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In this chapter, the authors present literature and discuss some applications of plant-derived edible nanoparticles (NPs) in cancer drug delivery. Plant-derived edible nanoparticles (PDENs) obtained from grapefruit, ginger, tomatoes, and garlic reportedly have plant-specific monodispersed size distributions, with median diameters of about 400 nm for edible grape NPs, and about 250 nm for edible grapefruit and ginger NPs. In contrast, edible carrot NPs has two such distributions, one about 100 nm and the other about 1,000 nm. Plant-derived exosome-like NPs might affect cancer progression, and inhibit cell proliferation in various tumor cell lines. Modified grapefruitderived lipid NPs conjugated with the targeting ligand folic acid mediated the targeted delivery of doxorubicin to Colon-26 tumors in vivo and enhanced the chemotherapeutic inhibition of tumor growth compared with free drug. Findings from these investigations showed that PDENs can be good candidates for the delivery of anti-cancer drugs.

Introduction: Combination therapy has been explored for its potential to reduce or eliminate multidrug resistance in treating different types of cancer including leukemia. Nutraceutical, small molecular drugs, and small interfering ribonucleic acid (siRNA) are some of the effective drugs. In order to avoid off-site targeting, reduce the dosage required, and increase the half-life of the drug in the circulation system, drug delivery vehicles, such as nanoparticles and microfibers have been explored.Areas covered: This review summarizes various therapies utilized in treating leukemia based on their effectiveness in inducing protein inhibition and/or apoptosis. In particular, treatment effectiveness using combination therapy using various devices is addressed. Recently explored drug delivery methods are reviewed, providing examples and their applications in cancer treatment. The drug listing, delivery systems classifications, along with the general modeling approach in this review, provide, to a full extent, a basis for cancer drug delivery future studies.Expert opinion: The reviewer's opinion tackles the potential of using a multi-delivery system to deliver multiple drugs, providing better control upon drug release and targeting. Both local and systemic delivery are considered and explored for their potential targets. Researchers are advised to pre-consider all aspects associated with their desired delivery method.

Fluorination of graphene nanomaterials has multitude merits owing to the peculiar temperament of the carbon-fluorine (C-F) bond. However, the current synthesis modalities of fluorinated graphene (FG) are based on the usage of toxic materials at high temperatures, which are problematic to be used. The methods to overcome these problems are challenging for chemists. Ionic liquids (ILs) have been used in several chemical processes as auxiliaries and eco-friendly alternatives instead of volatile organic solvents because of their properties. Consequently, herein we exploited a highly effective and green process for the synthesis of FG at mild temperature (80 °C) by using ammonium fluoride salt as fluorine agent and a synthesized acidic IL ([TEA]+[TFA]–) as a solvent. Our goal was to synthesize enriched FG with a high degree of fluorination (66.4 wt.% of F) and F/C ratio (2.2), which measured and confirmed by XPS analysis. Subsequently, the obtained FG was used as a nanocarrier for delivery of curcumin to cancerous cells. The in-vitro results showed that these nanosheets possessed a higher Cur-loading efficiency (78.43%) than commercial FG (52.12%) due to the sheet-like structure with folded edges. This, in turn, translated into an excellent in-vitro anti-cancer effect when tested against cancerous cells.

Due to the great progress of nanotechnology in clinical application, numerous types of small drug delivery systems have been developed and utilized to improve the efficacy of anti-cancer drugs. Due to their excellent physiological properties, stimuli-responsive systems or “smart” systems that are able to release the drug at the desire site within the human body have received much interest in biomedical and cancer drug delivery. Herein, the recent advances and progress in the design and development of various stimuli-responsive drug delivery systems and their mechanisms of action are discussed in details.

