Nanoparticulate Drug Delivery Systems Research Articles

Targeting Nanoparticles to Bioengineered Human Vascular Networks.

Pharmacotherapy of vascular anomalies has limited efficacy and potentially limiting toxicity. Targeted nanoparticle (NP) drug delivery systems have the potential to accumulate within tissues where the vasculature is impaired, potentially leading to high drug levels (increased efficacy) in the diseased tissue and less in off-target sites (less toxicity). Here, we investigate whether NPs can be used to enhance drug delivery to bioengineered human vascular networks (hVNs) that are a model of human vascular anomalies. We demonstrate that intravenously injected phototargeted NPs enhanced accumulation of NPs and the drug within hVNs. With phototargeting we demonstrate 17 times more NP accumulation within hVNs than was detected in hVNs without phototargeting. With phototargeting there was 10-fold more NP accumulation within hVNs than in any other organ. Phototargeting resulted in a 6-fold increase in drug accumulation (doxorubicin) within hVNs in comparison to animals injected with the free drug. Nanoparticulate approaches have the potential to markedly improve drug delivery to vascular anomalies.

Tumor-Associated Fibroblast-Targeting Nanoparticles for Enhancing Solid Tumor Therapy: Progress and Challenges.

Even though nanoparticle drug delivery systems (nanoDDSs) have improved antitumor efficacy by delivering more drugs to tumor sites compared to free and unencapsulated therapeutics, achieving satisfactory distribution and penetration of nanoDDSs inside solid tumors, especially in stromal fibrous tumors, remains challenging. As one of the most common stromal cells in solid tumors, tumor-associated fibroblasts (TAFs) not only promote tumor growth and metastasis but also reduce the drug delivery efficiency of nanoparticles through the tumor's inherent physical and physiological barriers. Thus, TAFs have been emerging as attractive targets, and TAF-targeting nanotherapeutics have been extensively explored to enhance the tumor delivery efficiency and efficacy of various anticancer agents. The purpose of this Review is to opportunely summarize the underlying mechanisms of TAFs on obstructing nanoparticle-mediated drug delivery into tumors and discuss the current advances of a plethora of nanotherapeutic approaches for effectively targeting TAFs.

Self-Assembled pH-Sensitive Nanoparticles Based on Ganoderma lucidum Polysaccharide-Methotrexate Conjugates for the Co-delivery of Anti-tumor Drugs.

In tumor therapy, polymer nanoparticles are ideal drug delivery materials because they can mask the disadvantages of anti-tumor drugs such as poor solubility in water, high toxicity, and side effects. However, most polymer-based nanoparticles do not themselves have anti-tumor properties. Herein, a novel pH-sensitive nanoparticle drug delivery system based on Ganoderma lucidum polysaccharides (GLPs), which have demonstrated anti-tumor activities, was designed to enable the delivery of methotrexate (MTX) and 10-hydroxycamptothecin (HCPT) to tumor cells, where they could exert synergistic anti-tumor effects. The prepared nanoparticles were irregularly spherical in shape with a uniform particle size of ∼190 nm, and they exhibited a high drug-loading capacity (MTX 21.5% and HCPT 22.6%) and excellent biocompatibility. Moreover, the loaded MTX and HCPT units were rapidly released under acidic conditions within the tumor cells while remaining stable under normal physiological conditions. Meanwhile, compared to free MTX and HCPT, the GLP-APBA-MTX/HCPT nanoparticles presented exhibited better tumor suppressive effects and fewer side effects in vivo, which indicates that they may be an effective anti-tumor treatment strategy.

