Nanosized Drug Carriers Research Articles

ТЕХНОЛОГИЯ ПОЛУЧЕНИЯ НАНОКАПСУЛ ДЛЯ ДОСТАВКИ ЛЕКАРСТВЕННЫХ СРЕДСТВ

Encapsulation of active ingredients in solid capsules made of biodegradable materials has attracted considerable attention over the past decades. In this brief review, we focus on the preparation of micro- and nanosized capsules and emulsions based on artificial peptides as a fully degradable material. It discusses various approaches to the preparation of polymer-based capsules as well as their critical properties such as size and stability. Dispersed polymer nanocapsules can serve as nanosized drug carriers to achieve controlled release as well as effective drug administration. The stability of the dispersion is determined by the type of surfactant and the nature of the outer shell of the capsule. Their release and degradation properties largely depend on the composition and structure of the capsule walls. Another important criterion is the capsule size, where the optimum is usually observed in the radius range of 100 to 500 nm. Nanocapsules can be prepared in fundamentally different ways: nanoprecipitation, emulsion diffusion, double emulsification, emulsion coacervation, polymer coating and layer-by-layer, and depend on the methodological and mechanistic aspects, encapsulation of the active substance and the raw materials used. Nanocapsules made using various biodegradable polymers are attracting increasing attention and are considered as one of the most promising drug delivery systems. Nanoencapsulated systems have a relatively higher intracellular absorption compared to microparticles, which can be modified depending on the surface charges of the nanocapsules and the hydrophilic or hydrophobic nature of the polymer used to form the shell.

Preparation of nanoparticle and nanoemulsion formulations containing repaglinide and determination of pharmacokinetic parameters in rats

Repaglinide (RPG) belongs to the class of drugs known as meglitinides and is used for improving and maintaining glycemic control in the treatment of patients with Type 2 diabetes. RPG is a Class II drug (BCS) because of its high permeability and low water solubility. It also undergoes hepatic first-pass metabolism. The oral bioavailability of RPG is low (about 56 %) due to these drawbacks. Our aim in this study is to prepare two different nano-sized drug carrier systems containing RPG (nanoparticle: RPG-PLGA-Zein-NPs or nanoemulsion: RPG-NE) and to carry out a pharmacokinetic study for these formulations. We prepared NPs using PLGA and Zein. In addition, a single NE formulation was developed using Tween 80 and Pluronic F68 as surfactants and Labrasol as co-surfactant. The droplet size values of the blank-NE and RPG-NE formulations were found to be less than 120 nm. The mean particle sizes of blank-Zein-PLGA-NPs and RPG-Zein-PLGA-NPs were less than 260 nm. The Cmax and tmax values of RPG-Zein-PLGA-NPs and RPG-NE (523 ± 65 ng/mL and 770 ± 91 ng/mL; 1.41 ± 0.46 h and 1.61 ± 0.37 h, respectively) were meaningfully higher than those of free RPG (280 ± 33 ng/mL; 0.72 ± 0.28 h) (p < 0.05). The AUC0-∞ values calculated for RPG-Zein-PLGA-NPs and RPG-NE were approximately 4.04 and 5.05 times higher than that calculated for free RPG. These nanosized drug delivery systems were useful in increasing the oral bioavailability of RPG. Moreover, the NE formulation was more effective than the NP formulation in improving the oral bioavailability of RPG (p < 0.05).

Dual Drug Delivery for Augmenting Bacterial Wound Complications via Tailored Ultradeformable Carriers.

