Localized Micro/Nanocarriers for Programmed and On-Demand Controlled Drug Release E-Book
Seyed Morteza Naghib
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Sprache: Englisch
This book provides a comprehensive overview of the localized drug delivery system landscape. The 10 chapters provide a detailed introduction in polymers, nanostructures and nanocomposites for developing localized controlled drug delivery systems (LCDDSs) in the form of stimuli-responsive delivery systems, targeted drug delivery systems or the combination of both. A discussion on manufacturing techniques, optimization, challenges and adaptation of LCDDSs for the treatment of a wide range of diseases is also included. This simple and informative resource conveys an understanding about designing novel drug delivery systems to students in advanced pharmacology, biotechnology, materials science and biochemistry study programs. Readers will be equipped with the knowledge of regulating drug release rates to get a desired pharmacological profile that helps a researcher to ensure a high therapeutic effectiveness. The detailed information about various drug delivery systems and a compilation of recent literature sources also paves the way for research scholars to construct a drug targeting framework for their research plans.
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Seitenzahl: 509
Veröffentlichungsjahr: 2003
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PREFACE
In the healthcare field, providing optimal treatment to individual patients is of primary concern. Drug delivery systems can regulate drug release rate to get the desired profile, ensure high therapeutic effectiveness, and reduce side effects that are very interesting in pharmaceutical and biomedical applications. The localized drug delivery presents various factors designed to enable the delivery of therapeutic agents, such as drugs, genes, proteins, etc., directly to the site of disease in a controlled manner, sparing off-target cell/tissue toxicities. In this context, one of the considerable challenges in systemic drug delivery systems is to get the desired drug concentration at the specific organ, reduce side effects, and prevent drug inefficiency. The present book entitled "smart stimuli-responsive micro/nanocarriers for programmed and on-demand localized controlled drug release" is one of the first books on the market that focuses on localized drug delivery with enhanced drug release at the target site, reduced local toxicity, and better patient compliance in order to inspire readers to design and create novel drug delivery systems for the treatment of a wide range of diseases.
In this book, the present chapters provide a detailed introduction to polymers, nanostructures, and stimuli-responsive materials and their great potential for opening new avenues to address several challenges in conventional dosage forms in localized drug delivery systems. This book is ideally designed for researchers working in pharmaceuticals, bionanotechnologies, biomedical engineering, materials science, and related industries.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The author declares no conflict of interest, financial or otherwise.
ACKNOWLEDGEMENT
Declared none.
Introduction to Localized Controlled Drug Delivery Systems (LCDDSs)
Seyed Morteza Naghib,Samin Hoseinpour,Shadi ZarshadAbstract
Localized controlled drug delivery systems (LCDDS) that can control drug release profiles to ensure high therapeutic efficacy and reduced side effects are highly desired in the pharmaceutical and biomedical fields. Biodegradable drug delivery depots have been investigated over the last several decades as the means to improve tumor targeting and severe systemic morbidities associated with intravenous chemotherapy treatments. These localized therapies exist in a variety of factors designed to facilitate the controlled drug delivery, directly to the disease site, sparing off-target tissue toxicities. Many of these depots are biodegradable and designed to maintain therapeutic concentrations of drugs at the tumor site for a prolonged period of time. The depots are placed inside the body through a single implantation procedure, sometimes simultaneously with the tumor excision surgery, following the complete release of the loaded active agent. Even though localized depot delivery systems have been widely investigated, only a small subset have demonstrated curative preclinical results for cancer applications, from which just a few have reached commercialization.
1.1. HISTORY AND STATISTICAL TRENDS IN LCDDS
Typical drug delivery systems may have some challenges which must be considered to obtain the best results. One of these challenges is to obtain the desired drug concentration in certain organs (Gooneh-Farahani et al., 2020, Gooneh-Farahani et al., 2019, Kalkhoran et al., 2018, Zeinali Kalkhoran et al., 2018). Another issue may be the degradation of the drug before reaching the intended organ or tissue. These challenges might cause failure even in adequate drug doses. However, with the development of local delivery, unstable drugs, which had to be delivered through frequent daily dosing, can be delivered once a week or even once a year (Singh et al., 2019, Aj et al., 2012, Singh et al., 2009). In this regard, Densby and Parkes developed the idea of implantable drug delivery systems by describing the effect of subcutaneous implantation of compressed pellets of crystalline estrone upon castrated male chickens in 1938. Furthermore,
Folkman and Long investigated biocompatible implantable drug release formulations with the use of silicone rubber (Silastic) as a method for prolonged systemic administrations in 1960, which was able to overcome the issues related to the oral administration of specific drugs. Inspite of significant attempts, the development and commercialization of safe implants have not matured (Kleiner et al., 2014).
