Encapsulation Of Drugs In Nanoparticles Research Articles

Novel cutting edge nano-strategies to address old long-standing complications in cardiovascular diseases. A comprehensive review.

Cardiovascular diseases (CVD) impact a substantial portion of the global population and represent a significant threat to experiencing life-threatening outcomes, such as atherosclerosis, myocardial infarction, stroke and heart failure. Despite remarkable progress in pharmacology and medical interventions, CVD persists as a major public health concern, and now ranks as the primary global cause of death and the highest consumer of global budgets. Ongoing research endeavours persist in seeking novel therapeutic avenues and interventions to deepen our understanding of CVD, enhance prevention measures, and refine treatment strategies. Nanotechnology applied to the development of new molecular probes with diagnostic and theranostic properties represents one of the greatest technological challenges in preclinical and clinical research. The application of nanotechnology in cardiovascular medicine holds great promise for advancing our understanding of CVDs and revolutionizing their diagnosis and treatment strategies, ultimately improving patient care and outcomes. In addition, the capacity of drug encapsulation in nanoparticles has significantly bolstered their biological safety, bioavailability and solubility. In combination with imaging technologies, molecular imaging has emerged as a pivotal therapeutic tool, offering insight into the molecular events underlying disease and facilitating targeted treatment approaches. Here, we present a comprehensive overview of the recent advancements in targeted nanoparticle approaches for diagnosing CVDs, encompassing molecular imaging techniques, underscoring the significant progress in theranostic, as a novel and promising therapeutic strategy.

Neurosurgically-Applied Chemotherapy for Childhood Brain Tumours Arising in the Posterior Fossa Using a Biodegradable Paste

Abstract AIMS This project aims to develop a local drug delivery system for treatment of childhood medulloblastoma (MB) and atypical teratoid/rhabdoid tumours (AT/RT), malignant brain neoplasms occurring in the posterior fossa for which prognoses remains poor. Our goal is to repurpose drug compounds reported as effective against MB and AT/RT, but which either cannot cross the blood-brain-barrier (BBB) or have not been assessed for localised delivery. We have developed a novel intra-cavity drug delivery system, consisting of polymer microparticles made from poly(DL-lactic-co-glycolic acid) and poly(ethylene glycol) (PLGA/PEG) which will be employed to release drugs over several weeks. METHOD Cell toxicity assays were undertaken using drugs of interest against an in vitro panel of relevant MB and AT/RT cell lines. PLGA/PEG paste incorporating the drugs were prepared and release kinetics assessed. RESULTS IC50 values of the drugs were assessed across all cell lines and a range of potencies were observed, with optimum conditions identified as dual treatments of PG545 (heparanse inhibitor) with CHIR99021 (glycogen synthase kinase-3 inhibitor) for MB and ribavirin (anti-viral) with CHIR99021 for AT/RT. Importantly, it was noted that the drugs retained their cytotoxicity following release from PLGA/PEG. Furthermore, release kinetics were finely tuned through careful control of the composition through addition of excipients and encapsulation of drugs in nanoparticles, and a library of formulations were prepared. CONCLUSION A local drug delivery system for MB and AT/RT has been developed and an optimum formulation, based upon in vitro cell assays and release kinetics, has been identified for in vivo efficacy studies in orthotopic models.

Structure, energetics and thermodynamics of PLGA condensed phases from Molecular Dynamics

Poly-lactic-co-glycolic acid (PLGA) is a biodegradable co-polymer with common use in nanoparticle drug encapsulation. Although well studied experimentally, the mechanical behavior of PLGA is not well understood at the atomic level. Here, we develop atomic charges for the all-atom Generalized Amber Force Field (GAFF) and conduct all-atom molecular dynamics simulations of PLGA with a 50:50 ratio between its two constituent monomers for five samples of the polymer condensed phases that span 1579 u to 20183 u in molecular weight. We predict several PLGA properties that will improve the knowledge of its atomistic organization in the glassy solid, rubber, and liquid states. We report the impact of molecular weight on cohesive energy, solubility, thermodynamic response properties, structural properties related to chain entanglement, and glass transition temperatures. Properties are compared against known experimental values when available. We find that the restrained electrostatic potential atomic charges are better for simulating the caloric curve leading to the glass transition temperature, which agrees very well with experiments.

