Nanoparticle-based Approaches Research Articles

An update of nanoparticle-based approaches for glioblastoma multiforme immunotherapy.

Glioblastoma multiforme is a serious medical issue in the brain oncology field due to its aggressiveness and recurrence. Immunotherapy has emerged as a valid approach to counteract the growth and metastasization of glioblastoma multiforme. Among the different innovative approaches investigated, nanoparticles gain attention because of their versatility which is key in allowing precise targeting of brain tumors and increasing targeted drug delivery to the brain, thus minimizing adverse effects. This article reviews the progress made in this field over the past 2 years, focusing on nonspherical and biomimetic particles and on vectors for the delivery of nucleic acids. However, challenges still need to be addressed, considering the improvement of the particles passage across the blood-meningeal barrier and/or the blood-brain barrier, promoting the clinical translatability of these approaches.

Safety and efficacy concerns of modern strategies of local anesthetics delivery.

In the last few decades, several formulations have evolved to realize better efficacy of administered anesthesia. These innovative formulations have facilitated surgeons to perform operations under purely local anesthesia, which provides extra protection and comfort to patients. Ease of delivery of local anesthesia is the need of the current generation, because some of the standard procedures are performed without the use of any sedative agent. Therefore, we are presenting here the various approaches of administration of local anesthetics by the surgeons. To construct a comprehensive report on various methods of anesthesia, we followed a systematic literature search of bibliographic databases of published articles recently in the international journals and publishers of repute. A comprehensive study of several reports of the field indicates that there are significant progresses towards developing novel formulations of anesthesia drugs as well as strategies of delivery. Among formulations, nanoparticle-based delivery approaches, including polymeric, liposomal, and micellar structures, have offered the much needed efficacy with low toxicity. Therefore, several of such techniques are at various stages of clinical trials. Nanotechnology-based delivery approaches have significantly emerged in recent past due to the low systemic toxicity and better efficacy of the nonconventional local anesthetics. The other methods of local anesthesia delivery such as transdermal, magnetophoresis, electrophoresis, and iontophoresis are frequently used due to them being minimally invasive and locally effective. Therefore, the combination of the nanotechnological methods with above mentioned techniques would significantly enhance the overall process of local anesthesia delivery and efficacy.

MMAE Delivery Using the Bicycle Toxin Conjugate BT5528.

The EphA2 receptor is found at high levels in tumors and low levels in normal tissue and high EphA2 expression in biopsies is a predictor of poor outcome in patients. Drug discovery groups have therefore sought to develop EphA2-based therapies using small molecule, peptide, and nanoparticle-based approaches (1-3). However, until now only EphA2-targeting antibody-drug conjugates (ADC) have entered clinical development. For example, MEDI-547 is an EphA2-targeting ADC that displayed encouraging antitumor activity in preclinical models and progressed to phase I clinical testing in man. Here we describe the development of BT5528, a bicyclic peptide ("Bicycle") conjugated to the auristatin derivative maleimidocaproyl-monomethyl auristatin E to generate the Bicycle toxin conjugate BT5528. The report compares and contrasts the Pharmacokinetics (PK) characteristics of antibody and Bicycle-based targeting systems and discusses how the PK and payload characteristics of different delivery systems impact the efficacy-toxicity trade off which is key to the development of successful cancer therapies. We show that BT5528 gives rise to rapid update into tumors and fast renal elimination followed by persistent toxin levels in tumors without prolonged exposure of parent drug in the vasculature. This fast in, fast out kinetics gave rise to more favorable toxicology findings in rats and monkeys than were observed with MEDI-547 in preclinical and clinical studies.Graphical Abstract: http://mct.aacrjournals.org/content/molcanther/19/7/1385/F1.large.jpg.