Fig. (1)) Schematic illustration of localized controlled drug delivery systems.“Localized drug delivery” refers to a particular kind of targeted drug delivery in which the movement and absorption of the drug to the bloodstream decreased, and the therapeutic agent is concentrated in a specific part of the body (Fig. (1). Localized delivery cuts down systemic effects on marginal organs or tissues, thereby reducing the side effects of the drug while having more control over the target site. The local effect may be achieved through injection, implantation or inhalation. In addition, systemic effects are also achievable by local administration (Rolfes et al., 2012, Dhanikula and Panchagnula, 1999, Ji and Kohane, 2019). In cases where delivery is not enough to prevent the restenosis process, local drug delivery plays an important role in delivering compounds to suppress the neointimal proliferation characteristics of the restenosis lesion. Meanwhile, anti-inflammatory agents, antiproliferative compounds, and specific antibodies may be delivered using local drug delivery. For example, the drugs used in the nonsurgical treatment process of periodontitis (a severe gum infection), have several side effects such as drug toxicity, nausea, vomiting, superimposed infections, drug interaction, and patient compliance. The aforementioned side effects have led to the enhancement of nonsurgical therapy and the introduction of local drug delivery. To develop periodontal health, controlled clinical trials were selected that measured the potential of local delivery. The clinical trials were used to demonstrate statistical and clinical data in order to investigate the results of local delivery (Ramesh et al., 2016, Gill et al., 2011, Lambert et al., 1993, Ibsen et al., 2012, Song et al., 1997, Kalsi et al., 2011, Szulc et al., 2018, Greenstein, 2006).
Fig. (2)) Schematic of comparison between oral, intravenous and local drug delivery methods (open access) (Rolfes et al., 2012).From another point of view, there are various ways to administrate drugs in order to treat different diseases, including oral systemic drug delivery and local drug delivery (Askari et al., 2021a, Askari et al., 2021b). Fig. (2) shows a comparison between intravenous delivery and oral delivery methods. As shown in Fig. (2), by reducing the gastrointestinal tract, variability is decreased, and control is increased. Moreover, dependence on patient circulation for distribution in local delivery procedures has decreased, thereby increasing control and decreasing variability. In the local drug delivery method, the required effective drug amount has decreased while the treatment has increased.
Many drugs, peptides, and proteins are administrated intravenously to avoid adverse conditions, because of their short half-life. One of the challenges of intravenous administration is the short drug action time, which as a result, requires regular injections to achieve drug efficacy. Over time, injectable controlled-release delivery seems to be more commercially successful due to factors such as safety and efficacy. Topical drug administration is another path for drug delivery, but is not very effective because of the physiological character of the drugs and low impermeability of the stratum corneum. Consequently, the local drug delivery system is a safe and immune method to deliver drug to the desired site of the body, offering unique advantages over other drug delivery systems (Singh et al., 2019, Aj et al., 2012, Rolfes et al., 2012).
When designing a biomaterial for drug delivery applications, several factors must be considered, such as biocompatibility, release rate tunability, over-elution or ‘burst’ release inhibition, post-drug release effects, dimensional penalties reduction, nonspecific elution reduction, material production scalability, physician and patient acceptability. Local drug delivery, or in other words, delivery of drugs to a specific area of the body, will decrease systemic drug concentration. According to this method and the drug activity protection during sequestration, numerous follow-up therapies can be lessened or even eliminated. For example, in cancer treatment, local delivery allows local and surgical administration of a therapeutic agent to the desired site, which reduces the side effects of systemic drug delivery and, at the same time, increases drug efficacy. As another example, drug-loaded nanoparticles may be used as a method for brain tumor treatment (Lam and Ho, 2009). Drug delivery systems eliminate all the off-target effects, as smaller dosages are required to achieve local therapeutic concentrations. These systems do not need to travel through the systemic circulation and are directly introduced to the inflammation site. For instance, local drug delivery systems are more useful in non-steroidal anti-inflammatory drugs (NSAID), as they do not require any extra surgery for implantation. Nanoparticles are good candidates for drug delivery due to their low viscosity and small particle size, which enables them to pass through a needle and move throughout the body easily. Localized controlled drug delivery system (LCDDS) aids the formation of periodontal pockets, which perform like a natural reservoir, meanwhile, the gingival crevicular fluid (GCF) provides a hydrated environment (leaching medium) that boosts drug distribution throughout the pocket (Haley and von Recum, 2019, Lee et al., 2017, Rajeshwari et al., 2019, Singh et al., 2014). In the treatment of a periodontal infection, which was studied as an example before, delivering antimicrobial agents to the pocket base is necessary. Therefore, the designed drug delivery system must simplify the retention of the drug long sufficiently to guarantee drug efficacy and healing process. Some drug delivery methods, such as mouth rinse, subgingival irritation, and systemic delivery, deliver poor concentrations of drug to the activity site, but local delivery can be used in combination with all the above-mentioned items to enhance periodontal health (Greenstein and Polson, 1998).
