Dendritic macromolecules as nano-scale drug carriers:Phase solubility,in vitro drug release,hemolysis and cytotoxicity study

Potential of nanoscale triazine based dendritic macromolecules G1,G2 and G3 as solubility enhancers of drug was investigated.Effect of pH,concentration and generation of synthesized dendritic macromolecules on solubility of ketoprofen was studied.G3 dendrimer was further exploited as carrier for sustained release.Ketoprofen was encapsulated by inclusion complex method and also characterized by Flourier Transform Infrared spectroscopy.Sustained release study of ketoprofen from ketoprofen loaded dendrimer was carried out and compared with free ketoprofen.Hemolytic potential and Cytotoxicity assay using A-549 lung cancer cell lines revealed that synthesized triazine based dendritic macromolecules having more potential that commercially available PAMAM dendrimer.

Molecularly imprinted nanoparticles and their releasing properties, bio-distribution as drug carriers

Molecular imprinted nanoparticles(MINPs) can memorize the shape and functional group positions complementary to template, which account for the large drug loading capacity and slow drug release behavior as drug carriers. We synthesized MINPs via precipitation polymerization with vinblastine(VBL) as a model drug, and investigated the drug loading,releasing property in vitro and bio-distribution in vivo. The obtained MINPs, from 300 to 450 nm,had smooth surface and favorable dispersibility. The entrapment efficacy and drug loading capacity of VBL loaded MINPs(MINPs-VBL) were 83.25% and 8.72% respectively. In PBS(pH 7.4),MINPs-VBL showed sustained release behavior. The cumulative release percentage reached about 70% during 216 h and no burst release was observed. The releasing behavior of MINPsVBL in vitro conformed to the first-order kinetics model. MINPs-VBL and commercially available vinblastine sulfate injection(VBL injection) were injected via tail vein of SD rats respectively to investigate the bio-distribution. MINPs-VBL group showed higher concentration of VBL in tissues and serum than VBL injection group after 60 min, and the drug level in liver was the highest. MINPs-VBL exhibited liver targeting trend to some extent, which was based on the evaluation of drug targeting index(DTI) and drug selecting index(DSI).

Microfluidics:Emerging prospects for anti-cancer drug screening

Cancer constitutes a heterogenic cellular system with a high level of spatio-temporal complexity.Recent discoveries by systems biologists have provided emerging evidence that cellular responses to anti-cancer modalities are stochastic in nature.To uncover the intricacies of cell-to-cell variability and its relevance to cancer therapy,new analytical screening technologies are needed.The last decade has brought forth spectacular innovations in the field of cytometry and single cell cytomics,opening new avenues for systems oncology and high-throughput real-time drug screening routines.The up-and-coming microfluidic Lab-on-a-Chip(LOC)technology and micrototal analysis systems(μTAS)are arguably the most promising platforms to address the inherent complexity of cellular systems with massive experimental parallelization and 4D analysis on a single cell level.The vast miniaturization of LOC systems and multiplexing enables innovative strategies to reduce drug screening expenditures while increasing throughput and content of information from a given sample.Small cell numbers and operational reagent volumes are sufficient for microfluidic analyzers and,as such,they enable next generation high-throughput and high-content screening of anticancer drugs on patient-derived specimens.Herein we highlight the selected advancements in this emerging field of bioengineering,and provide a snapshot of developments with relevance to anti-cancer drug screening routines.

HPLC Method Research of Picoplatin-a New Platinum Anti-cancer Drug and Its Impurities

Purpose: To establish a HPLC testing method of the content of bulk picoplatin and its impurities. Method: the separation was perform on a C18 column(4.6 mm×250 mm, 5 m) with potassium dihydrogen phosphate-aceton-itrile as the mobile phase at a flow rate of 1.0 mL/min. The detecting wavelength was set at 210 nm, and the column temperature was set at 30℃. Result: in the method validation, the linear relationship modulus of picoplatin is 0.9999, the systemic precision is 0.44%, the method precision is 0.74%, the average recovery rate is 99.62%, the LOD and LOQ of picoplatin is 0.2 ng and 1.0 ng. The average resolution of picoplatin and its impurities is more than 2. Conclusion: The established method is good specificity, high sensitivity, and good repeatability which could provide scientific evidence for the quality control of picoplatin and its impurities.