Addressing the complex challenge of healing of bacterially infected wounds, this study explores the potential of lipid nanomaterials, particularly advanced ultradeformable particles (UDPs), to actively influence the wound microenvironment. The research introduces a novel therapeutic approach utilizing silver sulfadiazine (SSD) coupled with vitamin E (VE) delivered through UDPs (ethosomes/transferosomes/transethosomes). Comparative physicochemical characterization of these nanosized drug carriers reveals the superior stability of transethosomes, boasting a zeta potential of -36.5 mV. This method demonstrates reduced side effects compared to conventional therapies, with almost 90% SSD and 72% VE release achieved in wound pH in a sustained manner. Cytotoxicity assessment shows 60% cell viability even at the highest concentration (175 μg/mL), while hemolysis test demonstrates RBC lysis below 5% at a concentration of 250 μg/mL. Vitamin E-SSD-loaded transethosomes (VSTEs) significantly enhance cellular migration and proliferation, achieving 95% closure within 24 h, underscoring their promising efficacy. The synergistic method effectively reduces bacterial burden, evidenced by an 80% reduction in Escherichia coli and Staphylococcus aureus within the wound microenvironment. This approach offers a promising strategy to address complications associated with skin injuries.

Behavior of Self‐Disintegrating Microparticles at the Air/Mucus Interface

In recent years, highly specialized nanoscopic drug carriers have been developed, which can, e.g., traverse biological barriers, protect drugs against harsh physiological conditions, and release such drugs in a controlled manner. However, for the delivery of particles via the respiratory pathway, aerodynamic diameters in the range of several micrometers are required to achieve good lung deposition and biodistribution. To combine the favorable properties of inhalable, micron‐sized particles with the advantages of nanosized drug carriers, herein, dry‐powder, hybrid microparticles (h‐μPs), which disintegrate upon contact with moist surfaces (as present in the lung) to release the embedded nanoparticles into the mucosa, are introduced. Furthermore, a microfluidic setup, which mimics the air–gel interface of the mucosal airway epithelium, is presented. With this setup, the interaction of airborne h‐μPs with the mucosal interface on a microscopic level is investigated. In detail, the influence of the h‐μP charge on their deposition efficiency is tested and it is found that this process is governed by a combination of electrostatic interactions between the mucosal surface and the h‐μPs as well as hygroscopic effects. Thus, this approach can help to optimize inhalable drug carriers to increase the efficiency of pulmonary drug administration via the respiratory pathway.

Inhalable porous particles as dual micro-nano carriers demonstrating efficient lung drug delivery for treatment of tuberculosis

Inhalation therapy treating severe infectious disease is among the more complex and emerging topics in controlled drug release. Micron-sized carriers are needed to deposit drugs into the lower airways, while nano-sized carriers are of preference for cell targeting. Here, we present a novel and versatile strategy using micron-sized spherical particles with an excellent aerodynamic profile that dissolve in the lung fluid to ultimately generate nanoparticles enabling to enhance both extra- and intra-cellular drug delivery (i.e., dual micro-nano inhalation strategy). The spherical particles are synthesised through the condensation of nano-sized amorphous silicon dioxide resulting in high surface area, disordered mesoporous silica particles (MSPs) with monodispersed size of 2.43 μm. Clofazimine (CLZ), a drug shown to be effective against multidrug-resistant tuberculosis, was encapsulated in the MSPs obtaining a dry powder formulation with high respirable fraction (F.P.F. <5 μm of 50%) without the need of additional excipients. DSC, XRPD, and Nitrogen adsorption-desorption indicate that the drug was fully amorphous when confined in the nano-sized pores (9–10 nm) of the MSPs (shelf-life of 20 months at 4 °C). Once deposited in the lung, the CLZ-MSPs exhibited a dual action. Firstly, the nanoconfinement within the MSPs enabled a drastic dissolution enhancement of CLZ in simulated lung fluid (i.e., 16-fold higher than the free drug), increasing mycobacterial killing than CLZ alone (p = 0.0262) and reaching concentrations above the minimum bactericidal concentration (MBC) against biofilms of M. tuberculosis (i.e., targeting extracellular bacteria). The released CLZ permeated but was highly retained in a Calu-3 respiratory epithelium model, suggesting a high local drug concentration within the lung tissue minimizing risk for systemic side effects. Secondly, the micron-sized drug carriers spontaneously dissolve in simulated lung fluid into nano-sized drug carriers (shown by Nano-FTIR), delivering high CLZ cargo inside macrophages and drastically decreasing the mycobacterial burden inside macrophages (i.e., targeting intracellular bacteria). Safety studies showed neither measurable toxicity on macrophages nor Calu-3 cells, nor impaired epithelial integrity. The dissolved MSPs also did not show haemolytic effect on human erythrocytes. In a nutshell, this study presents a low-cost, stable and non-invasive dried powder formulation based on a dual micro-nano carrier to efficiently deliver drug to the lungs overcoming technological and practical challenges for global healthcare.