Background: Chemotherapy, the predominant cancer treatment modality, suffers from elimination in renal and hepatic systems causing reduced bioavailability and increased toxicity leading to harmful side effects. Targeted release of formulations encapsulated in protective biocompatible polymer or polymer-lipid microbubbles can improve bioavailability and potency while reducing systemic toxicity, resulting in a higher therapeutic index. Objective: Double emulsion, the most common method for microbubble fabrication suffers from low encapsulation efficiency and wide size distributions. In this concise article, we analyze the emergent coaxial electrospray technique vis-à-vis established double emulsion methods to manufacture biocompatible polymer microbubbles for targeted drug delivery systems. Method: Specifically, we investigate size, morphology, and encapsulation efficiencies of microbubbles fabricated using double emulsion and coaxial electrospray techniques. Results: We found that microbubbles produced via coaxial electrospray displayed higher encapsulation efficiency and a narrower size distribution. Conclusion: Coaxial electrospray is a promising technology with considerably improved size distribution and encapsulation efficiency; however, reproducibility across facilities and scale remain challenging.

Regenerative medicine seeks to assess how materials fundamentally affect cellular functions to improve retaining, restoring, and revitalizing damaged tissues and cancer therapy. As potential candidates in regenerative medicine, hydrogels have attracted much attention due to mimicking of native cell-extracellular matrix (ECM) in cell biology, tissue engineering, and drug screening over the past two decades. In addition, hydrogels with a high capacity for drug loading and sustained release profile are applicable in drug delivery systems. Recently, self-healing supramolecular hydrogels, as a novel class of biomaterials, are being used in preclinical trials with benefits such as biocompatibility, native tissue mimicry, and injectability via a reversible crosslink. Meanwhile, the localized therapeutics agent delivery is beneficial due to the ability to deliver more doses of therapeutic agents to the targeted site and the ability to overcome post-surgical complications, inflammation, and infections. These highly potential materials can help address the limitations of current drug delivery systems and the high clinical demand for customized drug release systems. To this aim, the current review presents the state-of-the-art progress of multifunctional and self-healable hydrogels for a broad range of applications in cancer therapy, tissue engineering, and regenerative medicine.

Nanomaterials are increasingly used as drug carriers for cancer therapy. Nanomaterials also appeal to researchers in the areas of cancer diagnosis and biomarker discovery. Several antitumor nanodrugs are currently being tested in preclinical and clinical trials and show promise in therapeutic and other settings. We review the development of nanomaterial drug carriers, including liposomes, polymer nanoparticles, dendritic polymers, and nanomicelles, for the diagnosis and treatment of various cancers. The prospects of nanomaterials as drug carriers for future clinical applications are also discussed.

A review of cytotoxicity associated with cancer treatments as presented in literature was discussed. In all the studies, the research is aware of the cytotoxic effects of the cancer drug and the delivery form such as nanotechnology-based delivery. The scope of the review was limited to showing 1) the need for modulating cytotoxicity and 2) how cytotoxicity has been controlled in actual studies on treatment plans in vivo and in vitro. Keywords: Cytotoxicity, in vivo, in vitro, nanotechnology, nanoparticles, apoptosis

Currently, nano-carriers for anti-cancer drug delivery are complex systems, which struggle with immunogenicity and enhanced permeability effect (EPR)-related problems that halt the clinical translation of many therapeutics. Consequently, a rapidly growing field of research has been focusing on biomimetic nano-vesicles (BNVs) as an effective delivery alternative. Nevertheless, the translation of many BNVs is limited due to scalability problems, inconsistent production process, and insufficient loading efficiency. Here we discuss the process of our previously published BNVs, termed Nano-Ghosts (NGs), which are produced from the membrane of mesenchymal stem cells. We demonstrate the flexibility of the process, while alternating physical methodologies (sonication or extrusion) to produce the NGs while preserving their desired characteristics. We also show that our NGs can be labeled using multiple methods (fluorescence, radiolabeling, and genetic engineering) for tracking and diagnostic purposes. Lastly, we demonstrate that the loading efficiency can be improved by using electroporation to accommodate a range of therapeutics (small molecules, peptides and DNA) that can be delivered by the NGs. Our results emphasize the robustness of the NGs technology, its versatility and a vast range of applications, differentiating it from other BNVs and leading the way towards clinical translation.