Topochemical assembly of levodopa nanoparticles network as a high-performance biosensing platform coupling with π-π stacking and electrostatic repulsion interactions

Topochemical assembly carbon materials with unique structure rarely investigated and reported. Herein, we demonstrate the feasibility of using topochemical assembly levodopa nanoparticles with dendritic structure (LNDS) network as a new high-performance biosensing platform based on noncovalent functionalization of LNDS with a fluorescent oligonucleotide. The proposed platform is dependent on the competition of π-π stacking and electrostatic repulsion interactions between LNDS and fluorescent oligonucleotide. The obtained LNDS with 96.1% quenching efficiency is synthesized by using levodopa as the single precursor by natural oxidation or microwave irradiation. The constructed platform can be used for simple and efficient probing single-nucleotide polymorphisms (SNPs) and cDNA by fluorescence restoration with a highly sensitivity and selectivity, remarkably superior to those based on graphenes. Additionally, an aptasensor is further constructed for small molecule ATP detention in serum with a low detection limit of 4 μM. To the best of our knowledge, this is the first attempt to use LNDS to design a biosensing platform, and therefore opens possibilities for new types of nanoparticle-based molecule approaches, and sequencing technologies.

Nanoparticle-Based Immunoengineered Approaches for Combating HIV.

Highly active antiretroviral therapy (HAART) serves as an effective strategy to combat HIV infections by suppressing viral replication in patients with HIV/AIDS. However, HAART does not provide HIV/AIDS patients with a sterilizing or functional cure, and introduces several deleterious comorbidities. Moreover, the virus is able to persist within latent reservoirs, both undetected by the immune system and unaffected by HAART, increasing the risk of a viral rebound. The field of immunoengineering, which utilizes varied bioengineering approaches to interact with the immune system and potentiate its therapeutic effects against HIV, is being increasingly investigated in HIV cure research. In particular, nanoparticle-based immunoengineered approaches are especially attractive because they offer advantages including the improved delivery and functionality of classical HIV drugs such as antiretrovirals and experimental drugs such as latency-reversing agents (LRAs), among others. Here, we present and discuss the current state of the field in nanoparticle-based immunoengineering approaches for an HIV cure. Specifically, we discuss nanoparticle-based methods for improving HAART as well as latency reversal, developing vaccines, targeting viral fusion, enhancing gene editing approaches, improving adoptively transferred immune-cell mediated reservoir clearance, and other therapeutic and prevention approaches. Although nanoparticle-based immunoengineered approaches are currently at the stage of preclinical testing, the promising findings obtained in these studies demonstrate the potential of this emerging field for developing an HIV cure.

Insights into Gastric Cancer

Gastric Cancer (GC) is one of the serious diseases prevailing globally. GC has immense global life-threatening health issues by taking 4th place among all the widespread cancers and 2nd foremost reason for fatality around the globe. Numerous patients have inoperable disease at diagnosis or have recurrent disease after resection with curative intent. In the present review, we have put forward all the possible advanced treatments for GC, which includes the application of Nanotechnology, Monoclonal antibodies, and Robotic surgery. Nanoparticle offers a potentially improved treatment of multidrug-resistant cancers. GC is uniquely positioned as an area of research for targeted and nanoparticle therapies. This review briefs about design and considerations to develop targeted nanoparticle-based approaches for overcoming physiological hurdles in GC treatment. Based on current knowledge, molecular and cellular mechanisms, a number of novel biologic approaches such as monoclonal antibodies have been recently introduced for cancer treatment that mainly affects the immune system or target signaling pathways playing a role in cancer and metastasis development. Surgical robotic systems have been presented into the area of GC therapy as an enhanced technology that has overwhelmed the technical limits of laparoscopy. A note is added to relevant studies dealing with treatment concepts and gives an overview of the latest trends and developments in the treatment of GC.

Strategies for nonviral nanoparticle-based delivery of CRISPR/Cas9 therapeutics.