Carbohydrate-associated epitope-based anti-cancer drugs and vaccines

RP215 is one of the three thousand monoclonal antibodies (Mabs) which were generated against the OC-3-VGH ovarian cancer cell line. RP215 was shown to react with a carbohydrate-associated epitope located specifically on glycoproteins, known as CA215, from cancer cells. Further molecular analysis by matrix adsorption laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) revealed that CA215 consists mainly of immunoglobulin super-family (IgSF) proteins, including immunoglobulins, T-cell receptors, and cell adhesion molecules, as well as several other unrelated proteins. Peptide mappings and glycoanalysis were performed with CA215 and revealed high-mannose and complex bisecting structures with terminal sialic acid in N-glycans. As many as ten O-glycans, which are structurally similar to those of mucins, were also identified. In addition, two additional O-linked glycans were exclusively detected in cancerous immunoglobulins but not in normal B cell-derived immunoglobulins. Immunizations of mice with purified CA215 resulted in the predominant generation of RP215-related Mabs, indicating the immunodominance of this carbohydrate-associated epitope. Anti-idiotype (anti-id) Mabs of RP215, which were generated in the rat, were shown to contain the internal images of the carbohydrate-associated epitope. Following immunizations of these anti-id Mabs in mice, the resulting anti-anti-id (Ab3) responses in mice were found to be immunologically similar to that of RP215. Judging from these observations, anti-id Mabs, which carry the internal image of the RP215-specific epitope, may be suitable candidates for anticancer vaccine development in humans.

Advances in Research on Cellulose-based Drug Carriers

Traditional drug delivery methods are prone to large fluctuations in drug concentration and require multiple frequent doses.As a green material with excellent properties,cellulose has been widely used as a drug carrier for the development and preparation of drug controlled-release system.Based on the mechanisms of slow drug release,such as dissolution-diffusion release,degradation release,and nanochannel-controlled release,the preparation methods of cellulose-based drug carriers are introduced in this paper.The applications of cellulose-based drug carriers in the fields of antitumor therapy,antibacterial therapy,chronic disease treatment,and viral disease treatment are summarized with the aim of providing a useful reference for research on cellulose-based drug carriers.

Perspectives on bone-targeted nano-drug carriers for bone tumor treatment

Bone tumour is one of most common primary cancer which exhibits cancerous osteoblastic differentiation and malignant osteoid in patients.At present,chemotherapy(pre-and post-operative)is used as a standard treatment protocol for bone tumour.However,drugs used in the treatment of bone tumour induce high toxicity to normal tissues including anaemia,neutropenia,thrombocytopenia,and heart damage which further reduce the survival rate of patients.Therefore,there is an urgent need to develop a new therapeutic approach for the treatment such that it induce maximum cell killing effect in tumor cells while sparing the healthy bone cells.In this article,some new perspectives were provided on the development of bone-targeted nano-drug carriers for bone cancer treatment.We hope such discussions wouldencourage more detailed and careful studies to support product development of bone-targeted drug carriers for bone cancer treatment.

Control the Silver Content in the Preparation Process of Platinum Group Anti-cancer Drugs

In order to control the silver content in the preparation process of platinum group anti-cancer drugs, we put two kinds of color reagent to color in the production process of the platinum anti-cancer drugs by UV spectra measurement to control drugs production of platinum anticancer, thus we could control the silver content in the drugs so that it meets the pharmacopoeia standards of US and

The application of open disk-like structures as model membrane and drug carriers

The objective of this review is to outline the application of bicelles(or called bilayer micelles)and bilayer nanodisks in pharmaceutics,pharmaceutical analysis and biochemistry.The application of open disk-like structures as model membrane and drug carrier has been described.The exploration of many reports in different fields suggested that these open disk-like structures have great potential in studying interactions between drug-membrane and structure/function studies of membrane-bound proteins.Furthermore,they could be applied as promising carriers for in vivo delivery of drugs,protein and peptide.