Construction of Oral Insulin-Loaded Solid Lipid Nanoparticles and Their Intestinal Epithelial Cell Transcytosis Study

To construct solid lipid nanoparticle (SNPs) drug delivery system loaded with peptide and protein drugs by using mixedsolvents, to study the transcytosis mechanisms of SNPs across intestinal epithelial cells, and to improve the endocytosis and transcytosis efficiency of peptide and protein drugs. The formulation of insulin-loaded water-in-oil-in-water solid lipid nanoparticles (INS-SNPs) was prepared by using a methanol-chloroform mixed solvent. The formulation was optimized with the single factor screening method. The optimized INS-SNPs were then characterized in terms of their morphology, stability and drug release properties. The cytotoxicity, cellular uptake and endocytosis mechanisms of INS-SNPs were then assessed on Caco-2 cells. The transcytosis efficiency of INS-SNPs was finally evaluated by using cellular monolayer in Transwell ® insert. The size, zeta potentials and drug loading efficiency of the optimized INS-SNPs were observed to be (145.4±0.5) nm, (-12.9±0.2) mV and (7.93±0.02)%, respectively. INS-SNPs were then shown to maintain desirable colloidal stability and sustained release of insulin in the simulated intestinal fluid. It was revealed that the cellular uptake of INS-SNPs reached its maximum after cellular incubation for 2 hours and was 1.53-fold higher than that of free insulin. Investigation of the endocytic mechanism revealed that INS-SNPs enter intestinal epithelial cells mainly through the clathrin-mediated and caveolae-mediated endocytosis pathways. Further investigation revealed that the amount of INS-SNPs permeating the cell monolayers was 1.54-fold higher than that of free insulin, which was comparable to the increase in their cellular uptake efficiency, indicating that INS-SNPs displayed enhanced absorption across the intestinal epithelium. The INS-SNPs prepared with mixed solvents in this study could significantly enhance the transcytosis efficiency of peptide and protein drugs, displaying great potentials in the application of oral drug delivery. This study may provide information and reference for the designing of efficient oral nano-drug delivery system in the future.

Liposomes and Extracellular Vesicles as Drug Delivery Systems: A Comparison of Composition, Pharmacokinetics, and Functionalization.

Over the past decades, lipid-based nanoparticle drug delivery systems (DDS) have caught the attention of researchers worldwide, encouraging the field to rapidly develop improved ways for effective drug delivery. One of the most prominent examples is liposomes, which are spherical shaped artificial vesicles composed of lipid bilayers and able to encapsulate both hydrophilic and hydrophobic materials. At the same time, biological nanoparticles naturally secreted by cells, called extracellular vesicles (EVs), have emerged as promising more complex biocompatible DDS. In this review paper, the differences and similarities in the composition of both vesicles are evaluated, and critical mediators that affect their pharmacokinetics are elucidate. Different strategies that have been assessed to tweak the pharmacokinetics of both liposomes and EVs are explored, detailing the effects on circulation time, targeting capacity, and cytoplasmic delivery of therapeutic cargo. Finally, whether a hybrid system, consisting of a combination of only the critical constituents of both vesicles, could offer the best of both worlds is discussed. Through these topics, novel leads for further research are provided and, more importantly, gain insight in what the liposome field and the EV field can learn from each other.

Development of carboplatin loaded bovine serum albumin nanoparticles and evaluation of its effect on an ovarian cancer cell line

Ovarian cancer has the highest mortality rate among gynecological cancers. It requires urgent therapy, but standard treatments are not sufficient to cure ovarian cancer completely. Chemotherapy has critical side effects due to non-specific toxicity. In this regard, nanoparticulate drug delivery systems, one of the most promising therapeutic approaches, have been developed for cancer therapy. The main objective of the present research was to develop novel bovine serum albumin (BSA) nanoparticle formulation encapsulating carboplatin (CRB) and to evaluate its anti-cancer activity against A2780 human ovarian cancer cell line. CRB-loaded BSA nanoparticles were prepared using a desolvation method and characterized by several physicochemical properties, including encapsulation efficiency, particle size and size distribution, surface charge, particle morphology, thermal behavior. Different CRB-loaded BSA nanoparticles were prepared using 33 factorial design in which varying the BSA concentration, ethanol/BSA solution ratio and glutaraldehyde/BSA ratio as three factors. The effects of these factors on the particle size, polydispersity index and encapsulation efficiency were evaluated to produce an optimized nanoformulation. Based on dependent variables, the formulation including 3% BSA concentration, 4/1 (v/v) ethanol/BSA solution ratio (v/v), 7.80 μg/mg glutaraldehyde/BSA ratio was selected as optimum. It was found to have spherical shapes with negative surface charges and about 253 nm particle size with a low polydispersity index indicating a narrow particle size distribution. According to the confocal laser microscopy and flow cytometer studies, it exhibited a high uptake into A2780 cells. In addition, cytotoxicity experiments revealed that CRB-loaded albumin nanoparticles showed more potent anti-cancer effect on A2780 ovarian cancer cell line with approximately 2-fold lower IC50 value, compared with free CRB.

