Nanoencapsulation Of Drugs Research Articles

Ultrasound enhanced delivery of cisplatin loaded nanoparticles

Cisplatin forms the basis for many chemotherapy regimens, however the maximum permissible dose is limited by its systemic toxicity. Nanoencapsulation of drugs has been shown to reduce off-target side effects and can potentially improve treatment burden on patients. However, uptake of nanoformulations at tumor sites is minimal without some form of active delivery. We have developed a submicron, polymeric nanoparticle based on biocompatible and degradable poly(lactic-co-glycolic acid) (PLGA) capable of encapsulating cisplatin and which can be bound to the surface of a phospholipid coated microbubble. The acoustic behavior and stability of the resulting nanoparticle loaded microbubbles will be compared with those of unloaded microbubbles. Results will also be presented on the extravasation of particles in a tissue mimicking phantom using a novel long working distance confocal microscope that enables particle distributions to be measured in situ and in real time.

Multistage Nanovectors Enhance the Delivery of Free and Encapsulated Drugs.

Nanoparticles have considerable potential for cancer imaging and therapy due to their small size and prolonged circulation. However, biological barriers can impede the delivery of a sufficient dose of a drug to the target site, thereby also resulting in the accumulation of toxic compounds within healthy tissues, and systemic toxicity. Multistage nanovectors (MSV) preferentially accumulate on inflamed endothelium, and can thus serve as carriers for drugs and nanoparticles. Herein, we describe the loading of free (i.e., melittin) and nano-encapsulated (i.e., doxorubicin-loaded micelles) drugs into MSV, and report the impact of surface charge and pore size on drug loading. For both drug formulations, negatively charged MSV (i.e., oxidized) with larger pores were shown to retain higher concentrations of payloads compared to positively charged (i.e., APTES-modified) MSV with small pores. Treatment of human umbilical vein endothelial cells (HUVEC) with melittin-loaded MSV (MEL@MSV) resulted in an 80% reduction in cell viability after 3 days. Furthermore, MEL@MSV conjugated with antivascular endothelial growth factor receptor 2 (VEGFR2) antibodies displayed preferential targeting and delivery of MEL to activated HUVEC expressing VEGFR2. Treatment of HUVEC and MCF7 cells with doxorubicin-loaded micelles (DOXNP@MSV) resulted in a 23% and 47% reduction in cell viability, respectively. Taken together, these results demonstrate increased loading of a payload in oxidized, large pore MSV, and effective delivery of free and nano-encapsulated drugs to endothelial and cancer cells.

Application of the “in-oil nanoprecipitation” method in the encapsulation of hydrophilic drugs in PLGA nanoparticles

Three hydrophilic model drugs with different characteristics and molecular weights, namely protamine sulphate, diclofenac sodium and N6-Cyclopentyladenosine (CPA), were nano-encapsulated in poly(d,l-lactide-co-glycolide) (PLGA) using a novel “in-oil nanoprecipitation” method recently developed for the purpose. Although the same settings were used for all three model drugs, the drug loading efficiency was greatly dependent on their chemical–physical characteristics, being considerably higher for protamine (roughly 93%), intermediate for diclofenac (roughly 50%), and very low for CPA (roughly 7%). The resulting particle size and drug release rates were also strictly model-drug dependent. In the attempt to improve the characteristics of the CPA-loaded nanoparticles, the respective effects of adding an excipient (lauric acid) and substituting PLGA with poly(d,l-lactide) polymer (PLA) were investigated by measuring in vitro drug release and drug degradation kinetics in human whole blood. The results indicate that the proposed method seems promising for the nanoencapsulation of hydrophilic drugs in hydrophobic polymers, and easily modifiable to suit molecules that are difficult to incorporate into a polymeric matrix.