Microfluidic Synthesis of Rifampicin Loaded PLGA Nanoparticles and the Effect of Formulation on their Physical and Antibacterial Properties

The encapsulation of drugs in nanoparticles serves as an effective way to modify pharmacokinetics and therapeutic efficacy. Nanoparticles comprised of poly(d,l-lactide-co-glycolide) (PLGA) are well suited for this purpose; they are accessible using multiple synthesis methods, are highly biocompatible and biodegradable, and possess desirable drug release properties. In the present study, we have explored the effects of various formulation parameters on the physical properties of PLGA nanoparticles synthesised using a microfluidic assisted nanoprecipitation method and loaded with a model drug. PLGA nanoparticles, with diameters ranging from 165–364nm, were produced using three alternate stabilisers; poly(vinyl alcohol) (PVA), d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), and didodecyldimethylammonium bromide (DMAB). Three additional formulations used PVA in addition to 20wt-% 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), and oleic acid. Spectrophotometric analysis demonstrated that the use of PVA increased the loading efficiency over that of TPGS and DMAB formulations, while the inclusion of oleic acid in the PVA formulation resulted in a further 3-fold increase in loading efficiency. Invitro release studies demonstrate that the inclusion of lipid additives significantly alters release kinetics; release was most rapid and complete in the formulation containing oleic acid, while the addition of DOTAP and DOTMA significantly reduced release rates. Finally, the antimicrobial activity of each formulation was tested against Staphylococcus aureus and Bacillus cereus, with minimum inhibitory concentrations nearing or exceeding that of free rifampicin.

Optimization of the Single Emulsion Method for Encapsulation of a Cancer Drug in Nanoparticles.

The goal of this study is to apply and optimize the single emulsion technique for encapsulation of an anti-tumor drug, Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), in nanoparticles (NPs) of poly(lactic-co-glycolic acid) (PLGA), as a step towards targeted delivery of this drug. We previously showed that the nanoprecipitation technique can effectively produce PLGA NPs carrying this drug. Here, we aim to examine the single emulsion technique as an alternative for the preparation of these NPs and to compare the resultant NPs to those from nanoprecipitation. We fabricated NPs with variations in (i) injection rate, (ii) the amount of surfactant poly (vinyl alcohol) (PVA) in aqueous phase, and (iii) concentration of PLGA in the organic phase. These NPs were characterized for size, surface potential, and encapsulation efficiency. The results revealed that increasing the injection rate (from manual addition to 90 mL/hr via syringe pump) greatly reduced the size of NPs (by 48%) and decreasing the PVA concentration in the aqueous phase (from 5 to 1% w/v) further reduced the NP size (by 32%) to 329 nm. All tested NP formulations had negative surface potential, suggesting good colloidal stability for these NPs. Focusing on the optimal injection rate and PVA percentage, we found that reducing the concentration of PLGA, from 100 to 1 mg/mL, significantly reduced the NP size to 136 nm, which is close to the optimal range for cancer therapeutic delivery. NPs produced by this method had a high encapsulation efficiency of 77% for Dp44mT and reducing the PLGA concentration slightly lowered this value to 74%. Overall, these NPs were comparable to those produced by nanoprecipitation and can thus, serve as an effective alternative for delivery of Dp44mT to cancer cells.

Design of antiretroviral drug-polymeric nanoparticles laden buccal films for chronic HIV therapy in paediatrics

Anti-HIV drug Lamivudine exhibit shorter half-life (2 h) and poor bioavailability (62% in paediatric patients), multiple dosing is required. To overcome the limitations, nanoparticles loaded buccal film was developed for prolonged drug release and improved efficiency. Nanoprecipitated Lamivudine-Eudragit E100 polymeric nanoparticles exhibited average particle size of 338 nm with polydispersity index 0.315. Buccal films prepared by solvent casting technique using sodium carboxy methyl cellulose and polyvinyl pyrrolidone (3:2) loaded with the nanoparticles showed initial drug release of 49% followed by sustained release to reach the maximum of 93% at the end of 8 h. Encapsulation of drug in nanoparticles and the film was confirmed through scanning electron microscopy, thermal and crystal characterization. Sustained drug release through Fickian diffusion mechanism from the matrix system was confirmed. The optimized formulation could be used to enhance therapeutic effect at reduced dose and side effects, especially for the paediatric anti-HIV therapy.

Biotransporting Biocatalytic Reactors toward Therapeutic Nanofactories.