CRISPR-based genome editing technology has become an important potential therapeutic tool for various diseases. A vital challenge is to reach a safe, efficient, and clinically suitable delivery of a CRISPR-associated protein and a single-guide RNA. A possible translational approach to applying CRISPR-based technology is the use of viral vectors such as adeno-associated virus. However, such vectors give long-term exposure in vivo that may increase potential off-target effects as well as the risk of immunogenicity. Therefore, limitations to clinical applications are addressed using nonviral delivery systems such as nanoparticle-based delivery strategies. Today, the nanoparticle-based delivery approach is becoming more and more attractive in gene therapeutics because of its specific targeting, scale-up efficiency, efficacy of customization, minor stimulation of immune response, and minimal exposure to nucleases. In this review, we will present the most recent advances in developing innovations and potential advantages of the nanoparticle delivery system in CRISPR genome editing. We will also propose potential strategies of CRISPR-based technology for therapeutic and industrial applications. Our review will differ in focus from previous reviews and advance the literature on the subject by (a) focusing on the challenges of the CRISPR/Cas9 delivery system; (b) focusing on the application of nanoparticle-based delivery of CRISPR components (Cas9 and sgRNA), such as lipids and polymeric vectors; (c) discussing the potential nanoparticle-based delivery approaches for CRISPR/Cas9 application. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Nanotechnology-Based Diagnostics and Therapy for Pathogen-Related Infections in the CNS.

The central nervous system (CNS) encompasses the brain, spinal cord, and nerves, where both brain and spinal cord are safeguarded by the meninges. However, serious bacterial, viral, or fungal infection in the brain causes life-threatening diseases such as meningitis. Engineered nanostructures hold great promise for not only in the diagnosis but also for combating microbial drug resistance owing to their high surface area and innate antibacterial activity. We delineate several nanoparticle-based approaches to enhance the CNS delivery of drugs across the blood-brain barrier (BBB). While pathogens invade the CNS by phagocytosis or receptor (e.g., EphA2)-mediated transcytosis, most of the nanoparticles cross the BBB via receptor-mediated transcytosis (e.g., antibody, peptide, protein). We also provide our perspectives on the diagnostic pathways based on nanotechnology for the detection of pathogens in the brain, thereby opening up new therapeutic avenues.

Evidence for Nanoparticle-Induced Lysosomal Dysfunction in Lung Adenocarcinoma (A549) Cells.

Background: Polystyrene nanoparticles (PNP) are taken up by primary rat alveolar epithelial cell monolayers (RAECM) in a time-, dose-, and size-dependent manner without involving endocytosis. Internalized PNP in RAECM activate autophagy, are delivered to lysosomes, and undergo [Ca2+]-dependent exocytosis. In this study, we explored nanoparticle (NP) interactions with A549 cells. Methods: After exposure to PNP or ambient pollution particles (PM0.2), live single A549 cells were studied using confocal laser scanning microscopy. PNP uptake and egress were investigated and activation of autophagy was confirmed by immunolabeling with LC3-II and LC3-GFP transduction/colocalization with PNP. Mitochondrial membrane potential, mitophagy, and lysosomal membrane permeability (LMP) were assessed in the presence/absence of apical nanoparticle (NP) exposure. Results: PNP uptake into A549 cells decreased in the presence of cytochalasin D, an inhibitor of macropinocytosis. PNP egress was not affected by increased cytosolic [Ca2+]. Autophagy activation was indicated by increased LC3 expression and LC3-GFP colocalization with PNP. Increased LMP was observed following PNP or PM0.2 exposure. Mitochondrial membrane potential was unchanged and mitophagy was not detected after NP exposure. Conclusions: Interactions between NP and A549 cells involve complex cellular processes leading to lysosomal dysfunction, which may provide opportunities for improved nanoparticle-based therapeutic approaches to lung cancer management.

Nanoscale systems for local drug delivery

Many diseases and conditions affect a relatively localized area of the body. They can be treated either by direct deposition of drug in the target area, or by giving the drug systemically. Here we review nanoparticle-based approaches to achieving both. We highlight advantages and disadvantages that nanoscale solutions have for locally administered therapies, with emphasis on the former. We discuss strategies to enable systemically delivered nanoparticles to deliver their payloads at specific locations in the body, including triggering (local and remote) and targeting.