An effective nanoparticles for drug delivery system

A simple and practical approach has been successfully explored for the transformation of methotrexate, to its nano form using bioenhancers like piperine and quercetin. The transformed MTX expressed better therapeutic response against cancer in comparison to free MTX. Different techniques have been employed to characterize the synthesized MTX nanoparticle. We utilized X-ray diffractometer (XRD) for determination of crystal properties, UV–Visible (UV–Vis) spectroscopy for optical properties, transmission electron microscopy (TEM) for surface morphology and Zetasizer to examine the average particle size. The observations demonstrated that the average particle size of transformed MTX was found between 24 and 30 nm. We conducted the hemolytic assay as well as cytotoxic tests to examine the biocompatibility of synthesized drug, no prominent inhibition on normal cell growth was observed and cytotoxicity was found in acceptable ranges.

A review of nanoparticle drug delivery systems responsive to endogenous breast cancer microenvironment

Breast cancer, as a malignant disease that seriously threatens women's health, urgently needs to be researched to develop effective and safe therapeutic drugs. Nanoparticle drug delivery systems (NDDS), provide a powerful means for drug targeting to the breast cancer, enhancing the bioavailability and reducing the adverse effects of anticancer drug. However, the breast cancer microenvironment together with heterogeneity of cancer, impedes the tumor targeting effect of NDDS. Breast cancer microenvironment, exerts endogenous stimuli, such as hypoxia, acidosis, and aberrant protease expression, shape a natural shelter for tumor growth, invasion and migration. On the basis of the ubiquitous of endogenous stimuli in the breast cancer microenvironment, researchers exploited them to design the stimuli-responsive NDDS, which response to endogenous stimulus, targeted release drug in breast cancer microenvironment. In this review, we highlighted the effect of the breast cancer microenvironment, summarized innovative NDDS responsive to the internal stimuli in the tumor microenvironment, including the material, the targeting groups, the loading drugs, targeting position and the function of stimuli-responsive nanoparticle drug delivery system. The limitations and potential applications of the stimuli-responsive nanoparticle drug delivery systems for breast cancer treatment were discussed to further the application.

Exploring Dendrimer Nanoparticles for Chronic Wound Healing

The United States spends billions of dollars to treat chronic wounds each year. Wound healing is complex in nature which involves several intricate multiphase processes that can be delayed for a number of reasons leading to the development of chronic wounds. Wound healing therapies range from topical preparations to surgical repair with treatment options that vary based on other underlying factors like co-infection, age, or co-morbidities such as diabetes. Historically, micelles and liposomes are some of the nanoparticle drug delivery systems explored to treat chronic wounds; however, recent data suggests that dendrimers have shown potential to rival these systems in treating chronic wounds as well as other diseases. This mini review examines advances in dendrimer nanoparticle drug delivery systems to treat chronic wounds.

Recent advances in prodrug-based nanoparticle therapeutics

Extensive research into prodrug modification of active pharmaceutical ingredients and nanoparticle drug delivery systems has led to unprecedented levels of control over the pharmacological properties of drugs and resulted in the approval of many prodrug or nanoparticle-based therapies. In recent years, the combination of these two strategies into prodrug-based nanoparticle drug delivery systems (PNDDS) has been explored as a way to further advance nanomedicine and identify novel therapies for difficult-to-treat indications. Many of the PNDDS currently in the clinical development pipeline are expected to enter the market in the coming years, making the rapidly evolving field of PNDDS highly relevant to pharmaceutical scientists.This review paper is intended to introduce PNDDS to the novice reader while also updating those working in the field with a comprehensive summary of recent efforts. To that end, first, an overview of FDA-approved prodrugs is provided to familiarize the reader with their advantages over traditional small molecule drugs and to describe the chemistries that can be used to create them. Because this article is part of a themed issue on nanoparticles, only a brief introduction to nanoparticle-based drug delivery systems is provided summarizing their successful application and unfulfilled opportunities. Finally, the review’s centerpiece is a detailed discussion of rationally designed PNDDS formulations in development that successfully leverage the strengths of prodrug and nanoparticle approaches to yield highly effective therapeutic options for the treatment of many diseases.

