Can dendrimer based nanoparticles fight neurodegenerative diseases? Current situation versus other established approaches

For several decades, the treatment of central nervous system (CNS) disorders such as, for instance, Alzheimer’s disease (AD), Huntington’s disease (HD), and Parkinson’s disease (PD) represented an important challenge due to the difficulty in delivering drug molecules and imaging agents to the brain. Two strategies have been developed aimed at achieving the efficient delivery of drugs to the brain: invasive (e.g., temporary osmotic Blood Brain Barrier (BBB) opening, direct local delivery of nanoparticles with encapsulated CNS drugs etc.) and noninvasive approaches. As a part of the noninvasive approach among systemic delivery of drug molecules across BBB using nanocarriers, dendrimers represent promising therapeutics agents per se or nanocarriers of CNS drugs and for gene therapies. This original review emphasizes and analyzes the use of dendrimers as promising systems in the treatment of AD and PD, ischemia/reperfusion injury, neuroinflammation including cerebral palsy, neurological injury after cardiac surgery and particularly after hypothermic circulatory arrest, and for retinal degeneration purposes.     

Design and Development of Nanomaterial-Based Drug Carriers to Overcome the Blood–Brain Barrier by Using Different Transport Mechanisms

Central nervous system (CNS) diseases are the leading causes of death and disabilities in the world. It is quite challenging to treat CNS diseases efficiently because of the blood–brain barrier (BBB). It is a physical barrier with tight junction proteins and high selectivity to limit the substance transportation between the blood and neural tissues. Thus, it is important to understand BBB transport mechanisms for developing novel drug carriers to overcome the BBB. This paper introduces the structure of the BBB and its physiological transport mechanisms. Meanwhile, different strategies for crossing the BBB by using nanomaterial-based drug carriers are reviewed, including carrier-mediated, adsorptive-mediated, and receptor-mediated transcytosis. Since the viral-induced CNS diseases are associated with BBB breakdown, various neurotropic viruses and their mechanisms on BBB disruption are reviewed and discussed, which are considered as an alternative solution to overcome the BBB. Therefore, most recent studies on virus-mimicking nanocarriers for drug delivery to cross the BBB are also reviewed and discussed. On the other hand, the routes of administration of drug-loaded nanocarriers to the CNS have been reviewed. In sum, this paper reviews and discusses various strategies and routes of nano-formulated drug delivery systems across the BBB to the brain, which will contribute to the advanced diagnosis and treatment of CNS diseases.     

Functional amphiphilic and biodegradable copolymers for intravenous vectorisation

This paper aims at reporting on the design of polymeric drug nanocarriers used in cancer therapy, with a special emphasis on the control of their biodistribution. First, the prominent role of poly(ethylene oxide) in the lifetime of nanocarriers circulating in the blood stream is highlighted, and the origin of a passive targeting based on a difference in the anatomy of tumors and normal tissues is discussed. The main body of the review is devoted to the targeting of nanocarriers towards tumors and the underlying concepts. As a rule, either the constitutive polymer is stimuli-responsive and the locus of drug release is where the stimulation occurs, or a ligand endowed with specific recognition is grafted onto the nanocarrier. Finally, the fate of the nanocarrier after drug delivery and the bioelimination of the polymer(s) involved are briefly considered.     

Poly(l‐histidine)‐containing polymer bioconjugate hybrid materials as stimuli‐responsive theranostic systems

For decades, researchers have aspired to develop materials for noninvasive treatment and monitoring of pathological conditions. Various organs, tissues, subcellular compartments, and their pathophysiological states can be characterized by their pH values. pH‐dependent intracellular tumor targeting has received particular attention due to the unique acidic environment of the solid tumors created by physiological and metabolical abnormalities. Responsive nanocarriers, when exposed to these pH stimuli, respond quickly to the physicochemical changes by undergoing structural deformations, such as swelling and phase transition, which favors the drug release specifically at the diseased site. Recently, researchers have developed several new poly(L ‐histidine) (p(His))‐based pH responsive systems for sustained drug release and molecular targeting. This review focuses on the p(His)‐based pH responsive nanocarriers, which are utilized in biomedical applications such as anti‐cancer drug delivery and nucleic acid delivery. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40796.     

