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Lipid-based nanoparticles, as drug delivery carriers, are commonly used for the delivery of anti-cancer therapeutic agents. Due to their smaller particle size and similarity to cell membranes, Lipid-based nanoparticles are readily internalized into cancer cells. Cancer cells also overexpress receptors for specific ligands, including folic acid, hyaluronic acid, and transferrin, on their surface, thus, allowing the use of their ligands for surface modification of the lipid-based nanoparticles for their specific recognition by receptors on cancer cells. This would also allow the gradual intracellular accumulation of the targeted functionalized nanoplatforms. These ligand-receptor interactions eventually enhance the internalization of desired drugs by increasing the nanoplatforms cellular uptake. The cellular internalization of the nanoplatforms varies and depends on their physicochemical properties, including particle size, zeta potential, and shape. The cellular uptake is also influenced by the types of ligand internalization pathways utilized by cells, such as phagocytosis, macropinocytosis, and multiple endocytosis pathways. This review classifies and discusses lipidbased nanoparticles engineered to carry specific ligands, their recognition by receptors on cancer cells, and their cellular internalization pathways. Moreover, the intracellular fate of nanoparticles decorated with specific ligands and their best internalization pathway (caveolae-mediated endocytosis) for safe cargo delivery are also discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Drug dosing in clinical practice, which determines optimal efficacy, toxicity or ineffectiveness, is critical to patients' outcomes. However, many orally administered therapeutic drugs are susceptible to biotransformation by a group of important oxidative enzymes, known as cytochrome P450s (CYPs). In particular, CYP3A4 is a low specificity isoenzyme of the CYPs family, which contributes to the metabolism of approximately 50% of all marketed drugs. Induction or inhibition of CYP3A4 activity results in the varied oral bioavailability and unwanted drug-drug, drug-food, and drug-herb interactions. This review explores the need for addressing intestinal CYP3A4 metabolism and investigates the opportunities to incorporate lipid-based oral drug delivery to enable precise dosing. A variety of lipid- and lipid-polymer hybrid-nanoparticles are highlighted to improve drug bioavailability. These drug carriers are designed to target different intestinal regions, including (1) local saturation or inhibition of CYP3A4 activity at duodenum and proximal jejunum; (2) CYP3A4 bypass via lymphatic absorption; (3) pH-responsive drug release or vitamin-B12 targeted cellular uptake in the distal intestine. Exploitation of lipidic nanosystems not only revives drugs removed from clinical practice due to serious drug-drug interactions, but also provide alternative approaches to reduce pharmacokinetic variability. [ABSTRACT FROM AUTHOR]

Messenger RNA (mRNA) is being extensively used in gene therapy and vaccination due to its safety over DNA, in the following ways: its lack of integration risk, cytoplasmic expression, and transient expression compatible with fine regulations. However, clinical applications of mRNA are limited by its fast degradation by nucleases, and the activation of detrimental immune responses. Advances in mRNA applications, with the recent approval of COVID-19 vaccines, were fueled by optimization of the mRNA sequence and the development of mRNA delivery systems. Although delivery systems and mRNA sequence optimization have been abundantly reviewed, understanding of the intracellular processing of mRNA is mandatory to improve its applications. We will focus on lipid nanoparticles (LNPs) as they are the most advanced nanocarriers for the delivery of mRNA. Here, we will review how mRNA therapeutic potency can be affected by its interactions with cellular proteins and intracellular distribution. [ABSTRACT FROM AUTHOR]

Nanomedicines have shown great potential in cancer therapy; in particular, the combination of chemotherapy and immunotherapy (namely chemoimmunotherapy) that is revolutionizing cancer treatment. Currently, most nanomedicines for chemoimmunotherapy are still in preclinical and clinical trials. Lipid-based nanoparticles, the most widely used nanomedicine platform in cancer therapy, is a promising delivery platform for chemoimmunotherapy. In this review, we introduce the commonly used immunotherapy agents and discuss the opportunities for chemoimmunotherapy mediated by lipid-based nanoparticles. We summarize the clinical trials involving lipid-based nanoparticles for chemoimmunotherapy. We also highlight different chemoimmunotherapy strategies based on lipid-based nanoparticles such as liposomes, nanodiscs, and lipid-based hybrid nanoparticles in preclinical research. Finally, we discuss the challenges that have hindered the clinical translation of lipid-based nanoparticles for chemoimmunotherapy, and their future perspectives. [ABSTRACT FROM AUTHOR]