Lipid-Based Nanoparticle Functionalization with Coiled-Coil Peptides for In Vitro and In Vivo Drug Delivery.

For the delivery of drugs, different nanosized drug carriers (e.g., liposomes, lipid nanoparticles, and micelles) have been developed in order to treat diseases that afflict society. Frequently, these vehicles are formed by the self-assembly of small molecules to encapsulate the therapeutic cargo of interest. Over decades, nanoparticles have been optimized to make them more efficient and specific to fulfill tailor-made tasks, such as specific cell targeting or enhanced cellular uptake. In recent years, lipid-based nanoparticles in particular have taken center stage; however, off-targeting side effects and poor endosomal escape remain major challenges since therapies require high efficacy and acceptable toxicity.To overcome these issues, many different approaches have been explored to make drug delivery more specific, resulting in reduced side effects, to achieve an optimal therapeutic effect and a lower required dose. The fate of nanoparticles is largely dependent on size, shape, and surface charge. A common approach to designing drug carriers with targeting capability is surface modification. Different approaches to functionalize nanoparticles have been investigated since the attachment of targeting moieties plays a significant role in whether they can later interact with surface-exposed receptors of cells. To this end, various strategies have been used involving different classes of biomolecules, such as small molecules, nucleic acids, antibodies, aptamers, and peptides.Peptides in particular are often used since there are many receptors overexpressed in different specific cell types. Furthermore, peptides can be produced and modified at a low cost, enabling high therapeutic screening. Cell-penetrating peptides (CPPs) and cell-targeting peptides (CTPs) are frequently used for this purpose. Less studied in this context are fusogenic coiled-coil peptides. Lipid-based nanoparticles functionalized with these peptides are able to avoid the endolysosomal pathway; instead such particles can be taken up by membrane fusion, resulting in increased delivery of payload. Furthermore, they can be used for targeting cells/organs but are not directed at surface-exposed receptors. Instead, they recognize complementary peptide sequences, facilitating their uptake into cells.In this Account, we will discuss peptides as moieties for enhanced cytosolic delivery, targeted uptake, and how they can be attached to lipid-based nanoparticles to alter their properties. We will discuss the properties imparted to the particles by peptides, surface modification approaches, and recent examples showing the power of peptides for in vitro and in vivo drug delivery. The main focus will be on the functionalization of lipid-based nanoparticles by fusogenic coiled-coil peptides, highlighting the relevance of this concept for the development of future therapeutics.

Nano-steps in altered opioid pharmacokinetics: a perspective on potential drug delivery post-bariatric surgery applications

Multifaceted elements in addressing the obese population: the blood brain barrier, nano-sized drug carriers, criteria for bariatric surgery as a treatment option, and comparative portrayal of Roux-en-Y gastric bypass and vertical sleeve gastrectomy.