Preparation and Characterization of Copolymer Micelles Formed by Poly(ethylene glycol)-Polylactide Block Copolymers as Novel Drug Carriers

Diblock copolymer poly(ethylene glycol) methyl ether–polylactide (MePEG–PLA) micelles were prepared by dialysis against water. Indomethacin (IMC) as a model drug was entrapped into the micelles by dialysis method. The critical micelle concentration (CMC) of the prepared micelles in distilled water investigated by fluorescence spectroscopy was 0.0051 mg/mL which is lower than that of common low molecular weight surfactants. The diameters of MePEGPLA micelles and IMC loaded MePEGPLA micelles in a number-averaged scale measured by dynamic light scattering were 52.4 and 53.7 nm respectively. The observation with transmission electron microscope and scanning electron microscope showed that the appearance of MePEGPLA micelles was in a spherical shape. The content of IMC incorporated in the core portion of the micelles was 18% (ω). The effects of the synthesis method of the copolymer on the polydispersity of the micelles and the yield of the micelles formation were discussed.

Regulation of “Checkpoint Molecule” Sheds New Light on Anti-Cancer Drug Development

The rivalry between T cells and tumor cells somewhat mimics the scene of 'Tom and Jerry,' an animated series in which Tom (a house cat) rarely succeeds in catching Jerry (a mouse), mainly because of Jerry’s cleverness and cunning abilities. In a way, tumor cells are like Jerry, in terms of their crafty and sneaky features.

Preparation and characterization of biodegradable nanoparticles from methoxy poly(ethylene glycol)-poly(D,L-lactide)block copolymers as novel drug carriers

Methoxy poly(ethylene glycol)-poly(D,L-lactide) block copolymers (PEG-PLA) were prepared through ring-opening polymerization.The oil in water suspension method was used to prepare block copolymer micelles. The critical micelle concentration (CMC) by fluorescence spectroscopy was 0.0056 mg·ml -1 . The physical state of the inner core region of micelles was characterized with 1HNMR. The size of indomethacin (IMC) loaded micelles measured by dynamic light scattering (DLS) showed narrow monodisperse size distribution and the average diameters were less than 50 nm. In addition, the nanoparticles with relatively high drug loading content (DLC) were obtained.

A hybrid genipin-crosslinked dual-sensitive hydrogel/nanostructured lipid carrier ocular drug delivery platform

The objective of this study was to develop a novel hybrid genipin-crosslinked dual-sensitive hydrogel/nanostructured lipid carrier(NLC) drug delivery platform. An ophthalmic antiinflammatory drug, baicalin(BN) was chosen as the model drug. BN –NLC was prepared using melt-emulsification combined with ultra-sonication technique. Additionally, a dual pH-and thermo-sensitive hydrogel composed of carboxymethyl chitosan(CMCS) and poloxamer 407(F127) was fabricated by a cross-linking reaction with a nontoxic crosslinker genipin(GP). GP-CMCS/F127 hydrogel was characterized by FTIR, NMR, XRD and SEM. The swelling studies showed GP-CMCS/F127 hydrogel was both pH-and thermo-sensitive. The results of in vitro release suggested BN –NLC gel can prolong the release of baicalin comparing with BN eye drops and BN –NLC. Ex vivo cornea permeation study was evaluated using Franz diffusion cells. The apparent permeability coefficient(Papp) of BN –NLC gel was much higher(4.46-fold) than that of BN eye drops. Through the determination of corneal hydration levels, BN –NLC gel was confirmed that had no significant irritation to cornea. Ex vivo precorneal retention experiments were carried out by a flow-through approach. The results indicated that the NLC-based hydrogel can prolong precorneal residence time. In conclusion, the hybrid NLCbased hydrogel has a promising potential for application in ocular drug delivery.

Superparticles Formed by Amphiphilic Tadpole-like Single Chain Polymeric Nanoparticles and Their Application as an Ultrasonic Responsive Drug Carrier