• "Lipidization" of drugs by SLN encapsulation enhances their GI absorption. • Chitosan/heparin complexes allow heparin encapsulation in SLN. • Hybrid PEC-SLN displayed suitable size and pH controlled release. • Caco2 internalization of PEC-SLN were rapid and not time-dependent. • Chitosan inside SLN-PEC does not altered the integrity of tight junctions. Enhancing oral bioavailability of hydrophilic drugs by encapsulation in lipid-based nanocarriers, including Solid Lipid Nanoparticles (SLN), has been well documented. In this work, high molecular weight heparin was "insolubilized" by an "ion-paring" approach, forming Chitosan/Heparin Polyelectrolyte Complexes (PEC) to promote its encapsulation in SLN. Hybrid PEC-SLN, heparin-loaded SLN (H-SLN) as well as naked PEC were prepared and characterized regarding size, Z potential, morphology, drug loading and drug release. Physicochemical characterization of the nanoparticles was also performed by differential scanning calorimetry (DSC), and Fourier Transform Infra-Red (FTIR) analysis. FITC-labeled naked PEC along with Nile Red labeled PEC-SLN were assessed on CaCo-2 cells to study cytotoxicity as well as cell internalization ability by cytometric and confocal analysis. Transepithelial electrical resistance (TEER) was measured on NCM460 cell monolayers to evaluate whether chitosan may induce a modification of tight junctions' integrity at epithelial level. Results showed that the minimum size of PEC (around 170 nm) was at pH 5.5 with a positive surface charge and after encapsulation in SLN produced hybrid PEC-SLN with a size of about 370 nm and a negative zeta potential. In comparison to both H-SLN and naked PEC, PEC-SLN were able to achieve a pH-controlled drug release and showed on CaCo-2 cells low toxicity and rapid internalization. Finally, TEER measurements highlighted that the hybrid nanocarriers were internalized without interference in the membrane resistance. Therefore, PEC-SLN could be considered valuable candidate for further in vivo investigations about the systemic bioavailability of oral heparin. [ABSTRACT FROM AUTHOR]

The management of chronic hepatitis B virus (CHB) infection is an area of massive unmet clinical need worldwide. In spite of the development of powerful nucleoside/nucleotide analogue (NUC) drugs, and the widespread use of immune stimulators such as interferon-alpha (IFNα) or PEGylated interferon-alpha (PEG-IFNα), substantial improvements in CHB standards of care are still required. We believe that the future for CHB treatment now rests with advanced therapeutics, vaccination, and precision medicine, if all are to bring under control this most resilient of virus infections. In spite of a plethora of active drug treatments, anti-viral vaccinations and diagnostic techniques, the management of CHB infection remains unresolved. The reason for this is the very complexity of the virus replication cycle itself, giving rise to multiple potential targets for therapeutic intervention some of which remain very intractable indeed. Our review is focused on discussing the potential impact that advanced therapeutics, vaccinations and precision medicine could have on the future management of CHB infection. We demonstrate that advanced therapeutic approaches for the treatment of CHB, in the form of gene and immune therapies, together with modern vaccination strategies, are now emerging rapidly to tackle the limitations of current therapeutic approaches to CHB treatment in clinic. In addition, precision medicine approaches are now gathering pace too, starting with personalized medicine. On the basis of this, we argue that the time has now come to accelerate the design and creation of precision therapeutic approaches (PTAs) for CHB treatment that are based on advanced diagnostic tools and nanomedicine, and which could maximize CHB disease detection, treatment, and monitoring in ways that could genuinely eliminate CHB infection altogether. [ABSTRACT FROM AUTHOR]

