Multifunctional polymeric micelles as cancer-targeted, MRI-ultrasensitive drug delivery systems

We describe the development of multifunctional polymeric micelles with cancer-targeting capability via alpha(v)beta(3) integrins, controlled drug delivery, and efficient magnetic resonance imaging (MRI) contrast characteristics. Doxorubicin and a cluster of superparamagnetic iron oxide (SPIO) nanoparticles were loaded successfully inside the micelle core. The presence of cRGD on the micelle surface resulted in the cancer-targeted delivery to alpha(v)beta(3)-expressing tumor cells. In vitro MRI and cytotoxicity studies demonstrated the ultrasensitive MRI imaging and alpha(v)beta(3)-specific cytotoxic response of these multifunctional polymeric micelles.     

Polyacrylamide–punicic acid conjugate‐based micelles for flutamide delivery in PC3 cells of prostate cancer: synthesis,characterisation and cytotoxicity studies

The aim of the present study was to synthesize a novel biopolymeric micelle based on punicic acid (PA) and polyacrylamide (PAM) for carrying chemotherapeutic drugs used in prostate cancer treatment. A polymer composite micelle was prepared by chemical conjugation between PAM and PA. The micelles were prepared by self‐assembly via film casting followed by ultrasonication method. The successful production of PAMPA copolymeric micelles was confirmed using FTIR, 1H‐NMR, and TEM. Then, flutamide was loaded in the designed nanomicelles and they were characterized. The cell cytotoxicity of the micelles was studied on PC3 cells of prostate cancer. The prepared nanomicelles showed the particle size of 88 nm, PDI of 0.246, zeta potential of −9 mV, drug loading efficiency of 94.5%, drug release of 85.6% until 10 hours in pH 7.4 and CMC of 74.13 μg/ml. The cell viability in blank nanocarriers was about 70% in PC3 cells at concentration of 25 μM. More significant cytotoxic effects were seen for flutamide loaded micelles at this concentration compared to the free drug. The results suggest that the PAMPA co‐polymeric nanomicelles can be utilized as an effective carrier to enhance the cytotoxic effects of flutamide in prostate cancer.Inspec keywords: nanoparticles, cellular biophysics, drugs, biomedical materials, drug delivery systems, colloids, hydrophilicity, pH, transmission electron microscopy, particle size, cancer, casting, toxicology, electrokinetic effects, polymer blends, proton magnetic resonance, nanomedicine, self‐assembly, nanofabrication, Fourier transform infrared spectraOther keywords: PC3 cells, chemotherapeutic drugs, prostate cancer treatment, polymer composite micelle, chemical conjugation, proton nuclear magnetic resonance, cell cytotoxicity, prepared nanomicelles, drug loading efficiency, drug release, critical micelle concentration, cell viability, cytotoxic effects, flutamideloaded micelles, flutamide delivery, polyacrylamide‐punicic acid conjugate‐based micelles, PAMPA copolymeric nanomicelles, biopolymeric micelle, PAM‐punicic acid copolymer copolymeric micelles, hydrophilic shell, self‐assembly, film casting, ultrasonication method, Fourier transform infrared spectra, transmission electron microscopy, particle size, polydisperity index, zeta potential, pH, blank nanocarriers, time 10.0 hour     

Soluplus/TPGS mixed micelles for dioscin delivery in cancer therapy

Background: Dioscin has shown cytotoxicity against cancer cells, but its poor solubility and stability have limited its clinical application. In this study, we designed mixed micelles composed of TPGS and Soluplus^® copolymers entrapping the poorly soluble anticancer drug dioscin.

Method: In order to improve the aqueous solubility and bioactivity of dioscin, TPGS/Soluplus^® mixed micelles with an optimal ratio were prepared using a thin-film hydration method, and their physicochemical properties were characterized. Cellular cytotoxicity and uptake of the dioscin-loaded TPGS/Soluplus^® mixed micelles were studied in MCF-7 breast cancer cells and A2780s ovarian cancer cells. The pharmacokinetics of free dioscin and dioscin-loaded TPGS/Soluplus^® mixed micelles was studied in vivo in male Sprague-Dawley rats via a single intravenous injection in the tail vein.