Mycolic acids, a promising mycobacterial ligand for targeting of nanoencapsulated drugs in tuberculosis

The appearance of drug-resistant strains of Mycobacterium tuberculosis (Mtb) poses a great challenge to the development of novel treatment programmes to combat tuberculosis. Since innovative nanotechnologies might alleviate the limitations of current therapies, we have designed a new nanoformulation for use as an anti-TB drug delivery system. It consists of incorporating mycobacterial cell wall mycolic acids (MA) as targeting ligands into a drug-encapsulating Poly dl-lactic-co-glycolic acid polymer (PLGA), via a double emulsion solvent evaporation technique. Bone marrow-derived mouse macrophages, either uninfected or infected with different mycobacterial strains (Mycobacterium avium, Mycobacterium bovis BCG or Mtb), were exposed to encapsulated isoniazid-PLGA nanoparticles (NPs) using MA as a targeting ligand. The fate of the NPs was monitored by electron microscopy. Our study showed that i) the inclusion of MA in the nanoformulations resulted in their expression on the outer surface and a significant increase in phagocytic uptake of the NPs; ii) nanoparticle-containing phagosomes were rapidly processed into phagolysosomes, whether MA had been included or not; and iii) nanoparticle-containing phagolysosomes did not fuse with non-matured mycobacterium-containing phagosomes, but fusion events with mycobacterium-containing phagolysosomes were clearly observed.

Amazon Nanotechnology Network Applied to Drugs (RANAF)

Submit Manuscript | http://medcraveonline.com Growing interest has been observed in the last years for nanostructures applied to biomedical area, especially regarding controlled release of drugs. Progressive release of the drug, transport to specific tissues, increase therapeutic index, reduce side effects, constant plasmatic levels, increased absorption and bioavailability can be considered special advantages of nanoformulations. Several types of nanoformulations have been developed, including a main group which can be classified as nanodispersions. Systems formed by two immiscible liquids and small droplets in a nanosize range, often stabilized by one or more surfactants, are called nanoemulsions. Bluish reflect associated to Tyndall effect can be observed when they are formed and several methods have been used to generate nanoemulsions, such as spontaneous emulsification, low or high energy methods. Considering the intrinsic nature of the drug, if solid insoluble substances are used, it may be usefull to prepared nanocrystals (nanosuspensions). More complex structures can be achieved by using polymeric coating, affording obtainment of nanoparticles. Polymer choice, on this specific case, is a critical point, considering that this component may modulate controlled release of substances. In all cases, utilization of economic viable methods is encouraged, which also must be reproducible and able to encapsulate the drug. Scales up have been successfully performed and nowadays, nanoformulations can be used as novel therapeutic agents by consumers. On this context, “Rede Amazonica de Nanotecnologia Aplicada a Farmacos (RANAF)” (Amazon Nanotechnology Network Applied to Drugs) was created and started with approval of the project entitled “Nanoencapsulation of anti-inflammatory drugs from synthetic and natural origin in polymeric matrix for controlled release”, with had finantial support from Brazilian Research Concil (CNPq, register number 564745/2010-3). RANAF has been performing a main whole to consolidate nanotechnology research through Amazon institutions, being also supported by important groups from other countries, such as Cuba and France (French Guyanne). Great Amazon biodiversity, which is outstanding in Amapa State (Brazil), can be sustainably used in order to achieve innovative natural product based nanoformulations. This is a main aim of RANAF studies, being applicable not only for pharmaceuticals, but also for food, cosmetics, pesticides and other products. Recently, the Laboratory of Phytopharmaceutical Nanobiotechnology was created to involve all development steps, being decisive together with Drug Research Laboratory, to carry RANAF research for different applications, including nanonutraceuticals and nanomedicines for anti-inflammatory, antidepressant, ansiolitica and erectile dysfunction treatment, among others. Commentary Commentary

Human Health, Environmental Sustainability and Food Production: Interfaces with Nanomedicine

In the case of animal production, use of high-density animals in the farm will be accompanied by challenges such as optimizing the use of inputs (e.g. antibiotics, antiparasitics, and nutrients), greater sanitary control, minimizing the risk of transmission of zoonoses, greater control of drug residues in food, and ensuring low environmental impact. These challenges are a window of opportunity for the use of nanotechnology. Coping with the loss of efficiency of pharmaceutical drugs against common pathogens is a great challenge to public health. Resistant pathogens have emerged due to indiscriminate use of drugs, and the massive use of drugs in food animals may be contributing to this situation. Worldwide, most antimicrobials and antiparasitics that are being used in animal production have to be used in a better way. Drug delivery systems may be important tools to optimize veterinary drug use and then mitigate its use. Nanoencapsulation of drugs can lead to therapeutic gains and reduce the amount of drugs used for animal treatment with goal of control and prevention infectious diseases. This can occur because of the changes in the pharmacokinetic profile of the drugs, reduced toxicity and appropriate delivery.