Most prostate cancer patients develop resistance to anti-androgen therapy. This is referred to as castration-resistant prostate cancer (CRPC). Docetaxel (DTX) is the mainstay treatment against CRPC. However, over time patients eventually develop DTX resistance, which is the cause of the cancer-related mortality. Curcumin (CUR) as a natural compound has been shown to have very broad pharmacological activities, e.g., anti-inflammatory and antioxidant properties. However, CUR is very hydrophobic. The objective of this study was to develop CUR nanoparticles (NPs) and evaluate their cytotoxicity in DTX-resistant CRPC cells for the treatment of DTX-resistant CRPC. We tested solubility of CUR in different lipids and surfactants. Finally, Miglyol 812 and D-alpha-tocopheryl poly (ethylene glycol) succinate 1000 (TPGS) were chosen to prepare lipid-based NPs for CUR. We fully characterized CUR NPs that had particle size < 150 nm, high drug loading (7.5%), and entrapment efficiency (90%). Moreover, the CUR NPs were successfully lyophilized without using cryoprotectants. We tested the cytotoxicity of blank NPs, free CUR, and CUR NPs in sensitive DU145 and PC3 cells as well as their matching docetaxel-resistant cells. Cytotoxicity studies showed that blank NPs were very safe for all tested prostate cancer cell lines. Free CUR overcame the resistance in PC3 cells, but not in DU145 cells. In contrast, CUR NPs significantly increased CUR potency in all tested cell lines. Importantly, CUR NPs completely restored CUR potency in both resistant DU145 and PC3 cells. These results demonstrate that the CUR NPs have potential to overcome DTX resistance in CRPC. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a prevalent disease worldwide, and patients at late stages of CRC often suffer from a high mortality rate after surgery. Adjuvant chemotherapeutics (ACs) have been extensively developed to improve the survival rate of such patients, but conventionally formulated ACs inevitably distribute toxic chemotherapeutic drugs to healthy organs and thus often trigger severe side effects. CRC cells may also develop drug resistance following repeat dosing of conventional ACs, limiting their effectiveness. Given these limitations, researchers have sought to use targeted drug delivery systems (DDSs), specifically the nanotechnology-based DDSs, to deliver the ACs. As lipid-based nanoplatforms have shown the potential to improve the efficacy and safety of various cytotoxic drugs (such as paclitaxel and vincristine) in the clinical treatment of gastric cancer and leukemia, the preclinical progress of lipid-based nanoplatforms has attracted increasing interest. The lipid-based nanoplatforms might be the most promising DDSs to succeed in entering a clinical trial for CRC treatment. This review will briefly examine the history of preclinical research on lipid-based nanoplatforms, summarize the current progress, and discuss the challenges and prospects of using such approaches in the treatment of CRC. [ABSTRACT FROM AUTHOR]

The efficacy of current standard chemotherapy is suboptimal due to the poor solubility and short half-lives of chemotherapeutic agents, as well as their high toxicity and lack of specificity which may result in severe side effects, noncompliance and patient inconvenience. The application of nanotechnology has revolutionized the pharmaceutical industry and attracted increasing attention as a significant means for optimizing the delivery of chemotherapeutic agents and enhancing their efficiency and safety profiles. Nanostructured lipid carriers (NLCs) are lipid-based formulations that have been broadly studied as drug delivery systems. They have a solid matrix at room temperature and are considered superior to many other traditional lipid-based nanocarriers such as nanoemulsions, liposomes and solid lipid nanoparticles (SLNs) due to their enhanced physical stability, improved drug loading capacity, and biocompatibility. This review focuses on the latest advances in the use of NLCs as drug delivery systems and their preparation and characterization techniques with special emphasis on their applications as delivery systems for chemotherapeutic agents and different strategies for their use in tumor targeting. [ABSTRACT FROM AUTHOR]