Self‐Amplified Drug Delivery with Light‐Inducible Nanocargoes to Enhance Cancer Immunotherapy

Chemoimmunotherapy by systemic administration of individual regimens suffers from inconsistent pharmacokinetics profiles, low tumor specificity, and severe side effects. Despite promising nanoparticle-based codelivery approaches in therapeutics, the pathophysiological barriers of solid tumors are a hurdle for tumor accumulation and deep penetration of the drug-loaded nanoparticles. A light-inducible nanocargo (LINC) for immunotherapy is reported. LINC is composed of a reduction-responsive heterodimer of photosensitizer pheophorbide A (PPa) and indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor, i.e., NLG919, and a light-activatable prodrug of oxaliplatin (OXA). LINC administrated through intravenous injection is passively accumulated at the tumor site to generate near-infrared (NIR) fluorescence signal. Under fluorescence imaging guidance, the first-wave of NIR laser irradiation induce reactive oxygen species (ROS) generation, trigger cleavage of the polyethylene glycol (PEG) corona, and thus promote tumor retention and deep penetration of LINC. When exposed to the second-wave NIR laser illumination, LINC efficiently elicits the immune response and promotes intratumoral infiltration of cytotoxic T lymphocytes (CTLs). Furthermore, NLG919 delivered by LINC reverses the immunosuppressive tumor microenvironment by suppressing IDO-1 activity. Chemoimmunotherapy with LINC inhibit the tumor growth, lung metastasis, and tumor recurrence. The light-inducible self-amplification strategy for improved drug delivery and immunotherapy shows potential.

Are nanotechnological approaches the future of treating inflammatory diseases?

The current treatments for chronic inflammatory diseases cause severe side effects due to nonspecific drug accumulation. Nanotechnology opens the way to new therapeutic strategies that exploit the ability of immune cells, and especially of phagocytes, to internalize nanoparticles. The cellular uptake of nanoparticles requires specific interactions and is affected by the chemical and physical properties of the carriers. Therefore, optimizing these properties is crucial for designing nanodrugs for immunotherapy. In perspective, we discuss the nanoparticle-based approaches that have been proposed to induce tolerance in autoimmune disorders and lessen the symptoms of inflammatory diseases.

Advanced Diagnostic Approaches for Necrotrophic Fungal Pathogens of Temperate Legumes With a Focus on Botrytis spp.

Plant pathogens reduce global crop productivity by up to 40% per annum, causing enormous economic loss and potential environmental effects from chemical management practices. Thus, early diagnosis and quantitation of the causal pathogen species for accurate and timely disease control is crucial. Botrytis Gray Mold (BGM), caused by Botrytis cinerea and B. fabae, can seriously impact production of temperate grain legumes separately or within a complex. Accordingly, several immunogenic and molecular probe-type protocols have been developed for their diagnosis, but these have varying levels of species-specificity, sensitivity and consequent usefulness within the paddock. To substantially improve speed, accuracy and sensitivity, advanced nanoparticle-based biosensor approaches have been developed. These novel methods have made enormous impact toward disease diagnosis in the medical sciences and offer potential for transformational change within the field of plant pathology and disease management, with early and accurate diagnosis at the point-of-care in the field. Here we review several recently developed diagnostic tools that build on traditional approaches and are available for pathogen diagnosis, specifically for Botrytis spp. diagnostic applications. We then identify the specific gaps in knowledge and current limitations to these existing tools.

