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1.
Cristina Fornaguera Natàlia Feiner-Gracia Aurora Dols-Perez Maria José García-Celma Conxita Solans 《Pharmaceutical research》2017,34(5):1093-1103
Purpose
Gold nanoparticles have been proved useful for many biomedical applications, specifically, for their use as advanced imaging systems. However, they usually present problems related with stability and toxicity.Methods
In the present work, gold-nanoparticles have been encapsulated in polymeric nanoparticles using a novel methodology based on nano-emulsion templating. Firstly, gold nanoparticles have been transferred from water to ethyl acetate, a solvent classified as class III by the NIH guidelines (low toxic potential). Next, the formation of nano-emulsions loaded with gold nanoparticles has been performed using a low-energy, the phase inversion composition (PIC) emulsification method, followed by solvent evaporation giving rise to polymeric nanoparticles.Results
Using this methodology, high concentrations of gold nanoparticles (>100 pM) have been encapsulated. Increasing gold nanoparticle concentration, nano-emulsion and nanoparticle sizes increase, resulting in a decrease on the stability. It is noteworthy that the designed nanoparticles did not produce cytotoxicity neither hemolysis at the required concentration.Conclusions
Therefore, it can be concluded that a novel and very versatile methodology has been developed for the production of polymeric nanoparticles loaded with gold nanoparticles.2.
Naoki Itoh Eiichi Yamamoto Tomofumi Santa Takashi Funatsu Masaru Kato 《Pharmaceutical research》2016,33(6):1440-1446
Purpose
Nanoparticles have been used in diverse areas, and even broader applications are expected in the future. Since surface modification can influence the configuration and toxicity of nanoparticles, a rapid screening method is important to ensure nanoparticle quality.Methods
We examined the effect of the nanoparticle surface morphology on the HPLC elution profile using two types of 100-nm liposomal nanoparticles (AmBisome? and DOXIL?).Results
These 100-nm-sized nanoparticles eluted before the holdup time (about 4 min), even when a column packed with particles with a relatively large pore size (30 nm) was used. The elution time of the nanoparticles increased with pegylation of the nanoparticles and protein adsorption to the nanoparticles; however, the nanoparticles still eluted before the holdup time.Conclusions
The results of this study indicate that HPLC is a suitable tool for rapid evaluation of the surface of liposomal nanoparticles.3.
Purpose
Pulmonary infection namely tuberculosis is characterized by alveolar macrophages harboring a large microbe population. The chitosan nanoparticles exhibit fast extracellular drug release in aqueous biological milieu. This study investigated the matrix effects of chitosan nanoparticles on extracellular drug diffusion into macrophages.Methods
Oligo, low, medium and high molecular weight chitosan nanoparticles were prepared by nanospray drying technique. These nanoparticles were incubated with alveolar macrophages in vitro and had model drug sodium fluorescein added into the same cell culture. The diffusion characteristics of sodium fluorescein and nanoparticle behavior were investigated using fluorescence microscopy, scanning electron microscopy, differential scanning calorimetry and Fourier transform infrared spectroscopy techniques.Results
The oligochitosan nanoparticles enabled macrophage membrane fluidization with the extent of sodium fluorescein entry into macrophages being directly governed by the nanoparticle loading. Using nanoparticles made of higher molecular weight chitosan, sodium fluorescein permeation into macrophages was delayed due to viscous chitosan diffusion barrier at membrane boundary.Conclusion
Macrophage-chitosan nanoparticle interaction at membrane interface dictates drug migration into cellular domains.4.
Antony V. Samrot Ujjala Burman Padmanaban S P. Yamini Arul Maximus Rabel 《Toxicology and Environmental Health Sciences》2018,10(3):162-167
Objective
To evaluate the toxicity of the silver nanoparticle against earthworms - Eudrilus eugeniae, a model for soil organism.Methods
Silver nanoparticles were synthesised by chemical reduction and further characterised by UV Visible Spectroscopy and FeSEM. Earthworms were allowed to interact with different concentrations of the synthesized silver nanoparticles. After exposure period, histology and inductively coupled plasma optical emission spectrometry (ICP-OES) were done to determine the accumulation and toxic effects exhibited by the nanoparticle on earthworms.Results
The synthesized nanoparticle was found to be between the size of 180 and 200 nm. Histology studies revealed that silver nanoparticles to cause fibrosis, lipofuscin-like deposits and also gut disruption in earthworms.Conclusion
Silver nanoparticles were found to be toxic to Eudrilus eugeniae, which was evidenced by histology.5.