The physicochemical properties of nanoparticles play critical roles in regulating nano-bio interactions. Whereas the effects of the size, shape, and surface charge of nanoparticles on their biological performances have been extensively investigated, the roles of nanoparticle mechanical properties in drug delivery, which have only been recognized recently, remain the least explored. This review article provides an overview of the impacts of nanoparticle mechanical properties on cancer drug delivery, including (1) basic terminologies of the mechanical properties of nanoparticles and techniques for characterizing these properties; (2) current methods for fabricating nanoparticles with tunable mechanical properties; (3) in vitro and in vivo studies that highlight key biological performances of stiff and soft nanoparticles, including blood circulation, tumor or tissue targeting, tumor penetration, and cancer cell internalization, with a special emphasis on the underlying mechanisms that control those complicated nano-bio interactions at the cellular, tissue, and organ levels. The interesting research and findings discussed in this review article will offer the research community a better understanding of how this research field evolved during the past years and provide some general guidance on how to design and explore the effects of nanoparticle mechanical properties on nano-bio interactions. These fundamental understandings, will in turn, improve our ability to design better nanoparticles for enhanced drug delivery.

In this final chapter we review the sequential developments that have led to the range of choices now available for treating various types of cancer at different stages, summarise the methodological advances described in this book and discuss promising avenues for future progress of drug delivery systems.

The nonhazardous radiofrequency (RF)-aided cancer treatment is very famous in the oncology field as it is highly penetrable in deep-rooted cancers, enabling better therapeutic efficacy. Recently various research works have focused on RF-sensitive nanocarriers for drug delivery applications. This chapter briefs about different RF-sensitive therapeutic nanocarriers based on metals and nonmetals for anticancer drug delivery. Additionally, more emphasis is placed on their applications and future perspectives.

© The Author(s) 2019., [Background]: Lack of effective tumor-specific delivery systems remains an unmet clinical challenge for successful translation of innovative therapies, such as, therapeutic oligonucleotides. In the past decade, exosomes have been suggested to be ideal drug delivery systems with application in a broad range of pathologies including cancer, due to their organotropic properties. Tumor-derived exosomes, having tumor-homing properties, can efficiently reach cancer cells and therefore behave as carriers for improved drug delivery to the primary tumor and metastases. However, due to their complex composition, and still undefined biological functions, safety concerns arise hampering their translation to the clinics., [Results]: We propose here the development of exosome-mimetic nanosystems (EMNs) that simulate natural tumor-derived exosomes with respect to their structure and functionality, but with a controlled composition, for the targeted delivery of therapeutic oligonucleotides to lung adenocarcinoma cells (microRNA-145 mimics). Making use of the well-known liposome technology, EMNs can be engineered, loaded with the therapeutic compounds, and tailored with specific proteins (integrin α6β4) providing them organotropic properties. EMNs show great similarities to natural exosomes with respect to their physicochemical properties, drug loading capacity, and ability to interact with the cancer target cells in vitro and in vivo, but are easier to manufacture, can be produced at high yields, and are safer by definition., [Conclusions]: We have designed a multifunctional nanoplatform mimicking exosomes, EMNs, and proved their potential to reach cancer cells with a similar efficient that tumor-derived exosomes but providing important advantages in terms of production methodology and regulations. Additionally, EMNs are highly versatile systems that can be tunable for a broader range of applications., This work was in part supported by grants from Instituto de Salud Carlos III (ISCIII) and European Regional Development Fund (FEDER) (CP12/03150, PI15/00828, and CB16/12/00328 from M.F. and PI16/0014, CIBERONC CB16/12/00295 from G.M.B). A.V.R. also acknowledges the fnancial support from the Spanish Ministry of Education, Culture, and Sport (FPU15/06595).