Matrix metalloproteinase-cleavable nanocapsules for tumor-activated drug release

In the war against cancer, nanotechnology-based drug delivery systems may play a significant role by enhancing the efficacy of conventional therapies. Here, we tried to address some major limitations plaguing anticancer drugs, namely, poor water solubility and off-target toxicity. The systems we propose are cross-linked polyelectrolyte nanocapsules based on an oil-core and a matrix metalloproteinase-2 (MMP-2)-cleavable shell. They can load hydrophobic drugs, prevent their systemic leakage, and release their payload upon an endogenous stimulus. Both the stability enhancement and the stimuli-responsive drug release mechanisms were achieved by cross-linking the nanocapsule shell with an MMP-2-sensitive peptide. On the basis of this strategy, the system maintained its stability in PBS up to one month. Further, when tested on 3D tumor and healthy spheroid models, the nanocapsules were able to disrupt their integrity preferentially in the tumor-like microenvironment. The high level of MMP-2 enzymes expressed by tumor spheroids, indeed, catalyzed the disassembly of the nanocapsules, which ultimately leads to drug release. Therefore, this device holds great potential as a smart system that allows for the safe transport of hydrophobic drugs and for a spatially controlled release upon an endogenous stimulus coming from the very nature of the tumor itself. Statement of significanceThe performance of nanoparticle-based therapeutic approaches is often hindered by some intrinsic limitations typically including laborious drug loading methods, synthetic routes of preparation and stability issues. In this work, we implemented for the first time a smart drug delivery strategy into oil-core multilayer nanocapsules, which represent an ideal family of nanocarriers. To this aim, we developed a robust method enabling the use of soft matters like oil-core nanocapsules combined with a microenvironmentally triggered release mechanism. The efficacy of nanocapsules was tested on tumor and healthy spheroids. Results clearly demonstrate their selective drug release, triggered by a stimulus intrinsically present in tumor microenvironment. We believe this study is of particular interest for cancer research and paves the way for the use of these robust stimuli-responsive nanocapsules in vivo.

Engineering Nanoparticles to Reprogram the Tumor Immune Microenvironment for Improved Cancer Immunotherapy.

Immunotherapy is rapidly maturing towards extensive clinical use. However, it does not work well in large patient populations because of an immunosuppressed microenvironment and limited reinvigoration of antitumor immunity. The tumor microenvironment is a complex milieu in which the principles of physiology and anatomy are defied and which is considered an immune-privileged site promoting T cell exhaustion. Tremendous research interest exists in developing nanoparticle-based approaches to modulate antitumor immune responses. The increasing use of immunotherapies in the clinic requires robust programming of immune cells to boost antitumor immunity. This review summarizes recent advances in the engineering of nanoparticles for improved anticancer immunotherapy. It discusses emerging nanoparticle-based approaches for the modulation of tumor cells and immune cells, such as dendritic cells, T cells and tumor-associated macrophages, with the intention to overcome challenges currently faced in the clinic. Furthermore, this review describes potentially curative combination therapeutic approaches to provoke effective tumor antigen-specific immune responses. We foresee a future in which improvement in patient's surveillance will become a mainstream practice.

Synchrotron-based infrared microspectroscopy study on the radiosensitization effects of Gd nanoparticles at megavoltage radiation energies.

The outcome of radiotherapy can be further improved by combining radiotherapy with nanoparticles. Previous biological studies showed a significant amplification of the biological damage in cells charged with nanoparticles prior to radiotherapy treatments. The rationale has been based on the physical dose enhancement. However, this subject is still a matter of controversy and there are clear indications that biochemical effects may play a key role in the radiosensitization effects of nanoparticles. Within this context, the main goal of our study was to provide new insights into the radiosensitization effects of F98 glioma cells exposed to gadolinium nanoparticles combined with clinical megavoltage beams, and compare them with respect to kilovoltage radiotherapy (commonly used in combination with nanoparticles). For this purpose, we used synchrotron-based Fourier transform infrared microspectroscopy (SR-FTIRM) to provide relevant information on the treatment-induced biochemical changes of the main cell biomolecules. Biochemical differences were evaluated after the treatments to assess cellular damage. Multivariate analysis revealed nanoparticle-dependent changes in megavoltage treated cells. The main spectral variations were related to conformational changes in the protein secondary structures, which might be induced by radiation damage and by changes or rearrangements in the nucleic acid structures due to the initiation of DNA repair mechanisms. We also observed significant changes in the phosphate I and II bands, which concerns DNA damage, while few changes were detected in the lipid region. Spectroscopic data showed that these changes increased as a function of the dose. Finally, PCA analysis did not discriminate clearly between megavoltage and kilovoltage groups treated with nanoparticles, indicating that megavoltage radiosensitization effects might not differ significantly from those in kilovoltage radiotherapy.