The effect of sugar stereochemistry on protein self-assembly: the case of β-casein micellization in different aldohexose solutions.

Protein self-assembly applications, such as nanoencapsulation of drugs and nutraceuticals, require deep understanding of the parameters governing the micellization process, including the effects of ionic and non-ionic co-solutes, like salts and sugars respectively, which is often overlooked. Herein, with the aim of shedding light on the effect of nonionic cosolute stereochemistry on protein self-assembly, we studied the ternary system of water-protein-sugar by examining the concentration-dependent effects of three aldohexoses, d-glucose (Glu), d-galactose (Gal) and d-mannose (Man) and that of urea, on the micellization of beta casein (β-Cas), using pyrene as a fluorescent probe for the formation of hydrophobic domains. Pyrene's excitation spectra were recorded for several sets of samples with rising protein concentration (0-5 mg ml(-1)), each set with a different co-solute type and concentration. Critical micellization concentration (CMC) and cooperativity of micellization were evaluated according to changes in pyrene spectra as it partitioned from the aqueous environment to the hydrophobic cores of β-Cas micelles. All sugars examined lowered the CMC of β-Cas with increasing sugar concentration and with a diminishing degree of effectiveness (Glu > Gal > Man) which correlated well with the sugars' dynamic hydration number, defined by Uedaira, and correlated negatively with their hydrophobic to hydrophilic molecular surface ratio. These results support the hypothesis that sugars affect protein self-assembly through both changes in water structure and by hydrophobic interactions, both of which are evidenced to be highly sensitive to sugar stereochemistry.

Nanoencapsulation for drug delivery.

Nanoencapsulation of drug/small molecules in nanocarriers (NCs) is a very promising approach for development of nanomedicine. Modern drug encapsulation methods allow efficient loading of drug molecules inside the NCs thereby reducing systemic toxicity associated with drugs. Targeting of NCs can enhance the accumulation of nanonencapsulated drug at the diseased site. This article focussed on the synthesis methods, drug loading, drug release mechanism and cellular response of nanoencapsulated drugs on liposomes, micelles, carbon nanotubes, dendrimers, and magnetic NCs. Also the uses of these various NCs have been highlighted in the field of nanotechnology.

Membrane Perturbation by Carbon Nanotube Insertion: Pathways to Internalization

Carbon nanotubes (CNTs) can penetrate the membranes of cells, offering prospects for nanomedicine but problems for nanotoxicity. Molecular simulations are used to provide a systematic analysis of the interactions of single-walled and multi-walled CNTs of different radii with a model lipid bilayer membrane. The simulations allow characterization of the mechanism of spontaneous exothermic insertion of CNTs into lipid bilayer membranes. The size and type of CNT determine the nature and extent of the local perturbation of the bilayer. Single-walled CNTs are shown to insert via a two-step mechanism with initial transient formation of a water filled pore followed by full insertion of the CNT into the bilayer. The latter stage is associated with formation of a persistent inverted micelle arrangement of lipid molecules trapped inside the CNT. This suggests a possible vehicle for nano-encapsulation of drugs, enabling their entry into and subsequent release within cells following endocytosis of CNT-containing membranes.