Indu Javeri Kaliappanadar Nellaiappan Charles McNemar Kirill Yakovlevsky Amina Soukrati Phanindra Velisetty Bijay Misra 《Pharmaceutical research》2018,35(9):168
Purpose
Accurate quantification of the intact proteins, antibodies or peptides and their impurities without interaction to silanols of HPLC column.Methods
Hydroxypropyl ß Cyclodextrin (HPCD) is added in the mobile phase at different concentrations. Different commercial SEC-HPLC columns and biologics with a molecular weight ranging from 5.8 kDa to 150kDa were assessed with and without cyclodextrin.Results
Addition of non-ionic sugars such as Hydroxypropyl ß Cyclodextrin in the mobile phase, resulted improved peak performance such as theoretical plates, peak resolution, peak width, peak height, and improved quantification of aggregates in biologics such as antibodies Humira and Actemra, and peptides such as insulin. There is an increase in peak height, reduced retention time, increased plate and reduced peak width with increasing concentration of cyclodextrin studied.Discussion
High ionic strength, basic amino acids such as arginine, organic solvents (with a concentration low enough not to precipitate protein), sodium perchlorate and ion pairing agents in the mobile phase used for separation of peptides, proteins and antibodies to prevent silanol interaction. These commonly used solutions are not always successful, as they not only interact with the biologic, but are sometimes, not compatible. The non-ionic cyclodextrin itself does not cause protein aggregation but prevents the nonspecific binding or interaction of protein itself and thereby allowing for improved resolution, and accurate quantification of aggregates in antibodies, and peptides. The data on the separation in presence of cyclodextrin in the mobile phase showed higher peak resolution, improved peak shape, accurate apparent molecular weight, improved efficiency, and less peak tailing for biological products.Conclusion
Hydroxypropyl ß Cyclodextrin in the mobile phase, resulted improved SEC-HPLC resolution, and quantitation of aggregates in biologics by preventing the interaction of biologics to silanol of the commercial SEC-HPLC columns.6.
Jehad M. Nasereddin Nikolaus Wellner Muqdad Alhijjaj Peter Belton Sheng Qi 《Pharmaceutical research》2018,35(8):151
Purpose
The filament-based feeding mechanism employed by the majority of fused deposition modelling (FDM) 3D printers dictates that the materials must have very specific mechanical characteristics. Without a suitable mechanical profile, the filament can cause blockages in the printer. The purpose of this study was to develop a method to screen the mechanical properties of pharmaceutically-relevant, hot-melt extruded filaments to predetermine their suitability for FDM.Methods
A texture analyzer was used to simulate the forces a filament is subjected to inside the printer. The texture analyzer produced a force-distance curve referred to as the flexibility profile. Principal Component Analysis and Correlation Analysis statistical methods were then used to compare the flexibility profiles of commercial filaments to in-house made filaments.Results
Principal component analysis showed clearly separated clustering of filaments that suffer from mechanical defects versus filaments which are suitable for printing. Correlation scores likewise showed significantly greater values with feedable filaments than their mechanically deficient counterparts.Conclusion
The screening method developed in this study showed, with statistical significance and reproducibility, the ability to predetermine the feedability of extruded filaments into an FDM printer.7.
Carolyn Schutt Stuart Ibsen Eran Zahavy Santosh Aryal Stacey Kuo Selin Esener Michael Berns Sadik Esener 《Pharmaceutical research》2017,34(10):2025-2035
Purpose
A major challenge facing nanoparticle-based delivery of chemotherapy agents is the natural and unavoidable accumulation of these particles in healthy tissue resulting in local toxicity and dose-limiting side effects. To address this issue, we have designed and characterized a new prodrug nanoparticle with controllable toxicity allowing a locally-delivered light trigger to convert the payload of the particle from a low to a high toxicity state.Methods
The nanoparticles are created entirely from light-activatable prodrug molecules using a nanoprecipitation process. The prodrug is a conjugate of doxorubicin and photocleavable biotin (DOX-PCB).Results
These DOX-PCB nanoparticles are 30 times less toxic to cells than doxorubicin, but can be activated to release pure therapeutic doxorubicin when exposed to 365 nm light. These nanoparticles have an average diameter of around 100 nm and achieve the maximum possible prodrug loading capacity since no support structure or coating is required to prevent loss of prodrug from the nanoparticle.Conclusions
These light activatable nanoparticles demonstrate tunable toxicity and can be used to facilitate future therapy development whereby light delivered specifically to the tumor tissue would locally convert the nanoparticles to doxorubicin while leaving nanoparticles accumulated in healthy tissue in the less toxic prodrug form.8.
