH systems, thermal and ultrasound polymer systems can be managed by external stimuli sources such as lasers and MRI guided systems in order to control drug release and delivery desirable for the disease or condition via the ability to tune specific parameters. Whereas pH systems can be designed to respond to pH environmental change but cannot be controlled and managed by external applied stimuli.

In keeping with the fact that these two advanced classes of polymers are commonly applied in chemotherapeutic delivery systems, as well as the potential overlap in their mechanism of stimulation and action, it is pertinent that a concise review of research in this area is assimilated as a foundation of work that has been undertaken, as well as highlighting the potential to achieve advancements in this field. This review provides a concise and critical exploration into the subject matter by discussing the advantages and shortcomings of thermal- and ultrasound-responsive drug delivery in cancer therapy. In addition to the functional properties, phase transitions, as well as underlying scientific mechanisms of these delivery systems are reviewed.

2. Advantages and Mechanisms of Cancer Targeting via Thermoresponsive Systems

There are many other advantages that exist with regard to thermoresponsive polymers from their function and design to their application and administration. They are widely used in biomedical applications such as drug delivery and gene therapy, as well as extending to tissue engineering. These smart polymers possess the ability to be developed and transformed into various formulations in order to carry out their function as intended; these include; micelles, hydrogels, particles, and films [18]. These formulations can be modified by adding additional elements such as gold or magnetic material for enhanced performance e.g., good heating properties. External sources of stimulation such as laser power can be used to create the desired response i.e., tumour specificity. Cancer is known to increase normal body temperature [19], augmenting the thermal stimulus towards thermoresponsive systems.

P(NIPAM) is amphiphilic with a lower critical solution temperature (LCST) between 30–34 °C, often used in cancer chemotherapeutics due to its excellent thermoresponsive behaviour. At room temperature, the P(NIPAM) hydrogel exists as an aqueous gel network. P(NIPAM) hydrogel is generally administered as a depot or an injectable implant exposed to body temperature (37 °C). Hydrogels contain hydrophilic segments which absorb water due to their polarity; the gel network swells as these segments become hydrated leaving the hydrophobic branches of the network exposed to water which in turn causes hydrophobically-bound water. Furthermore, additional absorption of water between the network chains occurs through osmosis [20]. At 32 °C the hydrophilic fragments of the gel network become hydrophobic due to the presence of the isopropyl group present in the polymer and the gel expels the aqueous content [21] from the network, known as a polymer-solvent interaction. These are osmotic mechanisms that are dependent on the polymer-polymer affinity, hydrogen ion pressure and the rubber elasticity of individual strands of the polymer, resulting in shrinkage of the network until all chains within the matrix collapse to form a solidified gel [22]. Once the matrix collapses the drug entrapped within the network is released into the tumour tissue (Figure 1). Various Pluronic® types also function via this mechanism, being used in long-term anti-cancer therapy as demonstrated by Chen and co-workers [23].

P(NIPAM) brushes undergo collapse once it surpasses the LCST. This property allows adsorption of proteins that promotes the adhesion of cells in tissue engineering whereas the swollen brushes cause the opposite extreme below the LCST. There are three mechanisms by which proteins may bind; an attraction between the surface of the brush wall (grafting surface) and the protein (primary adsorption), van der Waals attraction forces between the protein and the surface (secondary adsorption), and protein polymer attractions within the brush. The binding of proteins can be determined by considering the self-consistent field (SCF) theory of brushes to measure the effect of tuning grafting density, degree of polymerization, and the protein dimension parameters [24]. Thermal changes between cell adhesion and cell detachment are based on the hydration state of P(NIPAM) i.e., swelling and osmotic forces. This hydration state is also described with relation to hydrophilic and hydrophobic states but through angle measurement [25].

Several amphiphilic block copolymers also exist as aqueous soluble systems in water at low temperature and have reversible phase transition properties after sol-gel conversion has occurred. This property is known as thermoreversibility, which is composition- and concentration-dependent. Thermogels were produced from polyethylene glycol (PEG)/polyester copolymers via the introduction of hydrophobic blocks onto the copolymer; for example the formation of thermogels has been achieved via introduction of poly(d,l-lactic acid-co-glycolic acid) (PLGA), poly(ε-caprolactone) (PCL), poly(ε-caprolactone-co-d,l-lactic acid) (PCLA), and poly(ε-caprolactone-co-d,l-lactic acid) (PCGA) as the hydrophobic blocks into PEG/polyester copolymers [26]. There is a fine line between the hydrophilic and hydrophobic ratio composition which falls within the viable region to produce a thermoreversible network for cancer therapy application [27]. A PLGA-PEG-PLGA amphiphilic co-polymeric injectable thermogel designed by Ci and co-workers [28] loaded with irinotecan, proved to regress colon tumours through a sustained release mechanism. The team demonstrated that the drug encapsulated within the thermogel provided improved bioavailability compared with drug unaided by the thermogel mechanism [29].

3. Advantages and Stimulation Mechanism of Ultrasound-Responsive Polymers in Cancer Therapy

Ultrasound affords a few advantages to drug delivery. As indicated, ultrasound offers more than one mechanism of stimulation i.e., through thermal induction, mechanical stimulus or gas vaporisation through microbubbles. These three mechanisms could also work as an adjunctive stimulus during drug delivery. Due to these multi-mechanisms and the ability to combine them, ultrasound stimulates enhanced permeation of tissues, cell membranes, and specialised barriers, such as the blood brain barrier. In certain cases ultrasound can act as an activator of drugs such as 5-aminolevulinic acid and haematoporphyrin [30], and is also used for guided therapy.