Nanoparticle-Based Strategies and Approaches for the Treatment of Chronic Wounds

Nanoparticle-Based Strategies and Approaches for the Treatment of Chronic Wounds

Nanoparticle-based approaches to immune tolerance for the treatment of autoimmune diseases.

Autoimmune diseases are caused by antigenically complex immune responses of the adaptive and innate immune system against specific cells, tissues or organs. Antigen-specific approaches for induction of immune tolerance in autoimmunity, based on the use of antigenic peptides or proteins, have failed to deliver the desired therapeutic results in clinical trials. These approaches, which are largely relying on triggering clonal anergy and/or deletion of defined autoreactive specificities, do not address the overwhelming antigenic, molecular, and cellular complexity of most autoimmune diseases, which involve various immune cells and ever-growing repertoires of antigenic epitopes on numerous self-antigens. Advances in the field of regulatory T-cell (Treg) biology have suggested that Treg cells might be able to afford dominant tolerance provided they are properly activated and expanded in vivo. More recently, nanotechnology has introduced novel technical advances capable of modulating immune responses. Here, we review nanoparticle-based approaches designed to induce immune tolerance, ranging from approaches that primarily trigger clonal T-cell anergy or deletion to approaches that trigger Treg cell formation and expansion from autoreactive T-cell effectors. We will also highlight the therapeutic potential and positive outcomes in numerous experimental models of autoimmunity.

Smart multifunctional nanoagents for in situ monitoring of small molecules with a switchable affinity towards biomedical targets

The great diversity of nanomaterials provides ample opportunities for constructing effective agents for biomedical applications ranging from biosensing to drug delivery. Multifunctional nanoagents that combine several features in a single particle are of special interest due to capabilities that substantially exceed those of molecular drugs. An ideal theranostic agent should simultaneously be an advanced biosensor to identify a disease and report the diagnosis and a biomedical actuator to treat the disease. While many approaches were developed to load a nanoparticle with various drugs for actuation of the diseased cells (e.g., to kill them), the nanoparticle-based approaches for the localized biosensing with real-time reporting of the marker concentration severely lag behind. Here, we show a smart in situ nanoparticle-based biosensor/actuator system that dynamically and reversibly changes its structural and optical properties in response to a small molecule marker to allow real-time monitoring of the marker concentration and adjustment of the system ability to bind its biomedical target. Using the synergistic combination of signal readout based on the localized surface plasmon resonance and an original method of fabrication of smart ON/OFF-switchable nanoagents, we demonstrate reversible responsiveness of the system to a model small molecule marker (antibiotic chloramphenicol) in a wide concentration range. The proposed approach can be used for the development of advanced multifunctional nanoagents for theranostic applications.

Nanoparticle-Based Modulation and Monitoring of Antigen-Presenting Cells in Organ Transplantation.

Donor-specific unresponsiveness while preserving an intact immune function remains difficult to achieve in organ transplantation. Induction of tolerance requires a fine modulation of the interconnected innate and adaptive immune systems. Antigen-presenting cells (APCs) predominate during allograft rejection and create a highly inflammatory context where allospecific T cells are primed. Currently, the available protocols to prevent allograft rejection include a cocktail of drugs that are efficient in the short-term, but with severe long-term side effects and considerable toxicity. Consequently, better and less burdensome strategies are needed to promote indefinite allograft survival. Targeted delivery of immunosuppressive drugs that prevent the alloimmune response may address some of these problems. Nanoparticle-based approaches represent a promising strategy to negatively modulate the alloresponse by specifically delivering small compounds to APCs in vivo. Nanoparticles are also used as integrating imaging moieties to monitor inflammation for diagnostic purposes. Therefore, nanotechnology approaches represent an attractive strategy to deliver and monitor the efficacy of immunosuppressive therapy in organ transplantation with the potential to improve the clinical treatment of transplant patients.