Ghobad Mohammadi Amineh Shakeri Ali Fattahi Pardis Mohammadi Ali Mikaeili Alireza Aliabadi Khosro Adibkia 《Pharmaceutical research》2017,34(2):301-309
Purpose
Nystatin loaded PLGA and PLGA-Glucosamine nanoparticles were formulated. PLGA were functionalized with Glucosamine (PLGA-GlcN) to enhance the adhesion of nanoparticles to Candida Albicans (C.albicans) cell walls.Method
Quasi-emulsion solvent diffusion method was employed using PLGA and PLGA-GlcN with various drug–polymer ratios for the preparation of nanoparticles. The nanoparticles were evaluated for size, zeta potential, polydispersity index, drug crystallinity, loading efficiency and release properties. DSC, SEM, XRPD, 1H-NMR, and FT-IR were performed to analyze the physicochemical properties of the nanoparticles. Antifungal activity of the nanoparticles was evaluated by determination of MICs against C.albicans.Results
The spectra of 1H-NMR and FT-IR analysis ensured GlcN functionalization on PLGA nanoparticles. SEM characterization confirmed that particles were in the nanosize range and the particle size for PLGA and PLGA-GlcN nanoparticles were in the range of 108.63?±?4.5 to 168.8?±?5.65 nm and 208.76?±?16.85 nm, respectively. DSC and XRPD analysis ensured reduction of the drug crystallinity in the nanoparticles. PLGA-GlcN nanoparticles exhibit higher antifungal activity than PLGA nanoparticles.Conclusion
PLGA-GlcN nanoparticles showed more antifungal activity with appropriate physicochemical properties than pure Nystatin and PLGA nanoparticles.9.
Purpose
Poly(D,L-lactide-co-glycolide) (PLG) nanoparticles containing doxorubicin and mineralized calcium carbonate were fabricated and their anti-tumor efficacy was tested using a neuroblastoma-bearing mouse model.Methods
PLG nanoparticles were prepared by a double emulsion (water-in-oil-in-water; W/O/W) method. Calcium carbonate was mineralized within the PLG nanoparticles during the emulsion process. Rabies virus glycoprotein (RVG) peptide was chemically introduced to the surface of the PLG nanoparticles as a targeting moiety against neuroblastoma. The cytotoxicity and cellular uptake characteristics of these nanoparticles were investigated in vitro. Moreover, their therapeutic efficacy was evaluated using a tumor-bearing mouse model.Results
Mineralized calcium carbonate in PLG nanoparticles was ionized at acidic pH and generated carbon dioxide gas, which resultantly accelerated the release of doxorubicin from the nanoparticles. RVG peptide-modified, gas-generating PLG nanoparticles showed a significantly enhanced targeting ability to neuroblastoma and an increased therapeutic efficacy in vivo as compared with free doxorubicin.Conclusions
Targeting ligand-modified polymer nanoparticles containing both anti-cancer drug and mineralized calcium carbonate could be useful for cancer treatment.10.
Purpose
A Surface Plasmon Resonance chip (SPR) was developed to study the activation of complement system triggered by nanomaterials in contact with human serum, which is an important concern today to warrant safety of nanomedicines.Methods
The developed chip was tested for its specificity in complex medium and its longevity of use. It was then employed to assess the release of complement fragments upon incubation of nanoparticles in serum. A comparison was made with other current methods assessing complement activation (μC-IE, ELISA).Results
The SPR chip was found to give a consistent response for C3a release upon activation by nanoparticles. Results were similar to those obtained by μC-IE. However, ELISA detection of iC3b fragments showed an explained high non-specific background. The impact of sample preparation preceding the analysis was assessed with the newly develop SPR method. The removal of nanoparticles before analysis showed an important modification in the obtained response, possibly leading to false negative results.Conclusion
The SPR chip developed in this work allows for an automated assessment of complement activation triggered by nanoparticles with possibility of multiplexed analysis. The design of the chip proved to give consistent results of complement activation by nanoparticles.11.