In Ukrainian

The aim of the work is the synthesis of nanodispersed phosphors based on lanthanum fluoride and phosphate, activated by terbium (LaF3:Tb3+ and LaРО4:Tb3+, respectively), promising for use in photodynamic therapy and optopharmacology, the study of their structural properties and luminescence spectra when excited by ultraviolet and X-ray radiation, as well as the possibility of their use in the composition of nanocomposites with magnetically sensitive nanosized Fe3O4 carriers and bioactive glass 60S. Nanocrystalline lanthanum fluoride and phosphate of hexagonal syngonium were synthesized, activated with terbium. The structural properties, chemical activity and biocompatibility of the surface, UV and X-ray luminescence spectra of the synthesized crystals were studied. The possibility of their use in the composition of nanocomposites with magnetically sensitive nanosized drug carriers and bioactive sol-gel glass is shown. The acid-base nature of the surface active centers of LaF3 and LaF3:Tb3+ NPs has been revealed. The proportions of negatively a––, positively a+ charged and neutral a0 active centers were calculated in the range of pH 2.4 – 12.7. The identified active surface centers can be represented by acidic (La3+) and basic (F-) Lewis centers, as well as basic Brønsted centers (OH- groups). The obtained data can be useful in optimizing the conditions of adsorption immobilization from a physiological solution of molecules of photosensitive substances (sensitizers) on the surface of phosphors based on lanthanum fluoride. Ensembles of particles of magnetically sensitive Fe3O4/LaF3:Tb3+ NCs of core-shell type were synthesized. The conditions of synthesis of NCs did not significantly change the magnetic properties of their cores – the initial single-domain Fe3O4 NPs. Composites of bioglass 60S with nanodispersed crystalline LaF3:Tb3+ and LaPO4:Tb3+ in the dry state and in distilled water medium demonstrated the presence of luminescence when excited by UV and X-ray radiation. The given data indicate the prospects of research of nanodispersed phosphors based on lanthanum fluoride and phosphate, their composites with magnetically sensitive nanosized carriers and bioactive glass, for use in optopharmacology and photodynamic therapy of tumor diseases, in particular, localized in organs of skull and bone tissues. In addition, research results can be useful for technical applications, in particular, in the creation of fluorescent detectors of high-energy electromagnetic radiation, development of photo- and optoelectronic devices, etc.

Herbal Nano Formulations for Topical Drug Delivery: Prospective for Multiple Skin Disorders

Dermatological conditions exert their influence across the globe, encompassing a broad spectrum of maladies ranging from commonplace afflictions such as acne and eczema to more formidable challenges like psoriasis and cutaneous malignancies. The realm of topical drug delivery stands as a pivotal modality in the domain of dermatology, proffering precise and minimally invasive therapeutic avenues. In recent times, the fusion of herbal curatives with the marvels of nanotechnology has surfaced as a pioneering strategy. This comprehensive review undertakes an exploration of the amalgamation of herbal constituents within nano-sized drug carriers, catering to the domain of topical applications, with a particular emphasis on their potential to address a myriad of dermatological conditions. The outset of this review is dedicated to the elucidation of the meticulous criteria governing the selection of herbal components and the underpinning rationale behind their integration into nanoscale formulations, thereby spotlighting the rich heritage of botanical remedies intrinsic to traditional medical practices. Subsequently, meticulous scrutiny of nanotechnology’s role in the domain of cutaneous drug conveyance ensues, elucidating diverse nanoparticle typologies and their respective mechanisms of therapeutic action. The crux of this review centers upon the manifold approaches of herbal nanoformulations, encompassing lipid-based matrices, polymer-driven carriers, liposomal constructs, micellar entities, nanoemulsions, solid lipid nanoparticles, dendritic platforms, and nanogels. For each of these approaches, illustrative case studies are presented, thereby affording perspicacity to their bespoke utility in the management of diverse dermatological conditions. In the ensuing discourse, the potential of herbal nanoformulations in the amelioration of acne, mitigation of psoriatic manifestations, alleviation of eczematous distress, acceleration of wound healing, attenuation of scar formation, and prophylaxis against cutaneous neoplasia is subjected to meticulous examination. The purview extends to the discerning analysis of clinical trials and the practice informed by empirical evidence, thereby shedding illuminative insight into the safety and efficacy profiles of these innovative formulations. Concomitantly, the challenges entailing regulatory adherence, standardization, and the enforcement of rigorous quality control are thoughtfully addressed, with a subsequent contemplation of the trajectories shaping the future of this burgeoning discipline. In summation, this review underscores the intrinsic value of interdisciplinary synergism and underscores the compelling imperative for relentless research efforts that propel herbal nanoformulations to the vanguard of mainstream dermatological therapeutics. In doing so, a new epoch in the management of cutaneous disorders is heralded, one that promises safe, efficacious, and patient-centric interventions, thus ushering in a transformative era in the domain of dermatological care.

Impact of a Polymer-Based Nanoparticle with Formoterol Drug as Nanocarrier System In Vitro and in an Experimental Asthmatic Model.