Drug‐delivery systems (DDSs), in which drug encapsulation in nanoparticles enables targeted delivery of therapeutic agents and their release at specific disease sites, are important because they improve drug efficacy and help to decrease side effects. Although significant progress has been made in the development of DDSs for the treatment of a wide range of diseases, new approaches that increase the scope and effectiveness of such systems are still needed. Concepts such as nanoreactors and nanofactories are therefore attracting much attention. Nanoreactors, which basically consist of vesicle‐encapsulated enzymes, provide prodrug conversion to therapeutic agents rather than simple drug delivery. Nanofactories are an extension of this concept and combine the features of nanoreactors and delivery carriers. Here, the required features of nanofactories are discussed and an overview of current strategies for the design and fabrication of different types of nanoreactors, i.e., systems based on lipid or polymer vesicles, capsules, mesoporous silica, viral capsids, and hydrogels, and their respective advantages and shortcomings, is provided. In vivo applications of biocatalytic reactors in the treatment of cancer, glaucoma, neuropathic pain, and alcohol intoxication are also discussed. Finally, the prospects for further progress in this important and promising field are outlined.

Therapeutic implications of nano-encapsulated rifabutin, azithromycin & ethambutol against experimental Mycobacterium avium infection in mice.

Background & objectives:Mycobacterium avium causes atypical infection in both immunocompetent and immunocompromised individuals. Conventional chemotherapy for M. avium infection is not efficient due to lengthy course of treatment and drug-associated toxic side effects. The present study was aimed at reducing dosing frequency of antimicrobial regimen consisting of azithromycin (AZM), rifabutin (RBT) and ethambutol (EMB) by encapsulation of drugs in nanoparticles (NPs) in experimental M. avium infection in mice.Methods:Poly (DL-lactide-co-glycolide) NPs containing anti-M. avium drugs were prepared, characterized and studied for their pharmacokinetics and pharmacodynamics parameters. Drug-loaded NPs were further analyzed for their therapeutic efficacy against experimental M. avium infection in mice.Results:Drug-loaded NPs were of size 227.3±16.4 for RBT, 334.35±11.7 for AZM and 509.85±20.5 for EMB with smooth surface morphology and negative zeta potential. AZM, EMB and RBT from NPs were detectable for 6, 4 and 5 days, respectively, in the mice plasma, whereas free drugs were cleared from mice circulation within 24 h. Chemotherapeutic effects of weekly administered drug-loaded NPs were equivalent to daily administered free drugs.Interpretation & conclusions:Our findings showed that NPs gave sustained release of drugs inside plasma and organs, thus decreasing dosage frequency, and their weekly dosage had therapeutic efficacy equivalent to daily dosage of free drugs.

Ultrasound Improves the Delivery and Therapeutic Effect of Nanoparticle-Stabilized Microbubbles in Breast Cancer Xenografts

Compared with conventional chemotherapy, encapsulation of drugs in nanoparticles can improve efficacy and reduce toxicity. However, delivery of nanoparticles is often insufficient and heterogeneous because of various biological barriers and uneven tumor perfusion. We investigated a unique multifunctional drug delivery system consisting of microbubbles stabilized by polymeric nanoparticles (NPMBs), enabling ultrasound-mediated drug delivery. The aim was to examine mechanisms of ultrasound-mediated delivery and to determine if increased tumor uptake had a therapeutic benefit. Cellular uptake and toxicity, circulation and biodistribution were characterized. After intravenous injection of NPMBs into mice, tumors were treated with ultrasound of various pressures and pulse lengths, and distribution of nanoparticles was imaged on tumor sections. No effects of low pressures were observed, whereas complete bubble destruction at higher pressures improved tumor uptake 2.3 times, without tissue damage. An enhanced therapeutic effect was illustrated in a promising proof-of-concept study, in which all tumors exhibited regression into complete remission.

Polymer-surfactant nanoparticles for improving oral bioavailability of doxorubicin

The oral bioavailability of several clinically relevant drugs is compromised because of their limited absorption across the gastrointestinal tract. Active efflux of the drug by transporters such as P-glycoprotein (P-gp) present on the luminal side of the intestinal epithelial cells limits drug absorption. Encapsulation of drugs in nanoparticles can reduce transporter-mediated efflux and increase drug absorption. The purpose of this manuscript is to determine if the bioavailability of doxorubicin, a P-gp substrate, could be increased by encapsulation in nanoparticles. We synthesized polymer-surfactant nanoparticles comprised of a sodium alginate core complexed with doxorubicin and stabilized by the surfactant Aerosol OT (AOT). Encapsulation of doxorubicin in nanoparticles improved its transport across cell monolayers as evidenced by Transwell® studies. Drug uptake studies were carried out in cells overexpressing P-gp and those with basal levels of P-gp. These studies revealed that AOT inhibited P-gp activity and improved drug uptake in P-gp expressing cells by ~5-6-fold. Increase in drug uptake was found only in cells expressing P-gp and was limited to P-gp substrates. We also determined the in vivo oral bioavailability of the nanoparticle formulation of doxorubicin in mice. Doxorubicin delivered in the form of nanoparticles had a higher bioavailability relative to that with the free drug. This study shows that the oral bioavailability of P-gp substrates such as doxorubicin can be enhanced by delivering them in AOT-alginate nanoparticles.