Results: The average size of the optimized mixed micelle was 67.15?nm, with 92.59% drug encapsulation efficiency and 4.63% drug loading efficiency. The in vitro release profile showed that the mixed micelles presented sustained release behavior compared to the anhydrous ethanol solution of dioscin. In vitro cytotoxicity assays were conducted on human cancer cell lines including A2780s ovarian cancer cells and MCF-7 breast cancer cells. The mixed micelles exhibited better antitumor activity compared to free dioscin against all cell lines, which may benefit from the significant increase in the cellular uptake of dioscin from mixed micelles compared to free dioscin. The pharmacokinetic study showed that the mixed micelle formulation achieved a 1.3 times longer mean residual time (MRT) in circulation and a 2.16 times larger area under the plasma concentration–time curve (AUC) than the free dioscin solution.

Conclusion: Our results suggest that the dioscin-loaded mixed micelles developed in this study might be a potential nano drug-delivery system for cancer chemotherapy.     

Chitosan nanoparticles for the oral delivery of tenofovir disoproxil fumarate: formulation optimization,characterization and ex vivo and in vivo evaluation for uptake mechanism in rats

Objective: Design chitosan based nanoparticles for tenofovir disoproxil fumarate (TDF) with the purpose of enhancing its oral absorption.

Significance: TDF is a prodrug that has limited intestinal absorption because of its susceptibility to gut wall esterases. Hence, design of chitosan based polymeric novel nanocarrier systems can protect TDF from getting metabolized and also enhance the oral absorption.

Methods: The nanoparticles were prepared using the ionic gelation technique. The factors impacting the particle size and entrapment efficiency of the nanoparticles were evaluated using design of experiments approach. The optimized nanoparticles were characterized and evaluated for their ability to protect TDF from esterase metabolism. The nanoparticles were then studied for the involvement of active transport in their uptake during the oral absorption process. Further, in vivo pharmacokinetic studies were carried out for the designed nanoparticles.

Results: The application of design of experiments in the optimization process was useful to determine the critical parameters and evaluate their interaction effects. The optimized nanoparticles had a particle size of 156?±?5?nm with an entrapment efficiency of 48.2?±?1%. The nanoparticles were well characterized and provided metabolic protection for TDF in the presence of intestinal esterases. The nanoparticles were able to increase the AUC of tenofovir by 380%. The active uptake mechanisms mainly involving clathrin-mediated uptake played a key role in increasing the oral absorption of tenofovir.

Conclusions: These results show the ability of the designed chitosan based nanoparticles in enhancing the oral absorption of TDF along the oral route by utilizing the active endocytic uptake pathways.     

Synthesis,in vitro characterization,and anti-tumor effects of novel polystyrene-poly(amide-ether-ester-imide) co-polymeric micelles for delivery of docetaxel in breast cancer in Balb/C mice

Objective: The goal of the present work was to make novel co-polymeric micellar carriers for the delivery of docetaxel (DTX).

Significance: Co-polymeric micelles can not only solubilize DTX and eliminate the need for toxic surfactants to dissolve it, but also cause passive targeting of the drug to the tumor and reduce its toxic side effects.

Methods: Poly(styrene-maleic acid) (SMA) was conjugated to poly (amide-ether-ester-imide)-poly ethylene glycol (PAEEI-PEG). Copolymer synthesis was proven by Fourier transform infrared (FTIR) and ¹H-nuclear magnetic resonance (¹H-NMR). The SMA-PAEEI-PEG micelles loaded with DTX were prepared and their critical micelle concentration (CMC), zeta potential, particle size, entrapment efficiency, and their release efficiency were studied. MCF-7 and MDA-MB231 breast cancer cells were used to evaluate the cellular uptake and cytotoxicity of the micelles. The antitumor activity of the DTX-loaded nanomicelles was measured in Balb/c mice.

Results: The FTIR and HNMR spectroscopy confirmed successful conjugation of SMA and PAEEI-PEG. The drug loading efficiency was in the range of 34.01–72.75% and drug release lasted for 120?h. The CMC value of the micelles was affected by the SMA/PAEEI-PEG ratio and was in the range of 29.85–14.28?µg/ml. The DTX-loaded micelles showed five times more cytotoxicity than the free drug. The DTX loaded micelles were more effective in tumor growth suppression in vivo and the animals showed an enhanced rate of survival.

Conclusion: The results show that the SMA-PAEEI-PEG micelles of DTX could potentially provide a suitable parenteral formulation with more stability, higher cytotoxicity, and improved antitumor activity.     