Cell-mediated drug delivery systems have attracted significant research interest in the past years owing to their superior properties such as excellent biocompatibility, potential long circulation, intrinsic homing properties, and ability to permeate biological barriers. Macrophages, as one of the major phagocytes of the innate immune system, represent a promising target for cancer drug delivery because, on the one hand, they play critical roles in the tumor microenvironment in various stages of tumor progression and, on the other hand, they can be harnessed as Trojan horses for enhanced drug delivery. This article provides a mini-review of the different aspects of macrophages for cancer therapy including tumor-associated macrophages (TAMs) in the tumor microenvironment, novel cancer treatment targeting TAMs, and nanoparticle-loaded macrophages as tumor-infiltrating drug carriers.

Over the past years, the emergence of various therapeutic approaches has attracted so much consideration, but chemotherapy remains the most effective way in experimental practice. However, due to obstacles and difficulties, there is a limitation for the additional clinical presentation of the outdated chemical treatments such as paclitaxel and doxorubicin. Some of the barriers are severe side effects, profound cytotoxicity, and low therapeutic efficacy. Drug delivery systems (DDS) such as polymeric micelles have been technologically advanced over the recent decades to advance the treatment efficacy and lessen the side effects incurred. The polymeric micelles self-assembled from amphiphilic polymers serve to sum up hydrophobic treatments in the core and regulate the discharge profile of the drugs through response towards stimuli of the tumor microenvironments, which in this case are pH, temperature, light, and reduction.

Research for synthesis of size-controlled carriers is currently challenging one. In this research paper, a method for size-controlled synthesis of biodegradable nanocarriers is proposed and described. Salting out method is suitable for both hydrophilic and hydrophobic drugs for the encapsulation on carriers. This synthetic method is based on polylactic acid (PLA) and non-ionic carboxymethyl cellulose (CMC) composed by CaCl2 as salting out agent. This method permits size-controlled synthesis of particles between 50 and 400 nm simply by varying the concentration of salting out agents. We have prepared cisplatin (CDDP)-loaded PLA-CMC nanocarriers by salting out method, with varying salting out agent (CaCl2) concentrations as 0.05, 0.2, 0.35 and 0.5 M. The nanocarriers were characterized for their size, surface charge and morphology by atomic force microscope, zeta potential analyser and transmission electron microscope, respectively. The encapsulation efficiency and in-vitro drug-releasing behaviour of the nanocarriers were investigated. The cytotoxicity effect of nanocarriers and drug-loaded nanocarriers was tested against MCF-7 breast cancer cell line.

Filomicelles and nanoworms are an emerging subclass of nanomaterials with a special elongated shape. The physical properties of a filomicelle are distinct from a traditional spherical micelle, and as such have attracted tremendous interest in a variety of research areas. In this review, we highlight the substantial progress in the synthesis and application of polymeric nanoworms over the past two decades. Synthetic techniques summarized in this review are particle replication in nonwetting templates (PRINT), film stretching, self-assembly (SA), crystallization-driven self-assembly (CDSA), polymerization-induced self-assembly (PISA), and temperature-induced morphological transformation (TIMT). The applications of filomicelles as (i) templates for inorganic nanoparticles, (ii) building blocks for superstructures, (iii) synthetic dendritic cells for immunotherapy, (iv) constituents of thermoresponsive gels for biomedical applications, and (v) nanocarriers for cancer drug delivery are subsequently discussed. In the conclusion, we describe the current trajectory of research in the field and identify areas where further developments are of urgent need.