In vitro and in vivo combinatorial anticancer effects of oxaliplatin- and resveratrol-loaded N,O-carboxymethyl chitosan nanoparticles against colorectal cancer

BackgroundOxaliplatin (OXE) combined with other chemotherapy drugs against colorectal cancer had been reported in the literature before, however, the efficacy of oxaliplatin combined with natural compounds was elusive. In addition, the clinical bioactivity and therapeutic dose of antitumor drugs are severely limited due to poor targeting and side effects. NDDSs offers an excellent strategy to overcome the disadvantages of small molecule anticancer drugs. MethodsHere, we have prepared N,O-carboxymethyl chitosan Oxaliplatin nanoparticles (CMCS-OXE NPs) and N,O-carboxymethyl chitosan Resveratrol nanoparticles (CMCS-Res NPs) were prepared by ion crosslinking and emulsification crosslinking, respectively. ResultsThe results revealed that the CMCS-OXE NPs exhibited a high encapsulation efficiency (60%) with a size of approximately 190.0 nm, and the CMCS-Res NPs exhibited a high encapsulation efficiency (65%) with a size of approximately 164.2 nm. The treatment with both types of nanoparticles combined exhibited more significant anti-colon cancer activity than the free drugs or either type of nanoparticle alone. In the in vivo experiments, the inhibition efficiency of the combined nanoparticle treatment was much stronger than the free drugs or either type of nanoparticle alone. ConclusionsOverall, combination of oxaliplatin and resveratrol into a nanoparticle-drug delivery systems (NDDSs) appears to be a promising strategy for colorectal cancer (CRC) therapy.

Nanoparticle delivery system, highly active antiretroviral therapy, and testicular morphology: The role of stereology.

The conjugation of nanoparticles (NPs) with antiretroviral drugs is a drug delivery approach with great potential for managing HIV infections. Despite their promise, recent studies have highlighted the toxic effects of nanoparticles on testicular tissue and their impact on sperm morphology. This review explores the role of stereological techniques in assessing the testicular morphology in highly active antiretroviral therapy (HAART) when a nanoparticle drug delivery system is used. Also, NPs penetration and pharmacokinetics concerning the testicular tissue and blood–testis barrier form the vital part of this review. More so, various classes of NPs employed in biomedical and clinical research to deliver antiretroviral drugs were thoroughly discussed. In addition, considerations for minimizing nanoparticle‐drugs toxicity, ensuring enhanced permeability of nanoparticles, maximizing drug efficacy, ensuring adequate bioavailability, and formulation of HAART‐NPs fabrication are well discussed.

Lipid Nanoparticles as Carriers for Bioactive Delivery.

Nanotechnology has made a great impact on the pharmaceutical, biotechnology, food, and cosmetics industries. More than 40% of the approved drugs are lipophilic and have poor solubility. This is the major rate-limiting step that influences the release profile and bioavailability of drugs. Several approaches have been reported to administer lipophilic drugs with improved solubility and bioavailability. Nanotechnology plays a crucial role in the targeted delivery of poorly soluble drugs. Nanotechnology-based drug delivery systems can be classified as solid lipid nanoparticulate drug delivery systems, emulsion-based nanodrug delivery systems, vesicular drug delivery systems, etc. Nanotechnology presents a new frontier in research and development to conquer the limitations coupled with the conventional drug delivery systems through the formation of specific functionalized particles. This review presents a bird's eye view on various aspects of lipid nanoparticles as carriers of bioactive molecules that is, synthesis, characterization, advantage, disadvantage, toxicity, and application in the medical field. Update on recent development in terms of patents and clinical trials of solid lipid nanoparticles (SLNs) and nanostructure lipid carriers (NLCs) have also been discussed in this article.

When Albumin Meets Liposomes: A Feasible Drug Carrier for Biomedical Applications.

