Localized Micro/Nanocarriers for Programmed and On-Demand Controlled Drug Release

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. 

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. 

Polymeric and biopolymeric materials and nanostructures have been extensively used in drug delivery, and especially in the development of localized controlled drug delivery systems (LCDDS). Stimuli-sensitive biopolymeric materials are achieving remarkable consideration as smart multipurpose systems that exhibit superb potential in several applications. LCDDS allow high delivery levels at the target area, low cytotoxicity, excellent biocompatibility and prolonged drug exposure that can be helpful for targeted cellular therapeutic molecules. This chapter focuses on synthetic and natural degradable biopolymeric materials for LCDDS, focusing on their advantages, challenges, and clinical applicability. Recent progress in typical and stimuli-sensitive biopolymeric materials has also been reviewed. The features of biodegradable polymers and biopolymers for various purposes are discussed, and the advantages of these materials and biomaterials are highlighted. Moreover, different emerging functions of these polymers in a drug delivery system are discussed.

Carbon nanostructures such as carbon nanotubes, graphene, graphene oxide and their derivatives, have been recognized in biomedicine and drug delivery, due to their outstanding optical, mechanical, thermal, and electrical characteristics. Carbon nanostructures/ polymer composites with various active and functional groups provide many binding sites for inorganic/organic species and biomolecules and are described as favorable candidates to label and drag different drugs, genes, proteins and therapeutic molecules. This chapter focuses on studies about the deployment of nanostructures/ polymer composites, for efficient drug delivery, especially localized controlled drug/gene delivery systems (LCDDS). Effects of various parameters and features, including composite microstructures, hydrophobicity and hydrophilicity of composites, glass transition and polymer matrix molecular weight, on LCDDS are fully examined and discussed. 

Localized controlled drug delivery systems (LCDDSs) have become the main topic in drug delivery, tissue engineering and pharmaceutical science by enhancing formulations and processes of controlled delivery. The side effects and problems of materials/biomaterials are critical and may lead to several issues, such as reducing the effective drug dose, delaying the treatment process, and not having a particular continuous treatment. Therefore, composites composed of hybrid materials/biomaterials with excellent release properties, biocompatibility, stability and biodegradability, with local adjusted release rates, are an alternate choice for protective drug delivery. Several approaches to fabricating composite-based LCDDSs include emulsification-solvent evaporation, spray drying, electrospraying, supercritical fluids processing, microfluidics, and nanoprecipitation/solvent displacement and emulsion. This chapter describes the advances in micro/nanoscaled composite-based LCDDSs and their fabrication methods. 

Stimuli-sensitive materials and micro/nanostructures can be manipulated to release their therapeutic drugs in the target site. The release is based on a particular extracellular/cellular stimuli, triggered via physical, biochemical, and chemical changes. The trigger may change the carrier structure/chemistry to release the therapeutic drug at a specific site. When a therapeutic drug is encapsulated with a stimuli-triggered material/polymer, the release may start with changes in structures like charge switching, surface layers de-shedding and degradation of materials. Furthermore, the disruption of the bonds may result in the release of therapeutic agents that are covalently immobilized in the functional groups of materials. Exogenous stimuli are the activation of reactions/phenomena from outside the body, such as ultrasound, temperature and light. Herein, we will describe thermosensitive, lightsensitive, and ultrasound-sensitive controlled drug release of LCDDS, as the mentioned exogenous stimuli have been extensively used in LCDD applications.

Responsive and smart materials/biomaterials are responsive/sensitive to signals originating from physiological systems, or to abnormalities originating from pathological defects that can interact with or be triggered by the biological environments. Responsive and smart materials/biomaterials are interesting in drug delivery platforms/devices for developing next-generation accurate medicines. For a deeper consideration of the different endogenous-responsive mechanisms of materials and biomaterials, many researches have been established for the development of micro/nano-fabrication, pharmaceutical science, biomedical engineering and materials chemistry to improve endogenous-responsive biomaterials for various drug delivery applications, such as medical bio-devices, drug delivery, localized controlled drug delivery systems (LCDDS), tissue engineering and theranostics. This chapter reports and discusses significant developments and progresses in the design and fabrication of endogenous-responsive LCDDS that have the ability to control or regulate the distribution of therapeutic agents (drugs) in response to a specific endogenous stimulus (changes in redox, pH, enzyme and oxidation).

Nanoparticles (NPs) and nanostructures can facilitate multianalyte detection, imaging and selective targeting of therapeutic molecules to cancer cells. This method increases the drug dose and maximizes at the anticipated location, and the healthy cells/tissues and their environments are protected simultaneously. To develop the targeting potential of therapeutic molecules, the surface and size characteristics of NPs should be improved, thereby enhancing their targeting effectiveness and circulation time. Here, we have highlighted recent advances and progress in smart stimuli-sensitive nanocarriers synthesized to improve the efficiency and localization of drugs compared to unmodified drugs. Multifunctional NPs could enhance the controlled release and targeting ability of drugs/therapeutic agents/biomolecules. The smart multifunctionality establishes versatile NPs, moreover, localized controlled drug delivery systems (LCDDSs) are promising and considerably increase the efficiency of therapy and diagnosis (theranosis) in pharmaceutical and biomedical science/engineering. 

Patients may show various defects to medications depending on race, gender, fitness, age, pharmacokinetic and health conditions. To address this challenge, there is a need to establish personalized, on-demand, programable and smart carriers that can control drug release with new and robust techniques. Additive manufacturing (AM) is the key sustenance of digital technology that has been developing and growing recently. AM offers several opportunities in localized controlled drug delivery systems (LCDDS), including materials recycling as well as on-site manufacturing, design freedom and full customization. Moreover, the industrial, biomedical and academic requests for AM for LCDDS have been continually rising, demonstrating significant marks for an extensive range of products. This chapter outlines AM approaches and their functions for LCDDS and describes AM technologies, such as recent advances in controlled drug release, as well as their processed materials and working principles. Furthermore, the benefits of 3D printing in the progressions of the LCDDS, the advantages of 4D printing, the impression of designing and material selection in these techniques are discussed. Finally, the potentials of AM approaches and their LCDD applications that designate a promising healthcare future are described.