Local drug delivery has the ability to deliver antibiotics to the target sites, and also limits both desirable and undesirable pharmacological effects to other parts of the body. In the controlled delivery method, drug access to off-target sites has decreased; drug efficacy has increased, and toxicity has decreased, which provides a safer treatment with the same effects. This method also provides constant-rate delivery of drugs, such that a smaller amount of drug is needed to treat disease for a sufficient duration. Therefore, injectable drug delivery systems are a potential route to deliver antibiotics to the action site, which noticeably decreases the cost compared to devices that require placement time and securing (Aj et al., 2012, Singh et al., 2009, Ji and Kohane, 2019, Singh et al., 2014).
Improvement of more useful drug delivery systems is important for microorganism eradication associated with bacterial infections. To protect against infection, an operative antibiotic release must occur at concentrations above the bacteria's minimum inhibitory concentration (MIC); and the antibiotic concentration must be above the minimum bactericidal concentration (MBC) to reach the treatment point and complete the curing process. Overcoming concerns related to short half-life issues, improving pharmacokinetic and pharmacodynamic profiles, and developing localized drug delivery, are facilitated. Local delivery of antibiotics leads to lowered toxicity, decreases required dosage and prevents systemic exposure. It is noteworthy that local drug delivery can administrate drugs at high dosages, without surpassing the systemic toxicity, and can decrease side effects at the special infection sites, for example, implant-related infections. Besides, by avoiding systemic administration, patient compliance is increased, as in most cases, patients do not finish all courses of the drug, leading to bacteria resistance (Stebbins et al., 2014).
Particular kinds of local delivery systems can start and continue local drug activity either by avoiding drug efflux from the arterial wall or by using delivery vehicles that will lengthen the release time. In comparison with other drug delivery systems, in local drug delivery, lower amounts of the drug are required, and thus, unfavorable effects are decreased or totally eliminated. As mentioned above, unstable biomolecules, for instance, oligonucleotides, nucleic acids and drugs with a short half-life, specifically peptides and proteins, can be delivered locally, but drug half-life is improved in localized drug delivery systems. From another point of view, localized treatment methods have minimum overlap with blood circulation and partial contact with the liver and kidneys, where drug metabolism occurs. In this case, the half-life of many drugs will increase and recover. Therefore, in local treatment, the amount of required drugs will decrease (Rolfes et al., 2012, Jain et al., 2005).
A standard local drug delivery system has characteristics such as simple administration, controlled drug release, biodegradability, biocompatibility, and drug concentration sustainability, meanwhile not harming other healthy tissues. Irrigating systems, gels, nanoparticles and microparticles are examples of local drug systems. Local drug delivery systems (LCDDS) have advantages compared to systemic drug delivery, which are briefly described below. One of the advantages of LCDDSs is minimized invasive effects. Moreover, LCDDSs can be applied directly to the desired site of the body, which as a result, reduces gastrointestinal concerns. Also, the drug dosage reduction, frequent drug administration and enhanced patient compliance serve as ideal means to incorporate agents which are not suitable for systemic administration, e.g., Chlorhexidine (Rajeshwari et al., 2019). As an example, in the delivery of metronidazole, using local drug delivery has shown minimum side effects wherein the drug is not easily adsorbed to other tissues, when prescribed in routine doses (Greenstein and Polson, 1998).
As macroscale methods for cancer treatment, LCDDS can be implanted or injected just near the solid tumors, and can present extensive therapies over the nanoscale. They can also be loaded with more drugs that are not cleared quickly. Some implantable, biodegradable polymers with the ability to release payloads after tumor removal, have been in clinical use for several years. One of the examples of these implantable, biodegradable polymers is poly (carboxyphenoxy propane-co-sebacic acid) wafers which can degrade after 3 weeks of implantation. Such biodegradable polymeric systems may be used in post-surgery treatments, to assure the complete removal of cancerous tissues. From another point of view, if drugs are loaded locally, side effects are decreased due to the avoidance of systemic circulation of chemotherapeutic drugs and healthy tissues are kept safe, and the damage to these healthy tissues is decreased. Some of the advantages of drug-loaded polymeric implants over customary systemic drug delivery methods are listed below: 1) the possibility of loading and releasing water-insoluble chemotherapeutic agents, 2) stabilization of the loaded drugs and maintenance of anti-cancer activity, 3) controlling the drug release rate and diffusing and up taking drug into the cancerous cells more precisely, 4) decreasing drug waste by the straight release of the drug at the disease site, and 5) one-time administration of the drug. Therefore, local chemotherapy of cancer has enhanced the treatment efficiency and has reduced patient morbidity (Campbell and Smeets, 2019, Wolinsky et al., 2012).
Localized treatment in slow-growing tumors such as prostate, lung, cervical, and breast count as a suitable substitute for surgery. For example, brachytherapy seeds applied at the surgical resection site, have been shown to reduce the incidence of local recurrence in lung cancer patients from 19% to 2%. Moreover, adding brachytherapy to a lobectomy performed for 2–3 cm lung cancer tumors, drastically reduced recurrence rates and increased patient endurance from 44.7 months to 70 months, which represents the influences of localized therapy on decreasing localized recurrence and developing survival in patients (Wolinsky et al., 2012).