Herein, we report self-assembly of tadpole-like single chain polymeric nanoparticles （TPPs） and the ultrasonic response of the resultant superparticles. The TPPs are with an intramolecularly crosslinked poly（2-（methacryloyloxy）ethyl pent-4-ynoate）-rpoly（hydroxyethyl methacrylate） （PMAEP-r-PHEMA） chain as the ＂head＂ and a poly（2- （dimethylamino）ethyl methacrylate （PDMAEMA） linear chain as the ＂tail＂, and are pre- pared simply and emciently by Glaser-coupling of the pendant alkynes in the PMAEP-r- PHEMA block in the common solvent methanol. The formation of the TPPs was confirmed by gel permeation chromatograph, nuclear magnetic resonance spectroscopy, dynamic light scattering, static dynamic scattering, and transmission electron microscopy. In aqueous solution, the amphiphilic TPPs could self-assemble into regular superparticles, driven by aggregation of the hydrophobic ＂heads＂. Since in the structure there is no chain entanglement and the embedding of PDMAEMA chains disturb close-packing of the ＂heads＂, the superpartieles are responsive to a low-energy ultrasonic vibration, as evidenced by greatly enhanced release of the functional molecules from the superparticles by treatment of a low-energy ultrasound. Therefore, the superparticles should be very promising in the use as the drug carriers that can be manipulated from a long distance, considering that ultrasonic energy can be focused at a small area in a relatively long distance from the ultrasound-radiating source.

High-density lipoprotein as a potential carrier for delivery of a lipophilic antitumoral drug into hepatoma cells

AIM: To investigate the possibility of recombinant highdensity lipoprotein (rHDL) being a carrier for delivering antitumoral drug to hepatoma cells. METHODS: Recombinant complex of HDL and aclacinomycin (rHDL-ACM) was prepared by cosonication of apoproteins from HDL (Apo HDL) and ACM as well as phosphatidylcholine. Characteristics of the rHDL-ACM were elucidated by electrophoretic mobility, including the size of particles, morphology and entrapment efficiency. Binding activity of rHDL-ACM to human hepatoma cells was determined by competition assay in the presence of excess native HDL. The cytotoxicity of rHDL-ACM was assessed by MTT method. RESULTS: The density range of rHDL-ACM was 1.063-1.210 g/mL, and the same as that of native HDL. The purity of all rHDL-ACM preparations was more than 92%. Encapsulated efficiencies of rHDL-ACM were more than 90%. rHDL-ACM particles were typical sphere model of lipoproteins and heterogeneous in particle size. The average diameter was 31.26±5.62 nm by measure of 110 rHDL-ACM particles in the range of diameter of lipoproteins. rHDL-ACM could bind on SMMC-7721 cells, and such binding could be competed against in the presence of excess native HDL. rHDL-ACM had same binding capacity as native HDL. The cellular uptake of rHDL-ACM by SMMC-7721 hepatoma cells was significantly higher than that of free ACM at the concentration range of 0.5-10 μg/mL (P<0.01). Cytotoxicity of rHDL-ACM to SMMC-7721 cells was significantly higher than that of free ACM at concentration range of less than 5 ug/mL (P<0.01) and IC50 of rHDL-ACM was lower than IC50 of free ACM (1.68 nmol/L vs3 nmol/L). Compared to L02 hepatocytes, a normal liver cell line, the cellular uptake of rHDL-ACM by SMMC-7721 cells was significantly higher (P<0.01) and in a dose-dependent manner at the concentration range of 0.5-10 μg/mL.Cytotoxicity of the rHDL-ACM to SMMC- 7721 cells was significantly higher than that to L02 cells at concentration range of 1-7.5μg/mL (P<0.01). IC50 for SMMC-7721 cells (1.68 nmol/L) was lower than that for L02 cells (5.68 nmol/L), showing a preferential cytotoxicity of rHDL-ACM for SMMC-7721 cells. CONCLUSION: rHDL-ACM complex keeps the basic physical and biological binding properties of native HDL and shows a preferential cytotoxicity for SMMC-7721 hepatoma to normal L02 hepatocytes, HDL is a potential carrier for delivering lipophilic antitumoral drug to hepatoma cells.

Advances in studies of phospholipids as carriers in skin topical application

Objective： This article provides an overview of characteristics of phospholipids, the characteristics and influential factors of liposome and microemulsion as carriers for skin delivery of drugs, and the latest advances of the phospholipids carriers in transdermal delivery systems. The perspective is that phospholipids carriers may be capable of a wide range of applications in the transdermal delivery system.