Ultrasound is not only known for its safety and inexpensive diagnostic capabilities through real-time imaging but also for its therapeutic proficiency through focusing high frequencies of ultrasound directed to malignant tumour tissue [31]. The tissue is ablated owing to the thermal, chemical and mechanical effects of High Intensity Focused Ultrasound (HIFU), with minimal side effects. Furthermore, ultrasound is a means of promoting healthy tissue regeneration as synergistic therapy [32]. Recent studies covered in this review highlight that ultrasound in cancer therapy is valuable for chemotherapeutic drug delivery and provides the positive desired outcomes from decreasing tumour growth and size to eradicating tumours completely.

Ultrasound plays a role in advancing cancer therapy due to its ability to be easily applied to thermoresponsive systems producing a dual functioning for cancer therapy. Ultrasound produces heat as a “secondary stimulus”, by energy vibration through acoustic cavitation initiated by acoustic vibrational waves. This heat is calculated via a collective time period at 43 °C based on Equation (1): where t represents the time of the treatment, R is the constant equivalent to 0.25 for temperatures 37–43 °C and 0.5 for temperatures above 43 °C and T is the average temperature throughout the treatment [33]; this increases the blood flow in the tumour vasculature. These acoustic waves employ a release mechanism through cavitation which increases the accumulation of chemotherapeutic drug within the site of the tumour. Once the ultrasound activates the polymer, the polymer responds by creating air-filled microbubbles that eventually burst causing temporary pores [34] in the tissue cell membrane at the focal point of application, enhancing tissue permeability [35] which allows increased passive targeting into tissue (Figure 2).

4. Overview of the Properties and Functionality of Diverse Thermo- and Ultrasound-Responsive Systems in Cancer Therapy

4.1. Properties of Thermoresponsive Polymer Systems: Temperature Ranges at Phase Transitions

The range of LCSTs for thermoresponsive polymers varies significantly. The LCST can be modified by blending various thermoresponsive polymers in order to customise the physicochemical properties of the system. These include the structural density, surface charge, toxicity, and transfection efficiency within cancer cells [37,38]. Copolymerisation of polymers has also been explored to synthesise thermoresponsive polymers with various LCSTs. Lai and co-workers have co-polymerised a total of ten thermoresponsive polymers with different LCST’s to observe the mechanism by which these polymers changed the 3D structure of a blood clot [39]. Chen and co-workers co-polymerized poly(glycidyl methacrylate) with P(NIPAM) as a pendant to provide a thermo-responsive gating system for the design of nanotubes with a LCST of 32 °C. They also demonstrated that above the LCST (37 °C), the nanotubes remain open sufficiently long enough for the activation of proficient drug release. Below the LCST (25 °C), the gates were in a closing state with no drug release until the activation temperature was once again reached [40].

Optimal cancer therapy focuses on targeted systems for clinical application. Thermoresponsive systems are designed with the LCST responding to the local tumour tissue temperature (~40 °C) that is required for the release of drugs into the cancer cells [41]. A common challenge with thermoresponsive systems is the duration they require to undergo phase transition that results in a burst phase of drug release. However, in recent developments a study has shown that altering the hydrophilic and hydrophobic fragments of the system can enhance the control of drug release by decreasing the thermo-gelling response time [12,42].

Phase transitions in thermoresponsive systems relate to the solubility properties that incorporates the common concepts of LCSTs and upper critical solution temperatures (UCSTs), also known as the cloud point [43,44]. Below the LCST temperature, the structural network of thermoresponsive systems is loosely arranged. As the system is exposed to heat, the network becomes denser until it reaches and surpasses the LCST with solidification at the site of action e.g., solid tumours or cancerous tissue. This subsequently produces an environment for sustained drug delivery, a common goal in cancer chemotherapy.

Colloidal-based thermoresponsive drug delivery systems designed for cancer therapy utilise polymers with a LCST due to the temperature difference between the body and the exterior environment. This facilitates the controlled delivery of the drug to the targeted site. These colloid-based thermoresponsive systems encompass liposomes, micelles, and nanoparticles. Thermoresponsiveness of nanosystems could also occur through thermoreversible swelling via cryotherapy or cold shock, which is used in tumour ablation therapy. This allows increased porosity of the system and promotes drug release from a state of encapsulation [45].

Shape Memory Polymers (SMPs) can provide polymeric systems with thermoreversible properties. These SMPs are frequently conveyed as thermoresponsive polymer systems used in a variety of biomedical applications. At lower temperatures the SMPs are maintained in a specific form. They undergo glass (Tg) and melting (Tm) transitions via the introduction of thermal stimuli greater than the transition temperature that initiates molecular movement. This causes a change in shape of the polymers through formation of crystalline domains (Tm) or an abrupt decrease in the free volume (Tg). After every cooling phase, the SMP system recovers its shape when thermal application is induced. The mechanisms of SMPs and thermoreversability are linked and therefore SMPs may be advantageous to use when designing thermoresponsive systems [46].

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