聚合物胶束纳米药物的研究进展

聚合物胶束纳米药物极具发展和应用前景,然而聚合物胶束纳米药物稳定性差严重制约着其在肿瘤化疗中的应用。为改善聚合物胶束纳米药物的稳定性,采取的策略大致可归纳为:一是制备具有稳定交联结构的聚合物胶束;二是构建聚合物前药胶束输送系统;三是进行聚合物结构设计制备具有低临界胶束浓度(CMC)的胶束或单分子胶束。文中着重综述近年来针对聚合物胶束纳米药物稳定性开展的研究和取得的进展,并对聚合物胶束纳米药物的研究和发展进行了展望。     

Glucose-installed biodegradable polymeric micelles for cancer-targeted drug delivery system: synthesis,characterization and <Emphasis Type="Italic">in vitro</Emphasis> evaluation

Glucose metabolism of cancer can be used as a strategy to target cancer cells which exhibit altered glycolytic rate. The facilitated glucose transporter (Glut) plays an important role in enhancement glycolytic rate resulting in increased glucose uptake into cancer cells. ¹⁸FGD-PET image is an example for using Glut as a targeting to diagnose the high glycolytic rate of tumor. Thus, Glut may be adapted to target cancer cells for drug delivery system. Herein, biodegradation polymeric micelles target cancer cells by Glut was fabricated. The amphiphilic block copolymer of poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) was synthesized where terminal group of the PEG chain was installed with glucose molecules. The ¹H-NMR confirmed the existence of glucose moiety from two distinct peaks (5.2 and 4.7 ppm) of protons at anomeric carbon of glucose. Glucose-PEG-b-PCL spontaneously forms micelles in an aqueous solution. The size and zeta potential were 22?nm and -7 mv, respectively. Glucose-micelles have high stability, and no evidence of cytotoxicity was found after incubation for 7 days. Doxorubicin, used as a fluorescent probe, was loaded into glucose-micelles. The enhanced amount of doxorubicin as a result of glucose-micelles in PC-3, MCF-7 and HepG2 was evaluated by fluorescence microscopy and flow cytometer. Glucose molecules on the surface of micelles increased internalization and enhanced uptake of micelles via bypassing endocytosis pathway. These results show the use of glucose as a targeting ligand on the micelle surface to target cancer cells via Glut.

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A novel eye drop of alpha tocopherol to prevent ocular oxidant damage: improve the stability and ocular efficacy

Abstract

The aim of this study was to design novel mixed micelles as an ophthalmic delivery system for alpha-tocopherol (TOC) to prevent its degradation and improve ocular efficacy. The nonionic polymers, Polyoxyl 15 Hydroxystearate (Solutol® HS15) and Pluronic® F127, were discovered to be the most effective agents for retaining the activity and solubilization of TOC, respectively. Prepared by a thin-film hydration method, HS15/Pluronic® F127 yielded good encapsulation percentages of TOC, with a 27.7% drug loading efficiency. Incorporation of cetalkonium chloride (CKC) into HS15/Pluronic® F127 mixed micelles made the zeta potential of the micelles +17?mV, potentially prolonging the residence time of formulations on ocular surfaces. The optimized micelle preparation remained stable when diluted in a synthetic tear solution. It is known that the antioxidant ability of TOC in typical formulations reduces to around 85% of its initial value after 1 month when stored at 4 or 25?°C under an air atmosphere, which limits ophthalmic applications to less than 1 month. However, encapsulated TOC in investigated micelles remained stable for at least 6 months when sealed with N₂. Finally, the cationic micelles were well tolerated after multiple administrations in rabbits, and they improved ocular accumulation of TOC. Taken together, these data suggest that the optimized micelle preparations described in this study may be suitable drug carriers for the treatment of ocular oxidant damage.     

Polymeric micelles modified by folate-PEG-lipid for targeted drug delivery to cancer cells in vitro

A novel technique was developed for the formation of ligand-targeted polymeric micelles that can be applicable to various ligands. For tumor-specific drug delivery, camptothecin (CPT)-loaded polymeric micelles were modified by folate to produce a folate-receptor-targeted drug carrier. Folate-linked PEG5000-distearoylphosphatidylethanolamine (folate-PEG5000-DSPE) was added when preparations of drug-loaded polymeric micelles, resulting in folate ligands exposed to the surface. Folate-modified CPT-loaded polymeric micelles (F-micelle) were evaluated by measuring cellular uptake using a flow cytometer, fluorescence microscopy, and confocal laser scanning microscopy, and by cytotoxicity measurement. The results revealed that F-micelle showed higher cellular uptake in KB cells overexpressing folate receptor (FR) and higher cytotoxicity compared with non-folate modified CPT-loaded polymeric micelles (plain micelles) in KB cells, but not in FR-negative HepG2 cells. This result indicated that polymeric micelles were successfully modified by the folate-linked lipid.     