Size,shape,charge and“stealthy”surface:Carrier properties affect the drug circulation time in vivo

The present review sets out to discuss recent developments of the effects and mechanisms of carrier properties on their circulation time.For most drugs,sufficient in vivo circulation time is the basis of high bioavailability.Drug carrier plays an irreplaceable role in helping drug avoid being quickly recognized and cleared by mononuclear phagocyte system,to give drug enough time to arrive at targeted organ and tissue to play its therapeutic effect.The physical and chemical properties of drug carriers,such as size,shape,surface charge and surface modification,would affect their in vivo circulation time,metabolic behavior and biodistribution.The final circulation time of carriers is determined by the balance between macrophage recognitions,blood vessel penetration and urine excretion.Therefore,when designing the drug delivery system,we should pay much attention to the properties of drug carriers to get enough in vivo circulation time to arrive at target site eventually.This article mainly reviews the effect of carrier size,size,surface charge and surface properties on its circulation time in vivo,and discusses the mechanism of these properties affecting circulation time.This review has reference significance for the research of long-circulation drug delivery system.

Optimization of indomethacin loaded nanostructured lipid carriers

Topical administration is the most common and acceptable use for the treatment of ocular disease.However,the major problem of ocular drug delivery is the rapid drug elimination from the pre-ocular area leading to poor ocular bioavailability[1].Nanostructure lipid carriers(NLC)possess a significant enhancement in ocular bioavailability by increasing the permeability and mucoadhesive property[2].In this study,indomethacin(IND),non-steroidal anti-inflammatory,was used as a model drug[3].

Research progress in nanoparticles as anticancer drug carrier

Nanoparticles drug delivery system has sustained and controlled release features as well as targeted drug delivery, which can change the characteristics of drug distribution in vivo. It can increase the stability of the drug and enhance drug bioavailability. The selective targeting of nanoparticles can be achieved through enhanced permeability and retention effect and a conjugated specific ligand or through the effects of physiological conditions, such as pH and temperature. Nanoparticles can be prepared by using a wide range of materials and can be used to encapsulate chemotherapeutic agents to reduce toxicity, which can be used for imaging, therapy, and diagnosis. In this research, recent progress on nanoparticles as a targeted drug delivery system will be reviewed, including positive-targeting, negative-targeting, and physicochemical-targeting used as anticancer drug carriers.

A New Type of Nanogel Carrier based on Mixed Pluronic Loaded with Low-Dose Antitumor Drugs

To design a new type of antitumor nanodrug carrier with good biocompatibility, a drug delivery system with a 2.19% drug-loading rate, measured by high-performance liquid chromatography(HPLC), was prepared by membrane hydration using a mixed polymer: Pluronic■ F-127, which binds folic acid(FA), Pluronic■ F-68 and triptolide(TPL)(FA-F-127/F-68-TPL). As a control, another drug delivery system based on a single polymer(FA-F-127-TPL) with a 1.90% drug-loading rate was prepared by substituting F-68 with F-127. The average particle sizes of FA-F-127/F-68-TPL and FA-F-127-TPL measured by a particle size analyzer were 30.7 nm and 31.6 nm, respectively. Their morphology was observed by atomic force microscopy(AFM). The results showed that FA-F-127-TPL self-assembled into nanomicelles, whereas FA-F-127/F-68-TPL self-assembled into nanogels. An MTT assay showed that a very low concentration of FA-F-127/F-68-TPL or FA-F-127-TPL could significantly inhibit the proliferation of multidrug-resistant(MDR) breast cancer cells(MCF-7/ADR cells) and induce cell death. The effects were significantly different from those of free TPL(P < 0.01). Using the fluorescent probe Nile red(Nr) as the drug model, FA-F-127/F-68-Nr nanogels and FAF-127-Nr nanomicelles were prepared and then incubated with human hepatocarcinoma(HepG2) and MCF-7/ADR cells, and the fluorescence intensity in the cells was measured by a multifunctional microplate reader. The results indicated that both FA-F-127/F-68-Nr and FA-F-127-Nr had sustained release in the cells, but HepG2 and MCF-7/ADR cells exhibited significantly higher endocytosis of FA-F-127/F-68-Nr than that of FA-F-127-Nr(P < 0.01). A nude mice transplanted tumor model was prepared to monitor FA-F-127/F-68-Nr in the tumor tissue and organs by whole-body fluorescent imaging. The results showed that FA-F-127/F-68-Nr targeted tumor tissues. The prepared nanogels had small particle size, were easy to swallow, exhibited slow release property,targeted tumor cells, and could improve the antitumor effects of TPL;hence, they are ideal carriers for low-dose antineoplastic drugs.