Albumin, the most abundant protein in plasma, possesses some inherent beneficial structural and physiological characteristics that make it suitable for use as a drug delivery agent, such as an extraordinary drug-binding capacity and long blood retention, with a high biocompatibility. The use of these characteristics as a nanoparticle drug delivery system (DDS) offers several advantages, including a longer circulation time, lower toxicity, and more significant drug loading. To date, many innovative liposome preparations have been developed in which albumin is involved as a DDS. These novel albumin-containing liposome preparations show superior deliverability for genes, hydrophilic/hydrophobic substances and proteins/peptides to the targeting area compared to original liposomes by virtue of their high biocompatibility, stability, effective loading content, and the capacity for targeting. This review summarizes the current status of albumin applications in liposome-based DDS, focusing on albumin-coated liposomes and albumin-encapsulated liposomes as a DDS carrier for potential medical applications.

β-Cyclodextrin-containing chitosan-oligonucleotide nanoparticles improve insulin bioactivity, gut cellular permeation and glucose consumption.

The main objective of the present study was to develop a nanoparticulate drug delivery system that can protect insulin against harsh conditions in the gastrointestinal (GI) tract. The effects of the following employed techniques, including lyophilisation, cross-linking and nanoencapsulation, on the physicochemical properties of the formulation were investigated. We herein developed a nanocarrier via ionotropic gelation by using positively charged chitosan and negatively charged Dz13Scr. The lyophilised nanoparticles with optimal concentrations of tripolyphosphate (cross-linking agent) and β-cyclodextrin (stabilising agent) were characterised by using physical and cellular assays. The addition of cryoprotectants (1% sucrose) in lyophilisation improved the stability of nanoparticles, enhanced the encapsulation efficiency, and ameliorated the pre-mature release of insulin at acidic pH. The developed lyophilised nanoparticles did not display any cytotoxic effects in C2C12 and HT-29 cells. Glucose consumption assays showed that the bioactivity of entrapped insulin was maintained post-incubation in the enzymatic medium. Freeze-drying with appropriate cryoprotectant could conserve the physiochemical properties of the nanoparticles. The bioactivity of the entrapped insulin was maintained. The prepared nanoparticles could facilitate the permeation of insulin across the GI cell line.

Improved Dermal and Transdermal Delivery of Curcumin with SmartFilms and Nanocrystals.

Poor aqueous solubility of active compounds is a major issue in today’s drug delivery. In this study the smartFilm-technology was exploited to improve the dermal penetration efficacy of a poorly soluble active compound (curcumin). Results were compared to the dermal penetration efficacy of curcumin from curcumin bulk suspensions and nanocrystals, respectively. The smartFilms enabled an effective dermal and transdermal penetration of curcumin, whereas curcumin bulk- and nanosuspensions were less efficient when the curcumin content was similar to the curcumin content in the smartFilms. Interestingly, it was found that increasing numbers of curcumin particles within the suspensions increased the passive dermal penetration of curcumin. The effect is caused by an aqueous meniscus that is created between particle and skin if the dispersion medium evaporates. The connecting liquid meniscus causes a local swelling of the stratum corneum and maintains a high local concentration gradient between drug particles and skin. Thus, leading to a high local passive dermal penetration of curcumin. The findings suggest a new dermal penetration mechanism for active compounds from nano-particulate drug delivery systems, which can be the base for the development of topical drug products with improved penetration efficacy in the future.

Development of Polymeric Nanoparticles for Blood-Brain Barrier Transfer-Strategies and Challenges.

Neurological disorders such as Alzheimer's disease, stroke, and brain cancers are difficult to treat with current drugs as their delivery efficacy to the brain is severely hampered by the presence of the blood–brain barrier (BBB). Drug delivery systems have been extensively explored in recent decades aiming to circumvent this barrier. In particular, polymeric nanoparticles have shown enormous potentials owing to their unique properties, such as high tunability, ease of synthesis, and control over drug release profile. However, careful analysis of their performance in effective drug transport across the BBB should be performed using clinically relevant testing models. In this review, polymeric nanoparticle systems for drug delivery to the central nervous system are discussed with an emphasis on the effects of particle size, shape, and surface modifications on BBB penetration. Moreover, the authors critically analyze the current in vitro and in vivo models used to evaluate BBB penetration efficacy, including the latest developments in the BBB‐on‐a‐chip models. Finally, the challenges and future perspectives for the development of polymeric nanoparticles to combat neurological disorders are discussed.