Using chemotherapy is a valid, useful and effective procedure for curing localized tumors. This procedure is used as an adjuvant to surgical treatment as it eliminates or postpones metastasis. Localized chemotherapy of cancers and particularly early-stage diagnosed cancers, is more effective compared to systemic cancer therapy due to locoregional recurrence, which remains a major failure in cancer cases, and sterilization of the resection site edges with the delivery of chemotherapy agent. Also, this method decreases locoregional tumor recurrence. Moreover, a drug-eluting implant enlarges the tumor resection margins, which might penetrate the surrounding tissues, and may result in extra limited resection of diseased parenchyma. For instance, limited wedge resections of lung parenchyma can restore the current standard of care whereby the total lobe of the lung is resected if locally delivered agents could prevent locoregional recurrence (Wolinsky et al., 2012, Morgan et al., 2009).
1.2. SCIENTIFIC AND TECHNOLOGICAL IMPACT OF LCDDS
Due to major progress in drug delivery systems over time, new techniques such as site-specific or local controlled release have been merged, offering decreased dosage of the drug with maximum concentration at the desired site of the body. Moreover, at a specific part of the body where other usual therapies might be unsuccessful, adjunctive use of local delivery might be useful. Local drug delivery systems are utilized specifically in patients who are in the maintenance phase, in institutionalized patients, in implants that have failed at the localized refractory sites, and in patients who cannot undergo surgery. LCDDSs have also performed well in regenerative surgery and development predictability by decreasing the bacterial load (Singh et al., 2009).
One of the easiest ways to gain targeted drug delivery is to place the device at the desired site where the drug must be delivered, which may be the best choice for most ocular situations. In another case, if the patient uses intravitreally injections such as antivascular endothelial growth factor (VEGF) drugs, which must be injected every 4-6 weeks and requires local and long-term delivery of a special drug, local delivery can deliver the drug for several months or years with identical procedural injection. Finally, a logical way to give local delivery is injecting a device or a matrix into the intravitreal space to have the local effect of the drug (Lavik et al.).
In the treatment of respiratory diseases, pulmonary drug delivery of may be a good option with advantages in comparison with other drug delivery routes. Delivering the drug agent through inhalation has the advantage of the direct delivery of the drugs inside the lungs. The local pulmonary administration of the drugs facilitates the targeted treatment of respiratory diseases such as pulmonary arterial hypertension (PAH). In this case, there is no need for extra doses, which are required in other administration routes (Gao et al., 2016).
Although in the last several years, developments in the detection of cancer in early stages and progress in technology had a major effect on decreasing the rate of cancer death in patients, there are still main limitations in treatment-associated morbidity and recurrence rates. There are possible intervention points in every phase of cancer where local therapy, either curative or palliative, could complement or substitute ordinary treatments (Wolinsky et al., 2012).
Nowadays, in cancer therapy, chemotherapy is still known as the most valuable approach. Chemotherapy has non-discriminating destructive effects on both normal and cancerous cells, which causes major side effects for the patient. One of the main challenges in the treatment of cancer or other diseases such as complicated sicknesses, is to release the drug within the organs and to achieve a drug delivery and release system directly at the tumor location. Hence, designing complicated plans to obtain targeted traceable drugs used for anti-cancer applications is vital (Zeng et al., 2016).
Despite tremendous efforts to improve nanotherapeutic delivery agents which can penetrate the blood-brain barrier (BBB), there are no accessible clinical treatments, and the efforts are in the development stages. There are several challenges, such as the challenge of obtaining high bioavailability to the cerebral activity site, as a large number of drugs cannot penetrate the BBB; the challenge of ensuring the biocompatibility of nanoparticles; the FDA approval challenge, and the long process time challenge. Therefore, the substitute option is the application of invasive methods. Injections and infusions are frequently used methods for severe sicknesses, although there are controlled release polymeric implants applied for the treatment of brain malignant gliomas. The first polymer with FDA approval in 1995 was poly (carboxyphenoxypropane-co-sebacic acid), a biodegradable polymeric wafer, containing an anti-cancer chemotherapeutic drug naming 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). This medication was applied to the tumor site after removing the tumor by surgery and the polymer released was eventually released after implantation and degraded after 3 weeks. After this research, several related bioresorbable implants, such as bioresorbable PLA-made microchips, were tested in clinical trials. The bioresorbable PLA-made microchips successfully decreased the size of tumors in an in vivo rat model via controlled and localized release of BCNU (Campbell and Smeets, 2019).