The incidence of Parkinson's disease (PD), the second most common neurodegenerative disorder, has increased exponentially as the global population continues to age. Although the etiological factors contributing to PD remain uncertain, its average incidence rate is reported to be 1% of the global population older than 60 years. PD is primarily characterized by the progressive loss of dopaminergic (DAergic) neurons and/or associated neuronal networks and the subsequent depletion of dopamine (DA) levels in the brain. Thus, DA or levodopa (l -dopa), a precursor of DA, represent cardinal targets for both idiopathic and symptomatic PD therapeutics. While several therapeutic strategies have been investigated over the past decade for their abilities to curb the progression of PD, an effective cure for PD is currently unavailable. Even DA replacement therapy, an effective PD therapeutic strategy that provides an exogenous supply of DA or l -dopa, has been hindered by severe challenges, such as a poor capacity to bypass the blood–brain barrier and inadequate bioavailability. Nevertheless, with recent advances in nanotechnology, several drug delivery systems have been developed to bypass the barriers associated with central nervous system therapeutics. In here, we sought to describe the adapted lipid-based nanodrug delivery systems used in the field of PD therapeutics and their recent advances, with a particular focus placed on DA replacement therapies. This work initially explores the background of PD; offers descriptions of the most recent molecular targets; currently available clinical medications/limitations; an overview of several lipid-based PD nanotherapeutics, functionalized nanoparticles, and technical aspects in brain delivery; and, finally, presents future perspectives to enhance the use of nanotherapeutics in PD treatment. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults. Although the overall incidence is less than 10 per 100,000 individuals, its poor prognosis and low survival rate make GBM a crucial public health issue. The main challenges for GBM treatment are related to tumor location and its complex and heterogeneous biology. In this sense, a broad range of nanoparticles with different sizes, architectures, and surface properties, have been engineered as brain drug delivery systems. Among them, lipid-based nanoparticles, such as liposomes, have been pointed out as promising materials to deliver antitumoral drugs to the central nervous system and thus, to improve brain drug targeting and therapeutic efficiency. Here, we describe the synthesis and general characteristics of lipid-based nanoparticles, as well as evidence in the past 5 years regarding their potential use to treat GBM.

Introduction: Immunological skin dysfunctions trigger the synthesis and release of inflammatory cytokines, which induce recurrent skin inflammation associated with chronic itching, inefficient barrier behavior, and reduced skin hydration. These features characterize a multifactorial chronic inflammatory disease atopic dermatitis (AD). AD therapy includes anti-inflammatory drugs and immunosuppressors as well as non-pharmacological alternatives such as emollients, moisturizers, and lipids (ceramides, phospholipids) for modulating the skin hydration and the barrier repair. However, these treatments are inconvenient with low drug skin penetration and insufficient maintenance on the application site., Areas Covered: Nanotechnology-based therapies can be a great strategy to overcome these limitations. Considering the particular skin morphological organization, SC lipid matrix composition, and immunological functions/features related to nanocarriers, this review focuses on recent developments of nanoparticulate systems (polymeric, lipid-based, inorganic) as parent or hybrid systems including their chemical composition, physico-chemical and biopharmaceutical properties, and differential characteristics that evaluate them as new effective drug-delivery systems for AD treatment., Expert Opinion: Despite the several innovative formulations, research in nanotechnology-based carriers should address specific aspects such as the use of moisturizers associated to pharmacological therapies, toxicity studies, scale-up production processes and the nanocarrier influence on immunological response. These approaches will help researchers choose the most appropriate nanocarrier system and widen nanomedicine applications and commercialization.