基于β-聚苹果酸衍生物的两种聚合物胶束的制备

合成聚苹果酸苄基酯（PMLABz）和聚苹果酸（PMLA）,在此基础上构建两种不同类型的聚合物胶柬,通过合成PMLABz、PMLA、聚乙二醇-聚苹果酸-喜树碱-I（P1）和聚乙二醇-聚苹果酸-喜树碱-II（P2）,利用动态透析法制备P1、P2胶柬,并进行表征、筛选。为了进一步增强胶束细胞的内摄作用和特定肿瘤细胞的靶向性,用靶向分子叶酸修饰胶柬,结果显示,该方法能成功制备药物载体PMLABz、PMLA及共聚物P1、P2,其中,P1是接枝共聚物,能够自组装成平均直径100nm星型胶束（载药量：11．2％,粒径：97.2±4．6nm,zeta电位：-18．5mV）;P2是嵌段共聚物,能够自组装成平均直径75nm的平头型胶束（载药量：20．5％,粒径：76．4±3．8nm,zeta电位：-16．4mv）;P1、P2胶柬形态圆整,粒径均匀,因此,P1、P2胶柬是一种潜在的自组装给药体系。     

An effective treatment approach of DPP-IV inhibitor encapsulated polymeric nanoparticles conjugated with anti-CD-4 mAb for type 1 diabetes

Nanotechnology based biomedical approaches and surface modification techniques made it easier for targeting specific site and improving the treatment efficacy. The present study reports on targeted polymeric nanoparticles conjugated with antibody as a site-specific carrier system for effective treatment of type 1 diabetes. Sitagliptin (SP)-loaded Poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NP) were prepared by nanoprecipitation cum solvent evaporation method and were characterized in terms of morphology, size, surface charge, and entrapment efficiency. Optimized batch demonstrated a particle size of 105.24?nm, with significant entrapment efficacy. In vitro release studies exhibited a controlled release pattern of 67.76?±?1.30% in 24?h, and a maximum of 96.59?±?1.26% at the end of 48?h. Thiol groups were introduced on the surface of SP-NPs whose concentration on SP-NPs was 27?±?2.6?mmol/mol PLGA-NPs, anti-CD4 antibody clone Q4120 was conjugated to the thiolated SP-NPs via a sulfo-MBS cross-linker, ～70% conjugation was observed. The in vitro cytotoxicity studies performed on RIN-5?F cells for mAb-SP-NPs presented an IC₅₀ of 76?µg/mL, and the insulin release assay had revealed an increased release at 5.15?±?0.16?IU/mL. The results indicate that mAb-SP-NPs allowed a controlled release of SP and thereby produced insulin levels comparable with control. Therefore, mAb-SP-NPs system appears to be effective in the treatment of auto immune diabetes, subject to further analysis.     

Surface functionalization of PLGA nanoparticles by non-covalent insertion of a homo-bifunctional spacer for active targeting in cancer therapy

This work reports the surface functionalization of polymeric PLGA nanoparticles by non-covalent insertion of a homo-bifunctional chemical crosslinker, bis(sulfosuccinimidyl) suberate (BS3) for targeted cancer therapy. We dissolved BS3 in aqueous solution of PVA during formulation of nanoparticles by a modified solid/oil/water emulsion solvent evaporation method. The non-covalent insertion of BS3 was confirmed by Fourier transform infrared (FTIR) spectroscopy. Curcumin and annexin A2 were used as a model drug and a cell specific target, respectively. Nanoparticles were characterized for particle size, zeta potential and surface morphology. The qualitative assessment of antibody attachment was performed by transmission electron microscopy (TEM) as well as confocal microscopy. The optimized formulation showed antibody attachment of 86%. However, antibody attachment was abolished upon blocking the functional groups of BS3. The availability of functional antibodies was evaluated by the presence of a light chain fraction after gel electrophoresis. We further evaluated the in vitro release kinetics of curcumin from antibody coated and uncoated nanoparticles. The release of curcumin is enhanced upon antibody attachment and followed an anomalous release pattern. We also observed that the cellular uptake of nanoparticles was significantly higher in annexin A2 positive cells than in negative cells. Therefore, these results demonstrate the potential use of this method for functionalization as well as to deliver chemotherapeutic agents for treating cancer.     