The implementation of nanotechnology in pulmonary delivery systems might result in better and more specific therapy. Therefore, a nano-sized drug carrier should be toxicologically inert and not induce adverse effects. We aimed to investigate the responses of a polymer nano drug carrier, a lysine poly-hydroxyethyl methacrylate nanoparticle (NP) [Lys-p(HEMA)], loaded with formoterol, both in vitro and in vivo in an ovalbumin (OVA) asthma model. The successfully synthesized nanodrug formulation showed an expectedly steady in vitro release profile. There was no sign of in vitro toxicity, and the 16HBE and THP-1 cell lines remained vital after exposure to the nanocarrier, both loaded and unloaded. In an experimental asthma model (Balb/c mice) of ovalbumin sensitization and challenge, the nanocarrier loaded and unloaded with formoterol was tested in a preventive strategy and compared to treatment with the drug in a normal formulation. The airway hyperresponsiveness (AHR) and pulmonary inflammation in the bronchoalveolar lavage (BAL), both cellular and biochemical, were assessed. The application of formoterol as a regular drug and the unloaded and formoterol-loaded NP in OVA-sensitized mice followed by a saline challenge was not different from the control group. Yet, both the NP formulation and the normal drug application led to a more deteriorated lung function and increased lung inflammation in the OVA-sensitized and -challenged mice, showing that the use of the p(HEMA) nanocarrier loaded with formoterol needs more extensive testing before it can be applied in clinical settings.

Diabetology and Nanotechnology: A Compelling Combination

Abstract:: The convergence of diabetology and nanotechnology has emerged as a promising synergy with the potential to revolutionize the management and treatment of diabetes mellitus. Diabetes, a complex metabolic disorder affecting millions worldwide, necessitates innovative approaches to enhance monitoring, diagnosis, and therapeutic interventions. Nanotechnology, a burgeoning field that manipulates materials at the nanoscale, offers unprecedented opportunities to address the challenges posed by diabetes. This abstract explores the multifaceted interface between diabetology and nanotechnology, highlighting key areas of integration. Nanotechnology has paved the way for the development of advanced glucose monitoring systems with enhanced accuracy, sensitivity, and patient convenience. Miniaturized biosensors and implantable devices equipped with nanoscale materials enable continuous and real-time glucose monitoring, empowering individuals with diabetes to make timely and informed decisions about their dietary and insulin management. Furthermore, nanotechnology has facilitated breakthroughs in targeted drug delivery, addressing the limitations of conventional therapies in diabetes treatment. Nano-sized drug carriers can improve bioavailability, enable controlled release, and enhance the selectivity of therapeutic agents, minimizing side effects and optimizing treatment outcomes. Moreover, nanoengineered materials have opened avenues for tissue engineering and regenerative medicine, offering the potential to restore damaged pancreatic islets and insulin-producing cells. The amalgamation of diabetology and nanotechnology also holds promise for early disease detection and prevention. Nanoscale diagnostic tools, such as biomarker-based nanoprobes and lab-onchip devices, offer rapid and accurate detection of diabetes-related biomolecules, enabling timely interventions and reducing the risk of complications. However, this compelling combination also presents challenges that warrant careful consideration. Safety, biocompatibility, regulatory approval, and ethical implications are crucial factors that demand meticulous evaluation during the translation of nanotechnology-based solutions into clinical practice. In conclusion, the integration of diabetology and nanotechnology represents a transformative paradigm that has the potential to reshape the landscape of diabetes management. By harnessing the unique properties of nanoscale materials, researchers and clinicians are poised to usher in an era of personalized and precise diagnostics, therapeutics, and preventive strategies for diabetes mellitus. As advancements in nanotechnology continue to unfold, the journey towards realizing the full potential of this compelling combination remains an exciting frontier in medical science.

Therapeutic Copolymer from Salicylic Acid and l-Phenylalanine as a Nanosized Drug Carrier for Orthotopic Breast Cancer with Lung Metastasis.