Cancer is a global disease. It is the second leading cause of death worldwide, according to the health report. Approximately 70% of deaths from cancer occurs in low- and middle-income countries. According to the WHO, in 2015 8.8 million deaths were reported due to cancer worldwide. The conventional system of medicine was used since a long for the management of the disease, but it comes with the drawback of low safety, less efficacy and non-targeting of cancer cells. Nanotherapeutics has become the most exploited drug targeting system based on the safety and efficacy this system provides over the conventional system. This review summarizes an advanced design consideration in anticancer therapy, recent advancements in the nanocarrier-based advanced drug targeting, challenges and limitations related to nanoparticles-based therapy in cancer and its future perspective. The review also lists the on-going clinical trials in the last five years on nano-based therapy for different types of cancer. The data for this article was obtained by an extensive literature review of related published scientific contents from the WHO's website, PubMed, Scopus, Scielo, clinicaltrials.gov and other relevant scientific archiving services. The safety and efficacy that nanoparticles provide, and the current research strongly support their application in cancer drug targeting. However, their presence in the market is still limited. Nanotherapeutics in cancer drug targeting needs extensive research in association with pharmaceutical industries. Nano-targeting based therapies are the future of pharmaceutical designing for the diagnosis, management and prevention of different forms of cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Restenosis is one of the major complications affecting outcomes of percutaneous coronary interventions. The aims of this study were to formulate curcumin (CUR) nanoparticles by using only lipidic ingredients in the absence of any organic solvent and to determine key formulation parameters using 2-level factorial design. CUR nanoparticles were prepared using triglyceride and egg phosphatidylcholine (EPC) by high-pressure homogenization (HPH) and fully characterized regarding drug loading, particle size, zeta potential, stability, drug release profile, conductivity, viscosity, refractive index, stability, morphology and FTIR analysis. The efficacy of CUR nanoparticles in inhibiting restenosis was investigated in a rat carotid artery model. Balloon-injured rats were randomly assigned to two control (saline and empty carrier) groups and CUR nanoparticle treated group. Arterial restenosis was assessed by histomorphometric, immunohistochemical and CT angiography analyses. Optimized CUR nanoparticles with almost 70% drug entrapment, an average particle size of 58 nm, PDI < 0.2, spherical nanostructures and sustained release profile were prepared. In morphometric analysis, neointimal area and neointima/media ratio significantly decreased in the animal group received CUR nanoparticles compared with control groups. Expression of Ki67 was markedly lower in the CUR nanoformulation group. CT angiograms confirmed patency of the artery in this group. These results suggest that the new strategy of intramural delivery of CUR lipid-based nanoparticles can be considered as a novel approach to prevent neointimal hyperplasia. Unlabelled Image • Curcumin lipid-based nanoparticles were prepared by a green formulation process. • A factorial design approach was conducted to optimize formulation parameters. • All nanoformulations were fully characterized. • Restenosis was assessed through histological, IHC and CT angiography analyses. • The anti-restenosis effect of curcumin nanoparticles was superior to controls. [ABSTRACT FROM AUTHOR]

Many therapeutically active molecules are non-soluble in aqueous systems, chemically and biologically fragile or present severe side effects. Lipid-based nanoparticle (LBNP) systems represent one of the most promising colloidal carriers for bioactive organic molecules. Their current application in oncology has revolutionized cancer treatment by improving the antitumor activity of several chemotherapeutic agents. LBNPs advantages include high temporal and thermal stability, high loading capacity, ease of preparation, low production costs, and large-scale industrial production since they can be prepared from natural sources. Moreover, the association of chemotherapeutic agents with lipid nanoparticles reduces active therapeutic dose and toxicity, decreases drug resistance and increases drug levels in tumor tissue by decreasing them in healthy tissue. LBNPs have been extensively assayed in in vitro cancer therapy but also in vivo, with promising results in some clinical trials. This review summarizes the types of LBNPs that have been developed in recent years and the main results when applied in cancer treatment, including essential assays in patients. [ABSTRACT FROM AUTHOR]