Nanoparticles (NPs) have been continuously utilized for different implementations, most particularly for cancer drug delivery. A large number of NP-based drug delivery systems (DDSs) have been explored for cancer therapy and a variety of materials have been investigated as potential drug delivery materials to ameliorate the therapeutic potency and harmlessness of anticancer drugs. Proteins NPs like albumin, lactoglobulin and gelatin are considered as outstanding alternatives to be formulated into the nanostructure platforms in conjugation with anticancer drugs because of their safety, biodegradability and biocompatibility. Also, their uncomplicated preparation and modification can be carried out under mild conditions with no concern toward the utilization of hazardous reagents. Therefore, in this paper we present an overview on the different methods for formulation of protein nanostructure including emulsification, simple desolvation/coacervation, complex coacervation (self-assembled), and electrospray. We then review the application of protein NPs especially gelatin NPs (GNPs) as potential candidates in DDSs which can be achieved through internal [pH, matrix metalloproteinase (MMP)] stimuli-responsive smart platforms for cancer therapy. Finally, many of the current challenges, future development of GNPs and their integration into clinical practice were discussed. This paper may pave the way to disclose some details about the healthcare transformation of GNPs toward precision medicine.

184 Background: Oral systemic therapy (ST) presents unique care delivery challenges. Gaps in patient education and monitoring for patients on oral ST delivery are well documented and can result in decreased adherence or increased toxicity. Within Ontario, cancer care is provincially coordinated through Ontario Health- Cancer Care Ontario (OH-CCO), but locally implemented by 14 Regional Cancer Programs (RCPs). Using a centrally coordinated, but regionally implemented quality improvement (QI) approach, we aimed to improve the quality of oral ST delivery across Ontario by enabling the use of patient specific monitoring plans to optimize treatment adherence and toxicity management. Methods: Between 2018 and 2020 a 2 year focused QI project was undertaken. A suite of 19 quality measures were developed to measure different quality domains for oral ST delivery including treatment plan documentation, patient education, toxicity/adherence monitoring and toxicity outcomes. In year 1, all regions used the suite of quality measures to establish baseline performance and develop a QI plan using rapid cycle improvement methodology to improve performance in at least 1 domain based on regional gaps and priorities. Projects were implemented and evaluated during year 2. OH-CCO provided QI coaching through dissemination of standardized QI tools, a monthly discussion forum and project specific feedback. At the end of year 2, a post-implementation evaluation was performed for each region. Results: 15 centers participated, representing all RCPs across Ontario. The participating centers implemented QI projects focused on treatment plan documentation (N = 3), patient education (N = 10) and toxicity/adherence management (N = 5), with some focusing on multiple domains. All centers reported an improvement in at least 1 domain (see Table). Key enablers identified include engagement with a multi-disciplinary team and the use of technology, while barriers include lack of onsite dispensing pharmacy. Future work will continue to focus on quality of oral ST delivery and better pharmacy integration. Conclusions: Through a centrally coordinated, locally implemented QI project, improvement in quality of oral ST care was achieved across Ontario. This model of QI focus has the potential to be adaptable across health systems. [Table: see text]

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Based on exceptional advantages of aptamers, increasing attention has been presented in the utilise of them as targeted ligands for cancer drug delivery. Recently, the progress of aptamer-targeted nanoparticles has presented new therapeutic systems for several types of cancer with decreased toxicity and improved efficacy. We highlight some of the promising formulations of aptamer-conjugated polymeric nanoparticles for specific targeted drug delivery to cancer cells. This review paper focuses on the current progresses in the use of the novel strategies to aptamer-targeted drug delivery for chemotherapy. An extensive literature review was performed using internet database, mainly PubMed based on MeSH keywords. The searches included full-text publications written in English without any limitation in date. The abstracts, reviews, books as well as studies without obvious relating of aptamers as targeted ligands for cancer drug delivery were excluded from the study. The reviewed literature revealed that aptamers with ability to modify and conjugate to various molecules can be used as targeted cancer therapy agents. However, development of aptamers unique to each individual's tumour to the development of personalised medicine seems to be needed.

Nature has designed nanosized particles, specifically viruses, equipped to deliver cargo to cells. We report the chemical bioconjugation and shape shifting of a hollow, rod-shaped tobacco mosaic virus (TMV) to dense spherical nanoparticles (SNPs). We describe methods to transform TMV rods to spheres, load TMV rods and spheres with the chemotherapeutic drug, doxorubicin (DOX), to deliver modified particles to breast cancer cells, and to determine the IC50 values of the plant virus-based drug delivery system.