Past, Present, and Future Drug Delivery Systems for Antiretrovirals

The human immunodeficiency virus has infected millions of people and the epidemic continues to grow rapidly in some parts of the world. Antiretroviral (ARV) therapy has provided improved treatment and prolonged the life expectancy of patients. Moreover, there is growing interest in using ARVs to protect against new infections. Hence, ARVs have emerged as our primary strategy in combating the virus. Unfortunately, several challenges limit the optimal performance of these drugs. First, ARVs often require life-long use and complex dosing regimens. This results in low patient adherence and periods of lapsed treatment manifesting in drug resistance. This has prompted the development of alternate dosage forms such as vaginal rings and long-acting injectables that stand to improve patient adherence. Another problem central to therapeutic failure is the inadequate penetration of drugs into infected tissues. This can lead to incomplete treatment, development of resistance, and viral rebound. Several strategies have been developed to improve drug penetration into these drug-free sanctuaries. These include encapsulation of drugs in nanoparticles, use of pharmacokinetic enhancers, and cell-based drug delivery platforms. In this review, we discuss issues surrounding ARV therapy and their impact on drug efficacy. We also describe various drug delivery–based approaches developed to overcome these issues.

Abstract B21: Use of polymeric nanoparticles for the delivery of YM155 to glioma cells in vitro and in vivo

Abstract YM155 (Sepantronium Bromide) is a potent survivin inhibitor that is the subject of clinical trials for multiple types of cancer including melanoma, lypmphoma, lung cancer, prostate and breast cancer. YM155 is a therapeutic candidate for the treatment of glioblastoma (GBM), however, its rapid plasma clearance and minimal blood-brain barrier penetration are obstacles to clinical translation (1). The encapsulation of drugs in nanoparticles can help increase drug circulation time by reducing clearance, and nanoparticles have the ability to increase drug concentration in the tumor through the enhanced permeability and retention effect (2). Here, we encapsulated YM155 in poly(lactic acid)-b-poly(ethylene glycol) nanoparticles (NPs) and evaluated the potency of YM155 in 4 glioma cell lines in vitro. Additionally, we investigated the ability of systemically administered NPs to inhibit tumor growth in vivo in mice bearing orthotopic gliomas. In vitro potency of YM155 was measured by CellTiter Glo in 3 immortalized GBM lines (GL261, U118, U87), as well as in patient derived tumor cells (GB7). Tumor growth inhibition was evaluated in C57 albino mice bearing orthotopic GL261-luc2 tumors. Mice were treated for 3 consecutive days with saline, free YM155 or NPs by tail vein injection, and tumor growth was measured by bioluminescence using an IVIS imaging system. All cells tested were sensitive to both free and encapsulated YM155. GL261 was the least sensitive of the cells tested, with an IC50 of 196 nM, while U118 and U87 had IC50s of 61 and 32 nM, respectively. The patient derived GB7 cells were the most sensitive to YM155, with an IC50 of 22 nM. Tumors grew exponentially for mice treated with free YM155 or saline, whereas tumor growth was halted in 2/5 subjects after one cycle of treatment with NPs. This work shows the potency of YM155 against multiple glioma cell lines in vitro. In vivo, free YM155 does not affect the growth of an orthotopic glioma; however, our initial treatment study provides evidence systemically administered YM155-loaded NPs allow for the delivery of a therapeutically relevant dose to orthotopic GBM. Success of this work shows the ability to encapsulate a water soluble drug in polymeric nanoparticles, which can be used to generate new options in the treatment of GBM. Further work will evaluate drug efficacy in additional patient derived cells and investigate the ability of NP encapsulated YM155 alone or in conjunction with radiation to treat mice bearing patient derived xenograft tumors.

Contact-mediated intracellular delivery of hydrophobic drugs from polymeric nanoparticles.