On the other hand, the systemic drug administration route has been utilized in curing vitreo-retinal diseases. Earlier studies have proved that a very small amount of drug was applicable to the eye, and because of the limitations caused by the blood-ocular barriers, considerable doses of the drug were required to achieve therapeutic drug amounts in the posterior segment of the eye. Therefore, these types of diseases are not easy to cure and have a long treatment time, using conventional topical or systemic drug delivery. Research has led to specialized drug delivery to the tissues of the posterior segment of the eye. Many implantable intravitreal tools used for drug delivery applications have been fabricated. However, none of the commercial products are verified to be all-comprehensive safe and simple tools. Generally, implantation methods were used to protect the tool in the posterior segment of the eye by ophthalmic surgery. The tools were entirely biodegradable and presented zero-order drug delivery in the vitreal cavity over several months or even years. As a result, several challenges need to be solved in order to devise a successful intravitreal drug delivery tool. (Choonara et al., 2010).
In another case, the main cause of the incidence of periodontal disease is the growth and proliferation of pathogenic bacteria, and mainly anaerobic gram-negative bacteria, in the plaque. Antibiotics are known as a common treatment of periodontal disease, but long-term administration of antibiotic drugs is required for the treatment of chronic stage periodontal disease. Long-term administration of antibiotics may cause bacterial resistance and result in side effects, such as, gastrointestinal disorders and superinfection. Consequently, for safety concerns, oral administration of medications for curing chronic periodontal diseases is not acceptable. Hence, researchers have focused on synthetic antimicrobial drugs and local administration of antibiotics. Meanwhile, according to the reports, conventional therapies, irrigation and mouth rinses are not leading to successful results. With progressions in drug delivery systems and improvement of knowledge in local drug delivery, periodontal disease treatment has been of great interest to researchers (HIGASHI et al., 1991, Yang et al., 2017).
In the case of periodontal disease, local delivery of antimicrobial drugs into periodontal pockets, has been comprehensively investigated since 1979. In systemic drug delivery, the drug was restricted at a specific site and the concentration of the drug at the targeted site was high. On the other hand, local drug delivery has gained more attention, specifically in periodontology, because of lower infection and side effects risk (Nadig and Shah, 2016).
Local delivery of drugs to vasculatures assists in obtaining a high local concentration of drugs, with prolonged maintenance at a lower dosage and therefore, lower systemic toxicity. Also, drugs with lower bioavailability can reach the desired site or organ in the body without any issues. It is noteworthy that in the localized drug delivery approach, drugs with a short half-life, such as recombinant proteins and peptides, have been successfully delivered with a minimum loss, earlier than their uptake into the desired organ or tissue. But, there are challenges in systemic drug delivery, such as the variability of pharmacokinetics, specifically in oral or intravenous procedures. Challenges resulting from different dosages, often seen in animal studies and extended to human clinical trials, are also solved by local drug delivery. Some types of local drug delivery have the potential to start and continue local drug action, either by avoiding drug efflux from the arterial wall or by using delivery vehicles that will prolong the release or action duration (Kavanagh et al., 2004).
For most solid tumors with locoregional lymphatic involvement in early or intermediate stages, surgical resection of the main tumor or, in some cases, nearby lymph nodes, is considered an important therapy. On the other hand, for late-stage tumors, debulking the tumor has a painkilling result, and the life quality of the patient may be improved better in some cases which depend on the tumor site. It must be considered that the advantage of eliminating cancerous tissue must be adjusted with the resulting patient morbidity (Wolinsky et al., 2012).
Intermittent oral delivery is considered as a common treatment for a majority of diseases, specifically cancer. Such methods, might lead to high concentration of drug in the blood immediately after administration which may have severe side effects in patients as the level of drug in the bloodstream increases. In cancer therapy, the drugs contain high amounts of toxic molecules which harm both normal and cancerous cells. When the drug level in the bloodstream is more than 1%, some parts in the body for example, the gastrointestinal system or the kidney are disabled. Therefore local and selective drug delivery systems with the ability to remotely control the drug release in the targeted site, may be used to reduce the side effects. For this reason, many local drug delivery systems on the basis of polymers, have been investigated (Mousavi et al., 2018).
Nanoparticles may be utilized as carriers for drugs and may have drug delivery applications. The prospect of designing nanoparticles over the past few years has been the enhancement of therapeutic effects of drugs and also decreasing side effects. The application of nanoparticles as drug carriers, may have advantages compared to general treatments. The first advantage of using nanoparticles as drug carriers is the uninterrupted and controlled release of the therapeutic agent, and as a result retaining the drug dosage at the required level. The second advantage of using nanoparticles as drug carriers is localized drug delivery and the supply of the drug at a special site or cell, leading to a decrease in drug dosage and, as a result improving patient compliance (Tığlı Aydın and Pulat, 2012). There are two important factors in the local delivery of nanoparticles: 1) nanoparticles are able to infuse in a slightly viscous, slightly hyperosmolar solution 2) the nanoparticle must have a negative or neutral charge (Patel et al., 2012).