Advances in drug delivery systems based on synthetic poly(hydroxybutyrate) (co)polymers

Within the general context of nanomedicine, drug delivery systems based on polymers have sparked a rapidly growing interest and raised many efforts to tackle various diseases, among which cancer. Polyester-based nanoparticulate drug delivery systems, including polymer-drug conjugates and amphiphilic block copolymers, represent a major class with promising outcomes, especially for those derived from poly(3-hydroxybutyrate) (PHB). This review describes recent advances in drug delivery systems designed from the self-assembly of synthetic (co)polymers derived from PHB. The various strategies for the synthesis of PHB-conjugates, PHB/poly(ethylene glycol) (PEG) and other PHB-based copolymers are first summarized. Nanoparticles, micelles, microparticles, and hydrogels elaborated from these (co)polymers following various preparation methods, along with their exploitation in the encapsulation and release of various therapeutic agents, are next detailed. Finally, we discuss the synthetic challenges, drug delivery outlooks, and perspectives of PHB-based drug delivery systems. Engineered nano-scaled materials based on PHB self-assembled systems are thus anticipated to emerge as a valuable platform for original drug delivery systems.     

Responsive theranostic systems: integration of diagnostic imaging agents and responsive controlled release drug delivery carriers

For decades, researchers and medical professionals have aspired to develop mechanisms for noninvasive treatment and monitoring of pathological conditions within the human body. The emergence of nanotechnology has spawned new opportunities for novel drug delivery vehicles capable of concomitant detection, monitoring, and localized treatment of specific disease sites. In turn, researchers have endeavored to develop an imaging moiety that could be functionalized to seek out specific diseased conditions and could be monitored with conventional clinical imaging modalities. Such nanoscale detection systems have the potential to increase early detection of pathophysiological conditions because they can detect abnormal cells before they even develop into diseased tissue or tumors. Ideally, once the diseased cells are detected, clinicians would like to treat those cells simultaneously. This idea led to the concept of multifunctional carriers that could target, detect, and treat diseased cells. The term "theranostics" has been created to describe this promising area of research that focuses on the combination of diagnostic detection agents with therapeutic drug delivery carriers. Targeted theranostic nanocarriers offer an attractive improvement to disease treatment because of their ability to execute simultaneous functions at targeted diseased sites. Research efforts in the field of theranostics encompass a broad variety of drug delivery vehicles, imaging contrast agents, and targeting modalities for the development of an all-in-one, localized detection and treatment system. Nanotheranostic systems that utilize metallic or magnetic imaging nanoparticles can also be used as thermal therapeutic systems. This Account explores recent advances in the field of nanotheranostics and the various fundamental components of an effective theranostic carrier.     

Polymer-functionalized carbon nanotubes in cancer therapy: a review

The increasing importance of nanotechnology in the field of biomedical applications has encouraged the development of new nanomaterials endowed with multiple functions. Novel nanoscale drug delivery systems with diagnostic, imaging and therapeutic properties hold many promises for the treatment of different types of diseases, including cancer, infection and neurodegenerative syndromes. Carbon nanotubes (CNTs) are both low-dimensional sp² carbon nanomaterials exhibiting many unique physical and chemical properties that are interesting in a wide range of areas including nanomedicine. Since 2004, CNTs have been extensively explored as drug delivery carriers for the intracellular transport of chemotherapy drugs, proteins and genes. In vivo cancer treatment with CNTs has been demonstrated in animal experiments by several different groups. Herein, the recent works on anticancer drug delivery systems based on carbon nanotubes are reviewed and some of more specific and important novel drug delivery devices are discussed in detail. This paper focuses on modifications of CNTs by polymers through covalent and non-covalent attachments: two different methods as critical steps in preparation of anticancer drug delivery systems from CNTs. In this respect the in vivo and in vitro behaviors and toxicity of the CNTs modified by polymers are summarized as well. Well-functionalized CNTs did not show any significant toxicity after injection into mice. Moreover, administration and excretion of CNT-based nanocarriers are discussed. It was concluded that future development of CNT-based nanocarriers may bring novel opportunities to cancer diagnosis and therapy.     

Polyaminoacid Based Core@shell Nanocarriers of 5-Fluorouracil: Synthesis,Properties and Theranostics Application

Cancer is one of the most important health problems of our population, and one of the common anticancer treatments is chemotherapy. The disadvantages of chemotherapy are related to the drug’s toxic effects, which act on cancer cells and the healthy part of the body. The solution of the problem is drug encapsulation and drug targeting. The present study aimed to develop a novel method of preparing multifunctional 5-Fluorouracil (5-FU) nanocarriers and their in vitro characterization. 5-FU polyaminoacid-based core@shell nanocarriers were formed by encapsulation drug-loaded nanocores with polyaminoacids multilayer shell via layer-by-layer method. The size of prepared nanocarriers ranged between 80–200 nm. Biocompatibility of our nanocarriers as well as activity of the encapsulated drug were confirmed by MTT tests. Moreover, the ability to the real-time observation of developed nanocarriers and drug accumulation inside the target was confirmed by fluorine magnetic resonance imaging (¹⁹F-MRI).     