Haiping Jiang Xinyan Shi Xiaoyun Yu Xinjia He Yongheng An Haijun Lu 《Pharmaceutical research》2018,35(4):73
Purpose
In this study, we have successfully prepared the hyaluronic acid (HA)-conjugated mesoporous silica nanoparticles loaded with 5-fluorouracil (5-FU) to increase the anticancer efficacy in colon cancers.Methods
The particles were nanosized and perfectly spherical. In vitro release kinetics clearly showed the enzyme-sensitive release of 5-FU from HA-conjugated 5-FU loaded mesoporous silica nanoparticles (HA/FMSN).Results
The presence of HA on the surface of nanoparticles targeted the CD44 receptors overexpressed in the colon cancer cells In vitro cell viability and apoptosis assay clearly showed the superior anticancer effect of HA/FMSN in HT29 colon cancer cells. HA/FMSN exhibited a remarkably higher 43% of cells in early apoptosis phase and 55% of cells in late apoptosis phase indicating the superior anticancer effect of HA/FMSN. HA/FMSN exhibited a significant reduction in the tumor burden compared to that of any group. HA/FMSN was 3-fold more effective than free drug and 2-fold more effective than -FU loaded mesoporous silica nanoparticles (FMSN).Conclusions
Overall, results suggest that the novel delivery strategy could hold enormous potential in colon cancer targeting.12.
Purpose
Colon adenocarcinoma is the most common form of gastro intestinal tract cancer, predominantly in ageing population. Chemotherapy with 5-Fluorouracil and oxaliplatin is an indispensable treatment regimen, nevertheless having limitation of systemic toxicity and lower therapeutic index. The present study is based on evaluation of anti-proliferative potential, pharmacokinetics parameters, safety profile, biodistribution and efficacy of 5-FU/oxaliplatin loaded lactoferrin nanoparticles in cell lines and wistar rats in order to overcome the above limitation.Methods
Nanoparticles were prepared by Water-in-oil process. The anti-proliferative efficacy and mode of cellular entry was evaluated in COLO-205 cells. The pharmacokinetics and biodistribution analysis were performed in healthy rats while efficacy and safety assay were performed in ACF induced rats.Results
5-FU and oxaliplatin loaded nanoparticles shows enhanced antiproliferative activity as compare to free drugs in COLO-205 cells. Lactoferrin nanoparticles also improve the pharmacokinetics profile, safety parameters and efficacy of 5-FU and Oxaliplatin.Conclusion
Lactoferrin nanoparticles demonstrated an attractive drug delivery module to manage the colon adenocarcinoma as it has improved the antiproliferative activity of 5-FU and Oxaliplatin against colon adenocarcinoma cells. Moreover, it also improves the pharmacokinetic profile and safety parameters of the same drug in wistar rat.13.
Jessica Bane Olivier Mozziconacci Li Yi Y. John Wang Alavattam Sreedhara Christian Schöneich 《Pharmaceutical research》2017,34(1):229-242
Purpose
Triply oxidized histidine in an IgG1 monoclonal antibody was noticed when exposed to ICH light conditions. In order to understand the role of light source, irradiation wavelengths and primary sequence, specifically those of a nearby tryptophan, we synthesized and exposed several peptides to ICH light conditions and analyzed the products using LC-MS analysis.Methods
Protein and peptide samples were photo-irradiated under ICH conditions as well as with monochromatic light at λ?=?254 nm and analyzed using either LTQ Orbitrap or a LTQ-FT ion cyclotron resonance mass spectrometer respectively.Results
A triply oxidized His residue was detected along with a second doubly oxidized His residue in an IgG1. Both of these oxidized His residues are located near Trp residues. In order to investigate the role of Trp photosensitization in His oxidation we synthesized model peptides and Ala mutants. Peptides exposed to ICH light stress conditions revealed a small percent of triply oxidized His in the Trp-containing peptide sequences but not in their corresponding Ala mutants.Conclusions
The differences in product formation under different photo-irradiation conditions underline the importance of light source, irradiation wavelengths and primary sequence in the photosensitivity of proteins.14.