The use of lipid-based nanoparticles for the delivery of biomacromolecules has attracted considerable attention due to the current interest in protein-based therapeutics. Cubosomes protect the incorporated therapeutics, which are susceptible to degradation by enzymes, thereby improving their bioavailability, and concomitantly enhance cellular uptake. The cubosome nanoparticles presented herein were loaded with bovine serum albumin (BSA) and characterized by small-angle X-ray scattering and dynamic light scattering techniques, while the BSA encapsulation and its release were evaluated in vitro . The ability of this formulation to increase the cellular uptake of albumin by 2-fold was tested on various types of renal tubular cells and confirmed by in vivo renal uptake experiments in mice. The obtained results show that cubosomes are able to deliver BSA inside the cell through distinct uptake and intracellular routing. These data were substantiated, with evidence of a high cubosome-mediated uptake of BSA in Clcn5 knockout mice characterized by defective receptor-mediated endocytosis. The use of cubosomes as a delivery system thus represents a promising approach to overcome the low endocytic uptake in diseased epithelial cells and to treat dysfunctions of the kidney proximal tubule.

Parkinson's disease (PD) is characterized by loss of dopaminergic neurons, oxidative stress and neuroinflammation. The classical therapeutic approach with L-DOPA is not able to control motor symptoms in the long term, thus new disease-modifying or neuroprotective treatments are urgently required in order to match such yet unmet clinical needs. Success in cell-based therapy has been accomplished at a clinical level with human fetal mesencephalic tissue, but ethical issues and a shortage of organs clearly underline the need for novel sources of dopaminergic neurons. Mesenchymal stem cells (MSCs) can be obtained from different adult and fetal tissues that are normally discarded as waste, including adipose tissue, placenta, umbilical cord, and dental tissues. Their neuroregenerative, anti-inflammatory and immunomodulatory properties are mainly mediated by the secretion of an array of bioactive molecules and are heightened when MSCs form tri-dimensional structures called spheroids. Not only can MSCs spontaneously produce neurotrophic factors (NFs) but they can be engineered to synthetize and secrete them in vivo. The aim of this review is to provide a picture of results gained with MSC secretome and spheroids in PD, as well as the possibility of harnessing MSC-based therapy with the use of nano- and micro-structured materials for NF delivery., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Molecular and diagnostic imaging has been recently a subject of intense research in the treatment of numerous diseases. In medical imaging, there are different modalities with unique strengths including MRI, ultrasound imaging, computed tomography, positron emission tomography and single photon emission computed tomography. These systems need specific contrast agents to achieve a suitable image with the best quality. Nanoparticles represent an innovative tool in imaging field research and diagnostics of various diseases, especially cancerous ones. Among the nanocarriers, lipid-based nanoparticles, such as nanostructured lipid carriers, solid lipid nanoparticles and liposomes, are the most used carriers in imaging because of having many advantageous properties. This review addresses advancements in different lipid-based nanoparticles as tools in medical diagnostic and imaging.