A group of biodegradable polymers is sensitive to changes in environmental circumstances such as temperature, pH, magnetic field and electric field. These systems are based on passive drug delivery and the drug release mechanism is often diffusion, which steadily carries out a determined dose of drug at a certain time. Administration of high levels of drugs in an organ is not feasible, as the control over drug release is decreased, and as a result, the drug release time increases. Moreover, controlled release drug delivery systems, using biodegradable polymers may have challenges such as the excessive release of drugs in the first implantation days. Consequently, the usual techniques of using polymers in drug delivery may have issues such as incomplete drug diffusion within the special site, and in some cases, unwanted interactions between the drug and deliver substances. To overcome the aforementioned issues associated with conventional drug delivery systems, smart and active drug delivery systems have been developed. Implantable chips for controlled drug release, that are known to deliver drugs on demand are an example of such systems. These systems can deliver therapeutic agents at any dosage, time, model and rate and can be externally controlled. In a specific study, a piezo-actuated silicon micropump has been investigated. The pump included a pair of check valves and a pumping membrane which directed liquid flow in the proper direction from a drug reservoir to the releasing location (Mousavi et al., 2018).
Ionic polymer metal composites (IPMCs) are smart electro-active polymers (EAP) with a low power driving force of less than 8 mW, but large displacements. IPMCs have been utilized as actuators in drug delivery chips and have been of interest over the past few years. IPMCs are more flexible compared to piezoelectric actuators, and work at a lower voltage. Lee et al. have studied the flow rate and design calculations of IPMC actuator micropump. The studie also used a limited part analysis to optimize the electrode shape of the IPMC diaphragm and studied the stroke volume. Researchers have developed a new and different design of a chip for drug delivery applications as a single reservoir with IPMC actuator as the capping layer of the reservoir. Some of the advantages of this implantable chip may include low operational power, easy designation, simple manufacturing, biocompatibility, and external controllability. This design solved the challenge of imperfect drug release due to the incapability of the actuator to pump the entire drug content in earlier models. The IPMC can be in the interstitial water of an organ and will be in charge of dissolving the whole drug inside the reservoir. For any disease that might require smart localized drug delivery (for example, breast cancer), these chips are significantly helpful as the organ is reachable, and the device may be located in the vicinity of the cancerous cells by surgery. After the surgery, the drug release parameters such as time and dosage of the drug may be controlled by the therapist (Mousavi et al., 2018).
Polymeric-based drug delivery tools that are locally administered guarantee the delivery of high dosages of anti-cancer drugs to the targeted site. However, there are several issues related to the effectiveness of the administered drug, which is influenced by the accessibility of anti-cancer drugs in the vicinity of cancerous cells. An important issue is the sufficient release of the drug to occult sites of the tumor, to avoid recurrence. For instance, lung cancer patients suffer from a 2-fold increase in locoregional recurrence following smaller “wedge” resections (17–24%) performed in the setting of limited cardiopulmonary function, as compared to a standard lobectomy resection, whereby ~50% of the entire lung affected by tumor is removed. Theoretically, local recurrence may occur, which is related to the existence of microscopic disease at or close to the surgical resection margins. The theory is confirmed by the doubling of recurrence rates following limited resections when the resection margin is less than 1 cm. According to the art, after surgical resection (curative limited resection), 39% of patients had malignant cells at the surgical margin, connecting the optimal distance of malignant negative margins to the maximum tumor diameter. Consequently, increasing the efficient curing radius of the resection margin used for local drug delivery may decrease the local recurrence possibility and increase the number of rescued patients after curative limited resection. Local drug delivery may enhance clinical results for patients in the early stage of cancer, if the targeted site receives sufficient therapeutic agents in the required time. Finally, the effectiveness of the therapy is associated with the radial diffusion profile of the embedded drug (Wolinsky et al., 2012).
1.3. CHALLENGES IN LOCALIZED STIMULI RESPONSIVE MATERIALS
To overcome challenges of local drug delivery systems, more research is required about the healing and inflammatory reactions to the local accumulation of drugs and also polymers in the post-operation process. Chemotherapy is a cancer treatment method that uses agents with significant disadvantages and a wide range of side effects. The drugs are extremely cytotoxic, therefore, the dose-dependent toxicity of healthy parenchyma must be considered, and connection to nearby tissues must be avoided to prevent severe injury. Moreover, anti-filtration drugs may prevent the curing of normal tissues, after the surgery process. This issue may be caused by interrupting the infiltration of immune cells such as neutrophils and macrophages. Also, severe injury may occur at the implantation site, due to the edema, which might raise drug diffusion into the local tissue or organ. However, after implantation, the external response of body to the polymer, may result in the fabrication of a thick fibrous capsule around the implant, which would act as a diffusion obstacle for drug release. Therefore, the interactions between the local cancer treatment drug delivery and the final outcome of curing on interstitial fluid flow and tissue density must be considered, in order to verify the release of sufficient dosages of a therapeutic agent to the desired site and on a scheduled time (Wolinsky et al., 2012).