Nanoparticle (NP)-mediated drug delivery systems are promising for treating various diseases. However, clinical translation has been delayed by a variety of limitations, such as weak drug loading, nonspecific drug leakage, lack of bioactivity, and short blood circulation. These issues are in part due to the unsatisfactory function of biomaterials for nanocarriers. In addition, the synthesis procedures of drug carrier materials, especially polymers, were usually complicated and led to high cost. In this report, a bioactive copolymer of hydroxy acid and amino acid, poly(salicylic acid-co-phenylalanine) (PSP), was developed for the first time via a one-step rapid and facile synthesis strategy. The PSP could self-assemble into NPs (PSP-NPs) to co-load relatively hydrophilic sphingosine kinase 1 inhibitor (PF543 in HCl salt format) and highly hydrophobic paclitaxel (PTX) to form PF543/PTX@PSP-NPs with efficient dual drug loading. Encouragingly, PF543/PTX@PSP-NPs showed long blood circulation, good stability, and high tumor accumulation, leading to significantly enhanced therapeutic effects on breast cancer. Furthermore, PF543/PTX@PSP-NPs could additionally suppress the lung metastasis of breast cancer, and more importantly, the PSP-NPs themselves as therapeutic nanocarriers also showed an anti-breast cancer effect. With these combined advantages, this new polymer and corresponding NPs will provide valuable insights into the development of new functional polymers and nanomedicines for important diseases.

Per-thiolated cyclodextrins: Nanosized drug carriers providing a prolonged gastrointestinal residence time

Oral delivery is one of the most advantageous routes for drug administration, but due to the short gastrointestinal (GI) residence time, the systemic uptake of poorly absorbed drugs is too low to reach the desired therapeutic effect. In order to prolong the GI residence time of orally given drugs, we synthesized per-thiolated β-cyclodextrin (CD) as mucoadhesive drug carrier. Due to thiolation, the mucoadhesive properties of CD on porcine intestinal mucosa were increased 2-fold. In vivo studies showed 4 h after oral administration, a 19.4-fold, 2.1- fold, and 4.5-fold higher quantity of per-thiolated β-CD vs. unmodified β-CD in the stomach, duodenum/jejunum, and the ileum of rat model, respectively. Eight hours after oral administration, still, 60 % of per-thiolated CD, but no native CD remained in the GI tract. These results provide evidence that due to thiolation of β-CD, GI-residence time can be essentially prolonged.

Scope of solid lipid nanoparticles per se as all-purpose moisturising sunscreens

Sun blocking effect is defined as the ability to protect the skin against ultraviolet-induced damage, indicated in terms of sun protection factor (SPF). This protection can be physical or chemical. Chemical sun protecting agents can permeate the skin leading to toxic side effects. Solid lipid nanoparticles (SLNs), also known as lipid carriers have been widely investigated across the world and have evolved as promising nano-sized drug carriers. In this study, different placebo SLN formulations demonstrate sun protection. Five different SLN formulations (F1–F5) with varying lipid content were developed using three industry amenable techniques viz. high speed stirring (HSH), high pressure homogenisation (HPH) and microemulsification method (MEM). A correlation between morphology (HR TEM), particle size-polydispersity index (DLS), sun protection factor (SPF) and occlusive effect (OE) were established. Results indicated promising SPF (6.0–24.0) and hydrating effects (OE 6.0–71.0) of spherical, mono disperse lipidic nanoparticles with lipid content of ≥4%. SLNs were found to offer hydration effects comparable to Vaseline® petroleum jelly (OE 71.0 and 82.0, respectively). Hence, SLNs per se can be regarded as: (i) safe alternative to current toxic chemical sunscreen agents, or (ii) carriers for latter, employed at low concentration to provide similar effects, and (iii) as suitable moisturisers.

Mechanisms of Uptake and Membrane Curvature Generation for the Internalization of Silica Nanoparticles by Cells.