Pedro Fonte Fernanda Andrade Cláudia Azevedo João Pinto Vítor Seabra Marco van de Weert Salette Reis Bruno Sarmento 《Pharmaceutical research》2016,33(11):2777-2793
Purpose
The freezing step in lyophilization is the most determinant for the quality of biopharmaceutics. Using insulin as model of therapeutic protein, our aim was to evaluate the freezing effect in the stability and bioactivity of insulin-loaded PLGA nanoparticles. The performance of trehalose, sucrose and sorbitol as cryoprotectants was evaluated.Methods
Cryoprotectants were co-encapsulated with insulin into PLGA nanoparticles and lyophilized using an optimized cycle with freezing at ?80°C, in liquid nitrogen, or ramped cooling at ?40°C. Upon lyophilization, the stability of protein structure and in vivo bioactivity were assessed.Results
Insulin was co-encapsulated with cryoprotectants resulting in particles of 243–394 nm, zeta potential of ?32 to ?35 mV, and an association efficiency above 90%. The cryoprotectants were crucial to mitigate the freezing stresses and better stabilize the protein. The insulin structure maintenance was evident and close to 90%. Trehalose co-encapsulated insulin-loaded PLGA nanoparticles demonstrated enhanced hypoglycemic effect, comparatively to nanoparticles without cryoprotectant and added with trehalose, due to a superior insulin stabilization and bioactivity.Conclusions
The freezing process may be detrimental to the structure of protein loaded into nanoparticles, with negative consequences to bioactivity. The co-encapsulation of cryoprotectants mitigated the freezing stresses with benefits to protein bioactivity.15.
Purpose
Cutaneous malignancies are the most common human cancers, and despite growing public awareness of the harmful effects of sun exposure, incidence and morbidity continue to rise which has generated great interest in unravelling of their aetiology and in the search for new non-invasive treatment strategies.Methods
A yearly increase in incidence of cutaneous malignancies has been reported since a long time worldwide, suggesting that prevalence of this cancer will soon equal that of all other cancers combined. Grouping of various skin lesions and malignancies under a common umbrella term poses challenges because clear differences exist in their aetiopathogenesis, clinical course and management strategies, suggesting the need of the novel and future therapeutic perspectives for the treatment from nanotechnology to immunotherapy.Results
Moreover, treatment modalities should comprised of gold standards of the current recommended therapies worldwide and the actual needs of these patients.Conclusion
The overall goal of this review was to explore the approaches for cutaneous malignancies’ new technological methods instead of new molecules.16.
Airama Albisa Emma Piacentini Victor Sebastian Manuel Arruebo Jesus Santamaria Lidietta Giorno 《Pharmaceutical research》2017,34(6):1296-1308
Purpose
The aim of this work is to develop a scalable continuous system suitable for the formulation of polymeric nanoparticles using membrane-assisted nanoprecipitation. One of the hurdles to overcome in the use of nanostructured materials as drug delivery vectors is their availability at industrial scale. Innovation in process technology is required to translate laboratory production into mass production while preserving their desired nanoscale characteristics.Methods
Membrane-assisted nanoprecipitation has been used for the production of Poly[(D,L lactide-co-glycolide)-co-poly ethylene glycol] diblock) (PLGA-PEG) nanoparticles using a pulsed back-and-forward flow arrangement. Tubular Shirasu porous glass membranes (SPG) with pore diameters of 1 and 0.2 μm were used to control the mixing process during the nanoprecipitation reaction.Results
The size of the resulting PLGA-PEG nanoparticles could be readily tuned in the range from 250 to 400 nm with high homogeneity (PDI lower than 0.2) by controlling the dispersed phase volume/continuous phase volume ratio. Dexamethasone was successfully encapsulated in a continuous process, achieving an encapsulation efficiency and drug loading efficiency of 50% and 5%, respectively. The dexamethasone was released from the nanoparticles following Fickian kinetics.Conclusions
The method allowed to produce polymeric nanoparticles for drug delivery with a high productivity, reproducibility and easy scalability.17.