Although huge advances have occurred in engineering new stimuli-responsive materials, some challenges and difficulties still remain to be addressed regarding nanomedicine applications. For instance, biodegradability and biocompatibility are two important parameters of drugs which must be ensured even before human clinical trials. As a result, there are many systems that have only been stated as an in vitro proof-of-concept and recorded work in vivo, and a few researches have reached preclinical models (Alsehli, 2020).
In general, for LSDDSs in cancer treatment by chemotherapy, the inherent toxicity of a chemotherapy agent within the body, determines the application time and dosage of the drug. In vivo investigations, including normal DOX administration, have solved drug resistance issues. Because of low diffusion rates and potent intracellular binding, therapeutic gradients were recognized, which have no delay after injection. The aforementioned therapeutic agents remained near blood vessels, leaving further cancerous cells removed from vessels unhurt. Moreover, the nonstop infusion administration, resulted in more gradual gradients. In case of multicellular layer models, research demonstrated that, significantly for cells away from blood vessels, gradual diffusion of specific drugs successfully increased chemotherapy efficacy. On the margins and also close to blood vessels, repeated treatments eliminate successive layers of cells. So, it can be concluded that local and permanent drug delivery can overcome issues related to drug diffusion. In the case of spheroids, due to the repeated infusion in cells located far from margins, the drug concentration was raised, which enhanced retention and therapeutic balance across the whole tumor. Nutrients diminish with durable approaches that delete subsequent layers of cells, and as a result, with the aim of reaching cancerous cells that are getting energy and therapy, which allow access to earlier elusive cells. Developed models for in vivo and in vitro investigations for drug diffusion, may have for novel ideas and approaches. Besides, developing local drug delivery systems may be significantly effective for controlling administrated dosages of a drug for a long period, with a platform for enhanced biocompatibility and versatility (Lam and Ho, 2009).
Three groups of devising an implantable tool for medical purposes, are the patient, the medical staff and the engineer. Therefore, implantable devices may be accessed by gathering information from these three groups. The progress of designing such a device depends on the requirements of patients, the doctors’ decisions, and the practical possibility of the model designed by the engineer. As a general rule, patients who have temporary or permanent implants inside their body, feel uncomfortable finding something external in their body. They prefer the use of medical methods, without any pain and terminating the healing process unconsciously. Great effort is needed to overcome these issues. Due to the initiation of minimally invasive medical methods, the insertion place has become unremarkable and restoration can happen unconsciously (Joung, 2013).
From a materials viewpoint, drug delivery systems require more signs of progress in the following directions: a combination of several diverse components into one exclusive device, the need for more biocompatible and flexible external materials which are inserted into the body during implantation, and the realization of closed-looped DDSs, through the integration of multiple advanced electronic devices, such as a wireless transductors or portable batteries (Puiggalí-Jou et al., 2019).
In the case of periodontal disease, presently, there is no information about the usefulness of local combinations used either together or sequentially. Theoretically, using the local and systemic drug delivery route simultaneously presents a high drug concentration at exact locations and suppresses the potential of bacterial reinfection reservoirs (e.g., tonsil, tongue, mucosa and saliva). The aforementioned method may be useful as it inhibits recolonization at cured locations, though it requires more assessment. When ordinary antimicrobial agents are not helpful, specific bacteria elimination methods are required to obtain optimum local drug administration results. In this regard, local drug delivery systems may be practical. When conventional therapy is unsuccessful to achieve clinical periodontal health, clinicians should utilize bacterial and drug sensitivity testing that can be addressed by local drug delivery (Greenstein and Polson, 1998).
Biocompatibility is one of the major issues associated with the long-time use of implantable materials, and the issue may only be resolved by concerted multi-disciplinary attempts. The low biocompatibility of materials may cause serious issues such as pain and discomfort in long-term implantable drug delivery, which might reduce patient acceptance. Cost/benefit ratio is another important factor that must be considered, as some local delivery systems may be costly. Another challenge is the complexity of local systems in comparison to oral routes and the required dosages for longer approval may be too expensive. Moreover, some local delivery systems need minor surgery for implants and explants, which may lower patient acceptance and raises the desire for a less invasive alternative. (Park and Park, 1996).
CONCLUSION
LCDDSs may be fabricated to establish localized controlled and triggered release by the endogenous and exogenous stimulus. LCDDSs decrease systemic cytotoxicity and enhance the efficiency of the therapeutic molecule. In specific cases, the shape/magnitude of the release profile may be manipulated for particular indications. A wide range of LCDDSs has been studied, with a specific emphasis on bio/cytocompatibility. The toxicity of the materials used in LCDDS, must be studied, especially when nanomaterials and nanostructures are used, as they may include several toxic agents that are unknown. Moreover, the therapeutic molecule/drug delivered from a LCDDS noticeably affects bio/cytocompatibility. LCDDS may manipulate the local concentration of therapeutic molecule/drug, which can result in high local toxicity in cell microenvironments and tissues. Developments in LCDDSs may require combining several fields, such as biomedicine, pharmaceutical sciences, chemical engineering, materials science, physics, chemistry and electrical engineering. The LCDDS may have closed-loop bio/nanofunctionalities so that the physiological condition may be monitored in order to manipulate the exact drug dosage online (smart LCDDSs that release the drug in response to endogenous/exogenous stimulus).