Application of activated nucleoside analogs for the treatment of drug-resistant tumors by oral delivery of nanogel-drug conjugates

A majority of nanoencapsulated drugs that have shown promise in cancer chemotherapy are administered intravenously. Development of effective oral nanoformulations presents a very challenging medical goal. Here, we describe successful applications of innovative polymeric nanogels in the form of conjugates with activated nucleoside analogs for oral administration in cancer chemotherapy. Previously, we reported the synthesis of amphiphilic polyvinyl alcohol and dextrin-based nanogel conjugates with the phosphorylated 5-FU nucleoside Floxuridine and demonstrated their enhanced activity against regular and drug-resistant cancers (T.H. Senanayake, G. Warren, S.V. Vinogradov, Novel anticancer polymeric conjugates of activated nucleoside analogs, Bioconjug. Chem. 22 (2011) 1983–1993). In this study, we synthesized and evaluated oral applications of nanogel conjugates of a protected Gemcitabine, the drug never used in oral therapies. These conjugates were able to quickly release an active form of the drug (Gemcitabine 5′-mono-, di- and triphosphates) by specific enzymatic activities, or slowly during hydrolysis. Gemcitabine conjugates demonstrated up to 127 times higher in vitro efficacy than the free drug against various cancer cells, including the lines resistant to nucleoside analogs. Surprisingly, these nanogel-drug conjugates were relatively stable in gastric conditions and able to actively penetrate through the gastrointestinal barrier based on permeability studies in Caco-2 cell model. In tumor xenograft models of several drug-resistant human cancers, we observed an efficient inhibition of tumor growth and extended the life-span of the animals by 3 times that of the control with orally treated Gemcitabine- or Floxuridine-nanogel conjugates. Thus, we have demonstrated a potential of therapeutic nanogel conjugates with the activated and stabilized Gemcitabine as a successful oral drug form against Gemcitabine-resistant and other drug-resistant tumors.

In vivo/in vitro pharmacokinetic and pharmacodynamic study of spray-dried poly-(dl-lactic-co-glycolic) acid nanoparticles encapsulating rifampicin and isoniazid

Poly-(dl-lactic-co-glycolic) acid (PLGA) nanoparticles were prepared by a double emulsion solvent evaporation spray-drying technique and coated with polyethylene glycol (PEG 1% v/v). The PLGA nanoparticles had a small size (229±7.6 to 382±23.9nm), uniform size distribution and positive zeta potential (+12.45±4.53mV). In vitro/in vivo assays were performed to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) performance of these nanoparticles following nanoencapsulation of the anti-tuberculosis drugs rifampicin (RIF) and isoniazid (INH). The results demonstrated the potential for the reduction in protein binding of these drugs by protection in the polymer core. Furthermore, in vitro efficacy was demonstrated using Mycobacterium tuberculosis (M. tb.) (strain H37Rv). Sustained drug release over seven days were observed for these drugs following once-off oral administration in mice with subsequent drug distribution of up to 10 days in the liver and lungs for RIF and INH, respectively. It was concluded by these studies combined with our previous reports that spray-dried PLGA nanoparticles demonstrate potential for the improvement of tuberculosis chemotherapy by nanoencapsulation of anti-tuberculosis drugs.

Nanocapsules Prepared from Amorphous Polyesters: Effect on the Physicochemical Characteristics, Drug Release, and Photostability

The influence of the polymeric amorphous materials on the physicochemical and drug release properties of drug-loaded nanocapsules as well as their role on the protection of the entrapped drug against the degradation induced by UV radiation was evaluated. Nanocapsules were prepared by interfacial deposition of preformed polymer (PLA, PLGA 50:50, and PLGA 85:15) using clobetasol propionate as the drug model. In vitro drug release was evaluated by the dialysis bag method. Photochemical stability was studied under UVA radiation. After preparation, all formulations presented nanometric mean size (180-200 nm), polydispersity index below 0.20, acid pH, negative zeta potential, and encapsulation efficiency close to 100%. Clobetasol propionate-loaded PLGA nanocapsules presented a lower physicochemical stability, showing a high drug leakage during 3 months of storage. In vitro studies showed biphasic drug release from all nanocapsules (according to an anomalous transport) and no influence of the hydrophilic characteristics of the amorphous polymeric material on the release rate. The photostability of clobetasol propionate under UVA radiation was improved by its incorporation into PLA and PLGA nanocapsules showing that besides semicrystalline polymers, amorphous polymers could also efficiently protect nanoencapsulated drugs against UV radiation.