Sarah K. Mann Ewa Czuba Laura I. Selby Georgina K. Such Angus P. R. Johnston 《Pharmaceutical research》2016,33(10):2421-2432
Purpose
The internalization of nanoparticles into cells is critical for effective nanoparticle mediated drug delivery. To investigate the kinetics and mechanism of internalization of nanoparticles into cells we have developed a DNA molecular sensor, termed the Specific Hybridization Internalization Probe - SHIP.Methods
Self-assembling polymeric ‘pHlexi’ nanoparticles were functionalized with a Fluorescent Internalization Probe (FIP) and the interactions with two different cell lines (3T3 and CEM cells) were studied. The kinetics of internalization were quantified and chemical inhibitors that inhibited energy dependent endocytosis (sodium azide), dynamin dependent endocytosis (Dyngo-4a) and macropinocytosis (5-(N-ethyl-N-isopropyl) amiloride (EIPA)) were used to study the mechanism of internalization.Results
Nanoparticle internalization kinetics were significantly faster in 3T3 cells than CEM cells. We have shown that ~90% of the nanoparticles associated with 3T3 cells were internalized, compared to only 20% of the nanoparticles associated with CEM cells. Nanoparticle uptake was via a dynamin-dependent pathway, and the nanoparticles were trafficked to lysosomal compartments once internalized.Conclusion
SHIP is able to distinguish between nanoparticles that are associated on the outer cell membrane from nanoparticles that are internalized. This study demonstrates the assay can be used to probe the kinetics of nanoparticle internalization and the mechanisms by which the nanoparticles are taken up by cells. This information is fundamental for engineering more effective nanoparticle delivery systems. The SHIP assay is a simple and a high-throughput technique that could have wide application in therapeutic delivery research.18.
Zhiqiang Tian Qin Yu Yunchang Xie Fengqian Li Yi Lu Xiaochun Dong Weili Zhao Jianping Qi Wei Wu 《Pharmaceutical research》2016,33(8):1988-1997
Purpose
To achieve controlled release of integral nanoparticles by the osmotic pump strategy using nanostructured lipid carriers (NLCs) as model nanoparticles.Methods
NLCs was prepared by a hot-homogenization method, transformed into powder by lyophilization, and formulated into osmotic pump tablets (OPTs). Release of integral NLCs was visualized by live imaging after labeling with a water-quenching fluorescent probe. Effects of formulation variables on in vitro release characteristics were evaluated by measuring the model drug fenofibrate. Pharmacokinetics were studied in beagle dogs using the core tablet and a micronized fenofibrate formulation as references.Results
NLCs are released through the release orifices of the OPTs as integral nanoparticles. Near zero-order kinetics can be achieved by optimizing the influencing variables. After oral administration, decreased C max and steady drug levels for as long as over 24 h are observed. NLC-OPTs show an oral bioavailability of the model drug fenofibrate similar to that of the core tablets, which is about 1.75 folds that of a fast-release formulation.Conclusion
Controlled release of integral NLCs is achieved by the osmotic pump strategy.19.
Karim S. Shalaby Mahmoud E. Soliman Giulia Bonacucina Marco Cespi Giovanni F. Palmieri Omaima A. Sammour Abdelhameed A. El Shamy Lisbeth Illum Luca Casettari 《Pharmaceutical research》2016,33(8):2010-2024
Purpose
Biodegradable polymeric nanoparticles of different architectures based on polyethylene glycol-co-poly(ε-caprolactone) block copolymers have been loaded with noscapine (NOS) to study their effect on its anticancer activity. It was intended to use solubility of NOS in an acidic environment and ability of the nanoparticles to passively target drugs into cancer tissue to modify the NOS pharmacokinetic properties and reduce the requirement for frequent injections.Methods
Linear and star-shaped copolymers were synthetized and used to formulate NOS loaded nanoparticles. Cytotoxicity was performed using a sulforhodamine B method on MCF-7 cells, while biocompatibility was determined on rats followed by hematological and histopathological investigations.Results
Formulae with the smallest particle sizes and adequate entrapment efficiency revealed that NOS loaded nanoparticles showed higher extent of release at pH 4.5. Colloidal stability suggested that nanoparticles would be stable in blood when injected into the systemic circulation. Loaded nanoparticles had IC50 values lower than free drug. Hematological and histopathological studies showed no difference between treated and control groups. Pharmacokinetic analysis revealed that formulation P1 had a prolonged half-life and better bioavailability compared to drug solution.Conclusions
Formulation of NOS into biodegradable polymeric nanoparticles has increased its efficacy and residence on cancer cells while passively avoiding normal body tissues.20.
Simone Aleandri Monica Schönenberger Andres Niederquell Martin Kuentz 《Pharmaceutical research》2018,35(3):69