Delivery of a cancer therapeutic to its intended extracellular or intracellular target, which is required for achieving therapeutic efficacy, involves multiple kinetic processes. This chapter outlines the complex and dynamic biological properties of solid tumors that may limit the therapeutic from reaching its target, and describes the application of chemical engineering tools (e.g., multiscale modeling and computational fluid dynamics) in quantitative systems pharmacology research. The discussions include both conventional small-molecule drugs and nanotherapeutics as the latter represents a new promising therapeutic strategy in translational cancer research. Examples of our earlier work demonstrate the successful use of computational modeling to predict drug delivery in solid tumors as functions of time and intratumoral location and to use such predictions for therapy development in cancer patients.

Spatial and temporal control over drug release has rendered stimuli-responsive nanoparticles to be one of the most popular cancer drug delivery systems. Nanomaterial-based photo-triggered drug delivery (PDD) encompasses the advantages of stimuli-responsive drug delivery by utilizing light in conjunction with a photosensitizer, drug, or imaging agent to trigger and enhance a diagnosis and increase therapeutic efficacy. Thus, by localizing these nanomaterials specifically at the tumor site, researchers have successfully achieved cancer cell-specific drug delivery, therapy, and diagnosis. This chapter explores these state-of-the-art nanomaterial based-PDD technologies for cancer theranostics. We will revisit several applications and mechanisms of PDD and review various factors to be considered while developing a PDD system. Finally, the limitations and the future of PDD will also be briefly discussed.

Calcium carbonate (CaCO3) has broad biomedical utilizations owing to its availability, low cost, safety, biocompatibility, pH-sensitivity and slow biodegradability. Recently, there has been widespread interest in their application as drug delivery systems for different groups of drugs. Among them, CaCO3 nanoparticles have exhibited promising potential as drug carriers targeting cancer tissues and cells. The pH-dependent properties, alongside the potential to be functionalized with targeting agents give them the unique property that can be used in targeted delivery systems for anticancer drugs. Also, due to the slow degradation of CaCO3 matrices, these nanoparticles can be used as sustained release systems to retain drugs in cancer tissues for longer times after administration.Development of drug delivery carriers using CaCO3 nanoparticles has been reviewed. The current state of CaCO3 nanoparticles as cancer drug delivery systems with focus on their special properties like pH-sensitivity and biodegradability has also been evaluated.According to our review, CaCO3 nanoparticles, owing to their special characteristics, will have a potential role in safe and efficient cancer treatment in future.

Polymeric nanoparticles and liposomes have been the platform of choice for nanoparticle-based cancer drug delivery applications over the past decade, but extensive research has revealed their limitations as drug delivery carriers. A hybrid class of nanoparticles, aimed at combining the advantages of both polymeric nanoparticles and liposomes, has received attention in recent years. These core/shell type nanoparticles, frequently referred to as lipid–polymer hybrid nanoparticles (LPNs), possess several characteristics that make them highly suitable for drug delivery. This review introduces the formulation methods used to synthesize LPNs and discusses the strategies used to treat cancer, such as by targeting the tumor microenvironment or vasculature. Finally, it discusses the challenges that must be overcome to realize the full potential of LPNs in the clinic. Published version

This paper presents chemotherapy scheduling of cancer patients using type 1 and type 2 fuzzy logic controllers which are optimized by genetic algorithm. To handle the uncertainties of the model, we introduce a method to adjust the foot print of uncertainty (FOU) in interval type 2 (IT2) fuzzy systems based on the amount of uncertainty. Based on previous researches, type two fuzzy logic is more effective than type 1 in handling uncertainties in a model. According to this fact, proposed method tries to change the FOU of fuzzy sets adaptively based on the amount of uncertainty in counting tumor cells which always exist in real world. In addition, we have introduced two new indices to evaluate the results. Simulation results show that the proposed method can control the drug regimens better than IT2 and type 1 (IT1) fuzzy controllers.