Nanosized drug carriers enter cells via active mechanisms of endocytosis but the pathways involved are often not clarified. Cells possess several mechanisms to generate membrane curvature during uptake. However, the mechanisms of membrane curvature generation for nanoparticle uptake have not been explored so far. Here, we combined different methods to characterize how silica nanoparticles with a human serum corona enter cells. In these conditions, silica nanoparticles are internalized via the LDL receptor (LDLR). We demonstrate that despite the interaction with LDLR, uptake is not clathrin-mediated, as usually observed for this receptor. Additionally, silencing the expression of different proteins involved in clathrin-independent mechanisms and several BAR-domain proteins known to generate membrane curvature strongly reduces nanoparticle uptake. Thus, nanosized objects targeted to specific receptors, such as here LDLR, can enter cells via different mechanisms than their endogenous ligands. Additionally, nanoparticles may trigger alternative mechanisms of membrane curvature generation for their internalization.

Triblock Copolymer Micelles with Tunable Surface Charge as Drug Nanocarriers: Synthesis and Physico-Chemical Characterization.

Polymeric micelles have gained increasing interest as efficient drug delivery systems for cancer treatment and diagnosis. The aim of the present study was to construct and to evaluate novel polymeric nanosized drug carriers with tunable surface charges. Initially, amphiphilic triblock copolymers with predetermined molar mass characteristics were synthesized by applying controlled polymerization techniques. The copolymers self-assembled in aqueous media into core–shell spherical micelles, comprising a biodegradable hydrophobic poly(D,L-lactide) core, positively charged middle layer of poly((2-dimethylamino)ethyl methacrylate), and an outer shell of neutral hydrophilic poly(oligo(ethylene glycol) methyl ether methacrylate), with various densities of the short polyether side chains. The block copolymer micelles with average diameters of about 70 nm and surface charges varying from strongly positive to neutral were characterized and loaded with the model, natural, hydrophobic drug curcumin. Characteristics such as drug loading efficiency, in-vitro drug release profiles, and stability under physiological conditions were evaluated and discussed in terms of nanocarriers’ composition. As a result, the most promising candidates for potential application in nanomedicine were identified.

Synthesis, Self-Assembly and In Vitro Cellular Uptake Kinetics of Nanosized Drug Carriers Based on Aggregates of Amphiphilic Oligomers of N-Vinyl-2-pyrrolidone.

Development of nanocarrier-based drug delivery systems is a major breakthrough in pharmacology, promising targeted delivery and reduction in drug toxicity. On the cellular level, encapsulation of a drug substantially affects the endocytic processes due to nanocarrier–membrane interaction. In this study we synthesized and characterized nanocarriers assembled from amphiphilic oligomers of N-vinyl-2-pyrrolidone with a terminal thiooctadecyl group (PVP-OD). It was found that the dissolution free energy of PVP-OD depends linearly on the molecular mass of its hydrophilic part up to = 2 × 104, leading to an exponential dependence of critical aggregation concentration (CAC) on the molar mass. A model hydrophobic compound (DiI dye) was loaded into the nanocarriers and exhibited slow release into the aqueous phase on a scale of 18 h. Cellular uptake of the loaded nanocarriers and that of free DiI were compared in vitro using glioblastoma (U87) and fibroblast (CRL2429) cells. While the uptake of both DiI/PVP-OD nanocarriers and free DiI was inhibited by dynasore, indicating a dynamin-dependent endocytic pathway as a major mechanism, a decrease in the uptake rate of free DiI was observed in the presence of wortmannin. This suggests that while macropinocytosis plays a role in the uptake of low-molecular components, this pathway might be circumvented by incorporation of DiI into nanocarriers.

Biomimetic-Coated Nanoplatform with Lipid-Specific Imaging and ROS Responsiveness for Atherosclerosis-Targeted Theranostics.