Encapsulation of drugs in nanoparticles can enhance the accumulation of drugs in tumours, reduce toxicity toward healthy tissue, and improve pharmacokinetics compared to administration of free drug. To achieve efficient delivery and release of drugs at the target site, mechanisms of interaction between the nanoparticles and cells and the mechanism of delivery of the encapsulated drug are crucial to understand. Our aim was to determine the mechanisms for cellular uptake of a fluorescent hydrophobic model drug from poly(butylcyanoacrylate) nanoparticles. Prostate adenocarcinoma cells were incubated with Nile Red-loaded nanoparticles or free Nile Red. Uptake and intracellular distribution were evaluated by flow cytometry and confocal laser scanning microscopy. The nanoparticles mediated a higher intracellular level and more rapid uptake of encapsulated Nile Red compared to model drug administered alone. The main mechanism for delivery was not by endocytosis of nanoparticles but by nanoparticle-cell contact-mediated transfer directly to the cytosol and, to a smaller extent, release of payload from nanoparticles into the medium followed by diffusion into cells. The payload thus avoids entering the endocytic pathway, evading lysosomal degradation and instead gains direct access to intracellular targets. The nanoparticles are promising tools for efficient intracellular delivery of hydrophobic anticancer drugs; therefore, they are clinically relevant for improved cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12645-014-0008-4) contains supplementary material, which is available to authorized users.

Cooperative sequential adsorption models on a Cayley tree: analytical results and applications

We present a class of cooperative sequential adsorption models on a Cayley tree with constant and variable attachment rates and their possible applications for ionic self-assembly of thin films and drug encapsulation of nanoparticles. Using the empty interval method, and generalizing results known from reaction–diffusion processes on Cayley trees, we calculate a variety of quantities such as time-dependent surface coverage and time-dependent probabilities of certain particle configurations.

Solid‐state Solubility Influences Encapsulation and Release of Hydrophobic Drugs from PLGA/PLA Nanoparticles

Biodegradable nanoparticles formulated from poly(D,L‐lactide‐co‐glycolide) (PLGA) and polylactide (PLA) polymers are being extensively investigated for various drug delivery applications. In this study, we hypothesize that the solid‐state solubility of hydrophobic drugs in polymers could influence their encapsulation and release from nanoparticles. Dexamethasone and flutamide were used as model hydrophobic drugs. A simple, semiquantitative method based on drug–polymer phase separation was developed to determine the solid‐state drug–polymer solubility. Nanoparticles using PLGA/PLA polymers were formulated using an emulsion–solvent evaporation technique, and were characterized for size, drug loading, and in vitro release. X‐ray powder diffraction (XRD) and differential scanning calorimetry (DSC) were used to determine the physical state of the encapsulated drug. Results demonstrated that the solid‐state drug–polymer solubility depends on the polymer composition, molecular weight, and end‐functional groups (ester or carboxyl) in polymer chains. Higher solid‐state drug–polymer solubility resulted in higher drug encapsulation in nanoparticles, but followed an inverse correlation with the percent cumulative drug released. The XRD and DSC analyses demonstrated that the drug encapsulated in nanoparticles was present in the form of a molecular dispersion (dissolved state) in the polymer, whereas in microparticles, the drug was present in both molecular dispersion and crystalline forms. In conclusion, the solid‐state drug–polymer solubility affects the nanoparticle characteristics, and thus could be used as an important preformulation parameter. © 2004 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 93:1804–1814, 2004

Electron microscopic analysis of nanoparticles delivering thioflavin-T after intrahippocampal injection in mouse: implications for targeting β-amyloid in Alzheimer's disease

Prevention of β-amyloid (Aβ) production, aggregation and formation of Aβ deposits is a key pharmacological target in Alzheimer's disease. The passage of Aβ-binding compounds through the blood–brain barrier is often hampered for free ligands, whereas it is enhanced by drug encapsulation in nanoparticles. Here, we describe the preparation and characterization of polymeric carriers containing thioflavin-T as a marker for fibrillar Aβ. This study is then focused on electron microscopic analyses of thioflavin-T after injection of thioflavin-T-containing nanoparticles into the mouse hippocampus. Therefore, the photoconversion of fluorescent thioflavin-T as model drug was performed in tissues fixed 3 days post-injection. Thioflavin-T delivered from nanospheres was predominantly found in neurons and microglia. Our data suggest that drugs delivered by nanoparticles might target Aβ in the brain.