Background Cancer stem cells (CSCs) have been described as a relevant contributor to tumorigenicity, metastasis, tumor recurrence and drug resistance, making this cell population a relevant target in solid tumors., Methods: This has stimulated the development of different therapeutic strategies often targeting surface markers (CD44, epithelial cell adhesion molecule (EpCAM), aldehyde dehydrogenase (ALDH) and nucleolin) and/or signaling pathways that are aberrantly activated and contribute to CSCs proliferation and survival., Results: There are a variety of signaling pathways often involved in physiological processes of cell function that aberrantly regulate CSCs, including Notch, Hedgehog, Wnt, PI3K/Akt, JAK/STAT and Ras/ERK signaling pathways. The inhibition of these pathways usually depletes CSC population and increases tumor sensitivity to chemotherapy. However, the recognition of the potential of cells to interconvert in response to environmental stimulus, turned both CSCs and non-stem cancer cells into two relevant therapeutic targets. Therefore, the use of drug combinations is increasingly needed. These drugs with different mechanisms of action often characterized by distinct pharmacokinetics profiles and, as such, will present distinct biodistribution patterns, following systemic administration. To synchronize pharmacokinetics, one can encapsulate synergistic drug combinations into lipid-based nanoparticles, assuring tumor delivery of the selected drug ratio., Conclusion: This review will focus on the multiple strategies to target CSCs, as well as on the potential of lipid-based nanoparticles to target both CSCs and non-stem cancer cells., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Brain, the centre of the nervous system and an integral part the body, is protected by two anatomical and physiological barriers- Blood-Brain Barrier (BBB) and Blood-Cerebrospinal Fluid Barrier (BCSFB). Blood-Brain Barrier is a very complex and highly organized multicellular structure that shields the brain from harmful substances and invading organisms from the bloodstream and thus offering protection against various brain diseases and injuries. However, it also impede the effective delivery of drug to the brain, thus, preventing treatment of numerous neurological disorders. Even though various traditional approaches such as Intra-Cerebro-Ventricular (ICV) injection, use of implants, disruption of BBB and use of prodrugs have achieved some success in overcoming these barriers, researchers are continuously working for promising alternatives for improved brain drug delivery. Recent breakthroughs in the field of nanotechnology provide an appropriate solution to problems associated with these delivery approaches and thus can be effectively used to treat a wide variety of brain diseases. Thus, nanotechnology promises to bring a great future to the individuals with various brain disorders. This review provides a brief overview of various brain drug delivery approaches along with limitations. In addition, the significance of nanoparticles as drug carrier systems for effective brain specific drug delivery has been highlighted. To show the complexity of the problems to be overcome for improved brain drug delivery, a concise intercellular classification of the BBB along with general transport routes across it is also included., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Understanding and exploiting molecular mechanisms in biology is central to chemical biology. In 20 years, chemical biology research has advanced from simple mechanistic studies using isolated biological macromolecules to molecular-level and nanomolecular-level mechanistic studies involving whole organisms. This review documents the best of my personal and collaborative academic research work that has made use of a solid organic chemistry and chemical biology approach toward nanomedicine, in which my focus has been on the design, creation and use of synthetic, self-assembly lipid-based nanoparticle technologies for the functional delivery of active pharmaceutical ingredients to target cells in vivo. This research is now leading to precision therapeutics approaches (PTAs) for the treatment of diseases that may define the future of nanomedicine.

Central nervous system (CNS) diseases constitute a set of challenging pathological conditions concerning diagnosis and therapeutics. For most of these disorders, there is a lack of early diagnosis, biomarkers to allow proper follow-up of disease progression and effective therapeutic strategies to allow a persistent cure. The poor prognosis of most CNS diseases is, therefore, a global concern, especially regarding chronic age-related neurodegenerative disorders, which are already considered problems of public health due to the increasing average of life expectancy. The difficulties associated with the treatment of CNS diseases are owed, at least in part, to very specific characteristics of the brain and spinal cord, when compared to peripheral organs. In this regard, the CNS is physically and chemically protected by the blood-brain barrier (BBB), which, while maintaining essential brain homeostasis, significantly restricts the delivery of most therapeutic agents to the brain parenchyma. On the other hand, regenerative properties of the tissue are lacking, meaning that a CNS insult resulting in neuronal death is a permanent phenomenon. Approaches for transposing the BBB aiming to treat CNS diseases, relying on specific properties of nanosystems, have been reported for therapeutic delivery to CNS without interfering with the normal function of the brain. In this chapter, we address the latest advances concerning the principles of such approaches, employing lipid-based nanoparticles and cell-produced exosomes as drug and nucleic acid delivery systems, and summarize recent example of applications in the context of neurological diseases. Major achievements obtained in preclinical studies and the trends identified by these studies are emphasized to provide new prospects for further developments in this area, thus enabling us to move from the research realm to the clinical arena., (© 2016 Elsevier Inc. All rights reserved.)