In Vitro and in Vivo Evaluation of Lactoferrin-Conjugated Liposomes as a Novel Carrier to Improve the Brain Delivery

In this study, lactoferrin-conjugated PEGylated liposomes (PL), a potential drug carrier for brain delivery, was loaded with radioisotope complex, ^99mTc labeled N,N-bis(2-mercaptoethyl)-N′,N′-diethylethylenediamine (^99mTc-BMEDA) for in vitro and in vivo evaluations. The hydrophilicity of liposomes was enhanced by PEGylation which was not an ideal brain delivery system for crossing the blood brain barrier (BBB). With the modification of a brain-targeting ligand, lactoferrin (Lf), the PEGylated liposome (PL) might become a potential brain delivery vehicle. In order to test the hypothesis in vitro and in vivo, ^99mTc-BMEDA was loaded into the liposomes as a reporter with or without Lf-conjugation. The mouse brain endothelia cell line, bEnd.3 cells, was cultured to investigate the potential uptake of liposomes in vitro. The in vivo uptake by the mouse brain of the liposomes was detected by tissue biodistribution study. The results indicated that Lf-conjugated PEGylated liposome showed more than three times better uptake efficiency in vitro and two-fold higher of brain uptake in vivo than PEGlyated liposome. With the success of loading the potential Single Photon Emission Tomography (SPECT) imaging probe, ^99mTc-BMEDA, Lf-PL might serve as a promising brain delivery system for loading diagnostics or therapeutics of various brain disorders.     

Saccharide‐based nanocarriers for targeted therapeutic and diagnostic applications

Many therapeutic and diagnostic agents suffer from short circulation times or poor selectivity resulting in the need for frequent drug administration and adverse side‐effects. On this basis, selective nanocarriers have been used to address most of the drawbacks via the encapsulation or conjugation of therapeutic and diagnostic agents to allow the targeted release of cargo to diseased sites or tumours, while maintaining low levels of cytotoxicity. Saccharides, which can be classified as monosaccharides, disaccharides and oligo/polysaccharides, have demonstrated great potential in the construction of nanocarriers, as well as the targeted guidance of the nanocarriers to diseased tissues. The fabrication of nanocarriers from natural materials such as polysaccharides affords biodegradability and biocompatibility, and in some instances confers targeting capabilities. The most recent progress in saccharide‐based targeted nanocarriers fabricated via facile one‐pot routes or complex two‐pot synthetic routes is reviewed here, with a particular focus on the high efficiency and flexibility of the one‐pot approach. In addition, inspired by the self‐assembly processes involving saccharides that occur in living organisms, particular emphasis is placed on disease‐targeting nanocarriers that are constructed from or modified by saccharides. © 2018 Society of Chemical Industry     

F3-functionalized nanoscale metal–organic frameworks for tumor-targeting combined chemotherapy and chemodynamic therapy

Nanoscale metal–organic frameworks (nMOFs) have attracted much attention as emerging porous materials as drug delivery carriers. Appropriate surface modification of them can greatly improve stability and introduce biocompatibility and cancer targeting functionality into drug delivery systems. Herein, we prepared nano-sized MIL-101(Fe)-N₃ and loaded anticancer drug doxorubicin (DOX) into it. The synthetic polymer layer Alkyne-PLA-PEG was then attached to the F3 peptide (labeled as Alkyne-PLA-PEG-F3), and the surface of DOX/MIL-101(Fe)-N₃ was covalently modified with it to obtain DOX/MIL-101-PLA-PEG-F3. Nano-sized MIL-101(Fe)-N₃ has high drug loading capacity and the modification of MIL-101(Fe)-N₃ by polymer Alkyne-PLA-PEG not only improved the dispersion, but also avoided the sudden release of the drugs and increased the biocompatibility of nanocarriers. The F3 peptide introduced into the nanocarriers also enabled it to specifically target tumor tissues and achieved active targeted drug delivery. As a nucleolin-mediated endocytosis drug delivery system, DOX/MIL-101-PLA-PEG-F3 can not only deliver anticancer drugs to tumors accurately, but also participate in Fenton-like reaction to generate hydroxyl radicals (•OH) for chemodynamic therapy (CDT), thus enabling combination therapy. It holds great promise as drug candidates to reduce systemic toxicity and improve the efficacy of cancer treatment.     