Microbubbles versus Extracellular Vesicles as Therapeutic Cargo for Targeting Drug Delivery.

Extracellular vesicles (EVs) and microbubbles are nanoparticles in drug-delivery systems that are both considered important for clinical translation. Current research has found that both microbubbles and EVs have the potential to be utilized as drug-delivery agents for therapeutic targets in various diseases. In combination with EVs, microbubbles are capable of delivering chemotherapeutic drugs to tumor sites and neighboring sites of damaged tissues. However, there are no standards to evaluate or to compare the benefits of EVs (natural carrier) versus microbubbles (synthetic carrier) as drug carriers. Both drug carriers are being investigated for release patterns and for pharmacokinetics; however, few researchers have focused on their targeted delivery or efficacy. In this Perspective, we compare EVs and microbubbles for a better understanding of their utility in terms of delivering drugs to their site of action and future clinical translation.

Nano-fats for bugs: the benefits of lipid nanoparticles for antimicrobial therapy.

Bacterial infections are an imminent global healthcare threat evolving from rapidly advancing bacterial defence mechanisms that antibiotics fail to overcome. Antibiotics have been designed for systemic administration to target planktonic bacteria, leading to difficulties in reaching the site of localized bacterial infection and an inability to overcome the biological, chemical and physical barriers of bacteria, including biofilms, intracellular infections and antimicrobial resistance. The amphiphilic, biomimetic and antimicrobial properties of lipids provide a promising toolbox to innovate and advance antimicrobial therapies, overcoming the barriers presented by bacteria in order to directly and effectively treat recalcitrant infections. Nanoparticulate lipid-based drug delivery systems can enhance antibiotic permeation through the chemical and physical barriers of bacterial infections, as well as fuse with bacterial cell membranes, release antibiotics in response to bacteria and act synergistically with loaded antibiotics to enhance the total antimicrobial efficacy. This review explores the barriers presented by bacterial infections that pose bio-pharmaceutical challenges to antibiotics and how different structural and functional mechanisms of lipids can enhance antimicrobial therapies. Different nanoparticulate lipid-based systems are presented as valuable drug delivery systems to advance the efficacy of antibiotics, including liposomes, liquid crystalline nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers and lipid nanocarriers. In summary, liquid crystalline nanoparticles are emerging with the greatest potential for clinical applications and commercial success as an "all-rounder" advanced lipid-based antimicrobial therapy that overcomes the multiple biological, chemical and physical barriers of bacteria.

Single- versus Dual-Targeted Nanoparticles with Folic Acid and Biotin for Anticancer Drug Delivery.

Cancer is one of the major causes of death worldwide and its treatment remains very challenging. The effectiveness of cancer therapy significantly depends upon tumour-specific delivery of the drug. Nanoparticle drug delivery systems have been developed to avoid the side effects of the conventional chemotherapy. However, according to the most recent recommendations, future nanomedicine should be focused mainly on active targeting of nanocarriers based on ligand-receptor recognition, which may show better efficacy than passive targeting in human cancer therapy. Nevertheless, the efficacy of single-ligand nanomedicines is still limited due to the complexity of the tumour microenvironment. Thus, the NPs are improved toward an additional functionality, e.g., pH-sensitivity (advanced single-targeted NPs). Moreover, dual-targeted nanoparticles which contain two different types of targeting agents on the same drug delivery system are developed. The advanced single-targeted NPs and dual-targeted nanocarriers present superior properties related to cell selectivity, cellular uptake and cytotoxicity toward cancer cells than conventional drug, non-targeted systems and single-targeted systems without additional functionality. Folic acid and biotin are used as targeting ligands for cancer chemotherapy, since they are available, inexpensive, nontoxic, nonimmunogenic and easy to modify. These ligands are used in both, single- and dual-targeted systems although the latter are still a novel approach. This review presents the recent achievements in the development of single- or dual-targeted nanoparticles for anticancer drug delivery.