Modulating T cell function by down-regulating specific genes using RNA interference (RNAi) holds tremendous potential in advancing targeted therapies in many immune-related disorders including cancer, inflammation, autoimmunity, and viral infections. Hematopoietic cells, in general, and primary T lymphocytes, in particular, are notoriously hard to transfect with small interfering RNAs (siRNAs). Herein, we describe a novel strategy to specifically deliver siRNAs to murine CD4(+) T cells using targeted lipid nanoparticles (tLNPs). To increase the efficacy of siRNA delivery, these tLNPs have been formulated with several lipids designed to improve the stability and efficacy of siRNA delivery. The tLNPs were surface-functionalized with anti-CD4 monoclonal antibody to permit delivery of the siRNAs specifically to CD4(+) T lymphocytes. Ex vivo, tLNPs demonstrated specificity by targeting only primary CD4(+) T lymphocytes and no other cell types. Systemic intravenous administration of these particles led to efficient binding and uptake into CD4(+) T lymphocytes in several anatomical sites including the spleen, inguinal lymph nodes, blood, and the bone marrow. Silencing by tLNPs occurs in a subset of circulating and resting CD4(+) T lymphocytes. Interestingly, we show that tLNP internalization and not endosome escape is a fundamental event that takes place as early as 1 h after systemic administration and determines tLNPs' efficacy. Taken together, these results suggest that tLNPs may open new avenues for the manipulation of T cell functionality and may help to establish RNAi as a therapeutic modality in leukocyte-associated diseases.

Glioblastoma multiforme (GBM) is one of the most infiltrating, aggressive, and poorly treated brain tumors. Progress in genomics and proteomics has paved the way for identifying potential therapeutic targets for treating GBM, yet the vast majority of these leading drug candidates for the treatment of GBM are ineffective, mainly due to restricted passages across the blood-brain barrier. Nanoparticles have been emerged as a promising platform to treat different types of tumors due to their ability to transport drugs to target sites while minimizing adverse effects. Herein, we devised a localized strategy to deliver RNA interference (RNAi) directly to the GBM site using hyaluronan (HA)-grafted lipid-based nanoparticles (LNPs). These LNPs having an ionized lipid were previously shown to be highly effective in delivering small interfering RNAs (siRNAs) into various cell types. LNP's surface was functionalized with hyaluronan (HA), a naturally occurring glycosaminoglycan that specifically binds the CD44 receptor expressed on GBM cells. We found that HA-LNPs can successfully bind to GBM cell lines and primary neurosphers of GBM patients. HA-LNPs loaded with Polo-Like Kinase 1 (PLK1) siRNAs (siPLK1) dramatically reduced the expression of PLK1 mRNA and cumulated in cell death even under shear flow that simulate the flow of the cerebrospinal fluid compared with control groups. Next, a human GBM U87MG orthotopic xenograft model was established by intracranial injection of U87MG cells into nude mice. Convection of Cy3-siRNA entrapped in HA-LNPs was performed, and specific Cy3 uptake was observed in U87MG cells. Moreover, convection of siPLK1 entrapped in HA-LNPs reduced mRNA levels by more than 80% and significantly prolonged survival of treated mice in the orthotopic model. Taken together, our results suggest that RNAi therapeutics could effectively be delivered in a localized manner with HA-coated LNPs and ultimately may become a therapeutic modality for GBM.

Pyropheophorbide a (Pyro) is a near-infrared (NIR) fluorescent dye and photosensitizer with high quantum yield that makes the dye suitable for tumor treatment both as an imaging and therapy agent. We have designed and synthesized a series of a Pyro-based NIR probes, based on the conjugation of Pyro with lipids. The nature of our probes requires the use of a lipophilic carrier to deliver the probes to cancer cell membranes. To address this, we have utilized lipid-based nanoparticles (LNPs) consisting of PEGylated lipids, which form the nanoparticle shell, and a lipid core. To endow the LNPs with targeting properties, nitrilotriacetic acid (NTA) lipids were included in the composition that enables the non-covalent attachment of His-tag targeting proteins preserving their functional activity. We found that the nature of the core molecules influence the nanoparticle size, shelf-life and stability at physiological temperature. Two different Pyro-lipid conjugates were loaded either into the core or shell of the LNPs. The conjugates revealed differential ability to be accumulated in the cell membrane of the target cells with time. Thus, the modular organization of the core-shell LNPs allows facile adjustment of their composition with goal to fine tuning the nanoparticle properties for in vivo application.