Folate-Equipped Nanolipoplexes Mediated Efficient Gene Transfer into Human Epithelial Cells

Since recombinant viral vectors have been associated with serious side effects, such as immunogenicity and oncogenicity, synthetic delivery systems represent a realistic alternative for achieving efficacy in gene therapy. A major challenge for non-viral nanocarriers is the optimization of transgene expression in the targeted cells. This goal can be achieved by fine-tuning the chemical carriers and the adding specific motifs to promote cellular penetration. Our study focuses on the development of novel folate-based complexes that contain varying quantities of folate motifs. After controlling for their physical properties, neutral folate-modified lipid formulations were compared in vitro to lipoplexes leading to comparable expression levels. In addition, no cytotoxicity was detected, unlike what was observed in the cationic controls. Mechanistically, the delivery of the transgene appeared to be, in part, due to endocytosis mediated by folate receptor targeting. This mechanism was further validated by the observation that adding free folate into the medium decreased luciferase expression by 50%. In vivo transfection with the folate-modified MM18 lipid, containing the highest amount of FA-PEG₅₇₀-diether co-lipid (w:w; 90:10), at a neutral charge ratio, gave luciferase transgene expression. These studies indicate that modification of lipids with folate residues could enhance non-toxic, cell-specific gene delivery.     

Anticancer drug delivery systems based on inorganic nanocarriers with fluorescent tracers

In recent years, anticancer nanomedicines have mainly been developed for chemotherapy and combination therapy in which the main contributing anticancer drugs are delivered by deliberately designed nano drug delivery systems (nano‐DDSs). Inorganic nanocarriers equipped with fluorescent tracers have become attractive tools to monitor the whole drug delivery and release processes. The fluorescence signal of tracers could be observed concomitantly with drug release, and thus, this strategy is of great benefit to evaluate the therapeutic effects of the nano‐DDSs. This review provides a brief overview about three inorganic nanocarriers for drug delivery, including mesoporous silica, Fe₃O₄, and hydroxyapatite. We mainly discussed about their preparation processes, drug loading capacities, and the development of different fluorescent materials (fluorescent dyes, quantum dots, fluorescent macromolecules, and rare earth metals) hybridized to nanocarriers for real‐time monitoring of drug release both in vitro and in vivo. This review also provides some recommendations for more in‐depth research in future. © 2017 American Institute of Chemical Engineers AIChE J, 64: 835–859, 2018     

Nanoscale carriers for targeted delivery of drugs and therapeutic biomolecules

This review highlights the recent developments in the area of nanocarrier‐based targeted delivery systems for both conventional drugs and therapeutic agents of increased complexity. A challenging objective of targeted drug delivery is the development of novel nanocarriers for the delivery of protein/peptide drugs via the oral, pulmonary and nasal administration routes. The nanocarriers need to be biocompatible, biodegradable, non‐toxic and stable in biological media, to protect their payload and deliver it to desired sites within the body, preferentially in a temporally regulated manner, and on the other hand to be manufactured in a simple scalable manner, with relatively low cost. © 2012 Canadian Society for Chemical Engineering     

Green clay ceramics as potential nanovehicles for drug delivery applications

Considering the recent discoveries on the potential of Clays for turning into an agent of nanotechnology and drug delivery systems, we focused on their different properties as practical nanocarriers for loading/bonding of various drugs. This study introduced a different type of clay as a nanocarrier and attempted to explain its high drug loading capacity, as well as provided data on the superior remedy efficacy of the experimented system. Furthermore, nano-clays displayed a miraculous potential in Nano-Vaccine technology that could be applied for preventing tumor growth and various infectious diseases such as COVID-19, Influenza, pathogenic Escherichia coli (E. coli), and Leptospira.     

Fluorescent Reporters for Drug Delivery Monitoring

Monitoring of drug delivery is an essential technique for innovative medical treatments, including cancer therapy. Fluorescence imaging has become an important tool in tracking drug delivery and thus improving treatment efficacy. Binding fluorescent reporters to therapeutic agents paves the way to real time monitoring of drug delivery and drug distribution in vitro and in vivo. This review discusses fluorescent reporters used in drug delivery monitoring and provides an overview of recent achievements in the development of fluorescence based drug delivery systems.     