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Seyed Morteza Naghib,Samin Hoseinpour,Shadi ZarshadAbstract
Nanotechnology has possible potential for developing future clinical applications. Nanoparticles may be used for biological and medical purposes due to their opportunities for multi-modal systems. Moreover, carbon nanostructures have received considerable attention in biomedicine. As an example, carbon nanomaterials have been extensively used to deliver therapeutic molecules in multi-functional controlled release systems. Carbon nanostructures may be used as nanocarriers, owing to their large surface area, privileged cumulation in tumors and excellent internalization in cancer cells. Carbon nanostructures may be used to deliver therapeutic agents preferentially to cancer tissues, to decrease side effects and cytotoxicity of drugs. However, the intrinsic cellular toxicity of carbon nanostructures remains a challenge. This chapter represents different characteristics of carbon nanostructures, resulting in their various applications in localized controlled drug delivery systems. Recent progress in methods and techniques for biofunctionalization, delivering and targeting by carbon nanostructures are presented and discussed.
2.1. Introduction
Cancer is one of the popular diseases in the 21st century. The treatment of cancer using chemotherapy methods has adverse influences and may have incomplete and different therapeutic reactions in different cases. Therefore, researchers have scrutinized various controlled release carriers to help control and target cancer drug delivery inside the lesion and potentially overcome the aforementioned issues. A variety of stimuli-responsive controlled release carriers have been explored for further progress in therapeutic efficacy. A specific group of studies has focused on the application of nanoscience and technology, for therapeutic applications, which have shown positive results in animal experiments. Stimuli-responsive drug delivery is studied to achieve controlled drug release and cell uptake in tumor region under stimulations, to further increase effectivity and reduce side effects (Yang et al., 2016).
Carbon allotropes are the result of different chemical bondings (covalent) between carbon atoms. Each carbon allotrope owns unique physicochemical characteristics due to the exclusive spatial organization of carbon atoms. Graphite, graphene, carbon nanotube, and diamond are examples of carbon allotropes. Graphene has characteristics such as simple fabrication and modification, low cost, two external surfaces, high surface area, and non-toxicity compared to carbon nanotubes (CNTs). Therefore, graphene may be superior to CNT in many applications, such as drug delivery, due to its lower toxicity and higher biocompatibility (Bitounis et al., 2013, Liu et al., 2013).
In general, nanocarriers can enter the cell and interact with the cell membrane by endocytosis. In the targeted delivery of drugs to the cell nucleus, it is vital for the drug to pass the endosomal section and reach the cytosolic section. Functionalized carbon-based nanomaterials are a group of materials that can be used in stimuli-responsive drug delivery systems. Carbon-based materials, and specifically graphene, can conjugate with numerous natural polymers, such as gelatin and chitosan, for controlled release purposes. These biocompatible polymers are biodegradable, cytocompatible, and have low immunogenicity, which can be used to decrease the toxic effects of graphene (Goenka et al., 2014). In the following sections, a summary of each carbon-based material is discussed.
2.2. Graphene
Carbon is the most widespread element in our living ecosystems, which is biologically and environmentally safer compared to inorganic materials (Chung et al., 2013). Graphene is composed of a single layer of carbon atoms with a hexagonal lattice structure. In this 2D planar structure, each carbon atom has an sp2 hybridization and includes 4 bonds which are r and π bonds. Graphene can be synthesized using both top-down approaches such as mechanical exfoliation methods, and bottom-up approaches such as chemical vapor deposition (CVD). The electronic and crystalline properties of graphene produced via CVD are better compared to graphene synthesized by the graphite. Graphene has properties such as high thermal conductivity (~5000 W/m/K), high mechanical strength (Young’s modulus, ~1100 Gpa), tunable bandgap, high intrinsic mobility, high electric conductivity (mobility of charge carriers, 200,000 cm2 V-1 s-1), and large surface area (2630 m2/g). Graphene may be categorized as a hydrophobic material and, because of the absence of oxygen groups, counts as a hydrophobic material (Shareena et al., 2018, Shen et al., 2012, Rao et al., 2009, Imani et al., 2018).
The unique properties of graphene have resulted in the wide application of this material in different fields such as biosensors, nanoelectronic devices, drug delivery, etc. (Salahandish et al., 2019). Moreover, the two-dimensional network of graphene decreases its toxicity in biomedical applications (Chung et al., 2013, Sattari et al., 2017