Atherosclerosis is one of the leading causes of cardiovascular diseases and is triggered by endothelial damage, local lipid cumulation, and inflammation. Despite the conventional medication treatment, nanosized drug carriers have become promising candidates for efficient drug delivery with lower side effects. However, the development of problems in nanocarriers such as drug leakage, accumulating efficiency, and accurate drug release, as well as the specific recognition of atherosclerotic plaques, still needs to be checked. In this study, a lipid-specific fluorophore (LFP) has been designed, which is further packaged with a reactive oxygen species (ROS)-responsive prednisolone (Pred) prodrug copolymer [PMPC-P(MEMA-co-PDMA)] to self-assemble into LFP@PMMP micelles. LFP@PMMP can be further coated with red blood cell (RBC) membrane to obtain surface-biomimetic nanoparticles (RBC/LFP@PMMP), demonstrating prolonged circulation, minimal drug leakage, and better accumulation at the plaques. With ROS responsiveness, RBC/LFP@PMMP can be interrupted at inflammatory atherosclerotic tissue with overexpressed ROS, followed by the dissociation of Pred from the polymer backbone and the release of LFP to combine with the rich lipid in the plaques. An accurate anti-inflammation and lipid-specific fluorescent imaging of atherosclerotic lesions was performed and further proven on ApoE-/- mice; this holds prospective potential for atherosclerosis theranostics.

ApoE-Targeting Increases the Transfer of Solid Lipid Nanoparticles with Donepezil Cargo across a Culture Model of the Blood-Brain Barrier.

Pharmacological treatment of central nervous system (CNS) disorders is difficult, because the blood–brain barrier (BBB) restricts the penetration of many drugs into the brain. To solve this unmet therapeutic need, nanosized drug carriers are the focus of research efforts to develop drug delivery systems for the CNS. For the successful delivery of nanoparticles (NPs) to the brain, targeting ligands on their surface is necessary. Our research aim was to design a nanoscale drug delivery system for a more efficient transfer of donepezil, an anticholinergic drug in the therapy of Alzheimer’s disease across the BBB. Rhodamine B-labeled solid lipid nanoparticles with donepezil cargo were prepared and targeted with apolipoprotein E (ApoE), a ligand of BBB receptors. Nanoparticles were characterized by measurement of size, polydispersity index, zeta potential, thermal analysis, Fourier-transform infrared spectroscopy, in vitro release, and stability. Cytotoxicity of nanoparticles were investigated by metabolic assay and impedance-based cell analysis. ApoE-targeting increased the uptake of lipid nanoparticles in cultured brain endothelial cells and neurons. Furthermore, the permeability of ApoE-targeted nanoparticles across a co-culture model of the BBB was also elevated. Our data indicate that ApoE, which binds BBB receptors, can potentially be exploited for successful CNS targeting of solid lipid nanoparticles.

Lecithin coating as universal stabilization and functionalization strategy for nanosized drug carriers to overcome the blood-brain barrier.

Lecithin coated cholesteryl oleate (ChOl) based nanoparticles (NPs) imitating natural lipoproteins represent a new and promising drug carrier strategy to cross the blood-brain barrier (BBB). In such systems lecithin serves as stabilizing as well as functionalizing agent and enables the adsorptive binding of apolipoprotein E3 (ApoE) as potential drug targeting ligand. The present work is focused on the effect of size reduction on the lecithin coating and ApoE binding. Furthermore, the transferability of this lecithin coating strategy to other NP cores, namely polylactic-co-glycolic acid (PLGA) and polylactic acid (PLA), is investigated in order to provide a universal strategy for a wide range of cores to overcome the BBB. The ChOl NPs' size was successfully reduced from 100nm to 70nm. Varying the core size of ChOl NPs illustrated, that the at least needed lecithin amount for sufficient stabilization could be calculated surface area dependently. However, the size reduction led to reduced dye loading per NP and increased ApoE need per NP mass. These effects turned out as huge disadvantages of smaller NPs by weakening the observed ApoE mediated effects. Nevertheless, the extended understanding of the lecithin coating could be used to transfer the concept to other core materials. PLGA and PLA NPs were investigated as alternative core materials for lecithin coating. PLGA was found to be unsuitable, whereas in the case of PLA sufficient stabilization and 100% adsorptive binding efficiency to ApoE could be achieved. The ApoE mediated effects of transcytosis at an in vitro BBB model by bypassing lysosomes were reproduced in even stronger quantities than with a ChOl core, proving lecithin coating as transferable strategy to disguise various NPs with a certain lipophilicity as lipoproteins.