Nanoparticle-Mediated Pulmonary Drug Delivery: A Review

Colloidal drug delivery systems have been extensively investigated as drug carriers for the application of different drugs via different routes of administration. Systems, such as solid lipid nanoparticles, polymeric nanoparticles and liposomes, have been investigated for a long time for the treatment of various lung diseases. The pulmonary route, owing to a noninvasive method of drug administration, for both local and systemic delivery of an active pharmaceutical ingredient (API) forms an ideal environment for APIs acting on pulmonary diseases and disorders. Additionally, this route offers many advantages, such as a high surface area with rapid absorption due to high vascularization and circumvention of the first pass effect. Aerosolization or inhalation of colloidal systems is currently being extensively studied and has huge potential for targeted drug delivery in the treatment of various diseases. Furthermore, the surfactant-associated proteins present at the interface enhance the effect of these formulations by decreasing the surface tension and allowing the maximum effect. The most challenging part of developing a colloidal system for nebulization is to maintain the critical physicochemical parameters for successful inhalation. The following review focuses on the current status of different colloidal systems available for the treatment of various lung disorders along with their characterization. Additionally, different in vitro, ex vivo and in vivo cell models developed for the testing of these systems with studies involving cell culture analysis are also discussed.     

Transport of Glial Cell Line-Derived Neurotrophic Factor into Liposomes across the Blood-Brain Barrier: In Vitro and in Vivo Studies

Glial cell line-derived neurotrophic factor (GDNF) was encapsulated into liposomes in order to protect it from enzyme degradation in vivo and promote its permeability across the blood-brain barrier (BBB). In this study, GDNF conventional liposomes (GDNF-L) and GDNF target sterically stabilized liposomes (GDNF-SSL-T) were prepared. The average size of liposomes was below 90 nm. A primary model of BBB was established and evaluated by transendothelial electrical resistance (TEER) and permeability. This BBB model was employed to study the permeability of GDNF liposomes in vitro. The results indicated that the liposomes could enhance transport of GDNF across the BBB and GDNF-SSL-T had achieved the best transport efficacy. The distribution of GDNF liposomes was studied in vivo. Free GDNF and GDNF-L were eliminated rapidly in the circulation. GDNF-SSL-T has a prolonged circulation time in the blood and favorable brain delivery. The values of the area under the curve (AUC_{(0–1 h)}) in the brain of GDNF-SSL-T was 8.1 times and 6.8 times more than that of free GDNF and GDNF-L, respectively. These results showed that GDNF-SSL-T realized the aim of targeted delivery of therapeutic proteins to central nervous system.     

Multifaceted polymersome platforms: Spanning from self-assembly to drug delivery and protocells

Biologically inspired self-assembly processes of amphiphilic copolymers have received an increasing attention for creating innovative and highly advanced functional materials for various biomedical applications. Polymersomes are versatile nanosystems with tremendous potential due to their increased colloidal stability, tunable membrane properties, chemical versatility, and the ability to accommodate a broad range of drugs and biomolecules. In this review, we present the principles of copolymers self-assembly and associated parameters that control the resulting self-assembled morphologies, and various methodologies developed for fabrication of polymersomes. We attempt to discuss how polymersome platforms can be applied for versatile biomedical research, from simple passive nanocarriers for drug delivery to functionalized polymersomes for active targeting approaches and advanced nanoreactors, and protocells to mimic structure and functions of biological systems.     

Delivery of drugs and biomolecules using carbon nanotubes

Carbon nanotubes (CNTs) have emerged as one of the most advanced nanovectors for the highly efficient delivery of drugs and biomolecules. They offer several appealing features such as large surface areas with well defined physico-chemical properties as well as unique optical and electrical properties. They can be conjugated non-covalently or covalently with drugs, biomolecules and nanoparticles. Albeit some pending concerns about their toxicity in vitro and in vivo, functionalized CNTs appear to exhibit very low toxicity and are not immunogenic. Thus, they could be promising carriers with a great potential for the development of a new-generation delivery system for drugs and biomolecules. There have been significant advances in the field of CNT-based drug delivery, especially in the specific targeting of anticancer and anti-inflammatory drugs for tissues and organs in the body, where their therapeutic effect is highly required. Other promising applications are the delivery of DNA, RNA and proteins.