In vitro evaluation of folic acid modified carboxymethyl chitosan nanoparticles loaded with doxorubicin for targeted delivery

The development of smart targeted nanoparticle that can deliver drugs to direct cancer cells, introduces better efficacy and lower toxicity for treatment. We report the development and characterizations of pH-sensitive carboxymethyl chitosan modified folic acid nanoparticles and manifest their feasibility as an effective targeted drug delivery vehicle. The nanoparticles have been synthesized from carboxymethyl chitosan with covalently bonded bifunctional 2,2′-(ethylenedioxy)-bis-(ethylamine) (EDBE) through the conjugation with folic acid. The conjugation has been analyzed by Fourier transform infrared spectroscopy and nuclear magnetic resonance spectroscopy. The resultant nanoparticles with an average size less then 200 nm measured by dynamic light scattering and transmission electron microscopy. Confocal microscopy and flow cytometric analysis have revealed that folate-mediated targeting significantly enhances the cellular uptake of the nanoparticle and thus facilitates apoptosis of cancer cells (HeLa, B16F1). For the application of the nanoparticles as a drug carrier, Doxorubicin a potent anticancer drug has been loaded into the nanoparticles, with the drug loading amount and the drug release pattern observed.     

Preparation and evaluation of self-assembly Soluplus®-sodium cholate-phospholipid ternary mixed micelles of docetaxel

Abstract

Ternary mixed micelles constituted of Soluplus^®, sodium cholate, and phospholipid were prepared as nano-delivery system of the anticancer drug, docetaxel. The formulation of docetaxel-loaded ternary mixed micelles (DTX-TMMs) with an optimized composition (Soluplus^®/sodium cholate/phospholipid= 3:2:1 by weight) were obtained. The main particle size of DTX-TMMs was 76.36?±?2.45?nm, polydispersity index (PDI) was 0.138?±?0.039, and the zeta potential was ?8.46?±?0.55?mv. The encapsulation efficiency was 94.24?±?4.30% and the drug loading was 1.25%. The critical micelle concentration value was used to assess the ability of carrier materials to form micelles. The results indicated that the addition of Soluplus^® to sodium cholate-phospholipid mixed micelles could reduce the critical micelle concentration and improve the stability. In vitro release studies demonstrated that compared with DTX-Injection group, the DTX-TMMs presented a controlled release property of drugs. In vivo pharmacodynamics results suggested that DTX-TMMs had the most effective inhibitory effect on tumor proliferation and had good biosafety. In addition, the relative bioavailability of mixed micelles was increased by 1.36 times compared with the DTX-Injection in vivo pharmacokinetic study indicated that a better therapeutic effect could be achieved. In summary, the ternary mixed micelles prepared in this study are considered to be promising anticancer drug delivery systems.     

MUC1 aptamer-conjugated mesoporous silica nanoparticles effectively target breast cancer cells

In the present study, we developed aptamer (Apt) conjugated mesoporous silica nanoparticles (MSNs) for specific delivery of epirubicin (EPI) to breast cancer cells. MSNs were synthesized and functionalized with 3-mercaptopropyltrimethoxysilane (3-MPTMS), followed by MUC1 aptamer conjugation through disulfide bonds. The nanoparticles were analyzed by transmission electron microscopy (TEM), particle size analyzer, zeta potential, elemental analysis (CHNS), aptamer conjugation efficiency, drug loading efficiency, and drug release profile. Cell uptake and in vitro cytotoxicity of different formulations were performed. The results of MSNs characterization confirmed spherical nanoparticles with thiol functional groups. Particle size of obtained nanoparticles was 163?nm in deionized water. After conjugation of MUC1 aptamer and EPI loading (MSN-MUC1-EPI), particle size increased to 258?nm. The aptamer conjugation to MSNs with disulfide bonds were confirmed using gel retardation assay. Cellular uptake studies revealed better cell uptake of MSN-MUC1-EPI compared to MSN-EPI. Moreover, cytotoxicity study results in MCF7 cell lines showed improved cytotoxicity of MSN-MUC1-EPI in comparison with MSN-EPI or EPI at the same concentration of drug. These results exhibited that MSN-MUC1-EPI has the potential for targeted drug delivery into MUC1 positive breast cancer cells to improve drug efficacy and alleviate side effects.     

基于β-聚苹果酸衍生物的两种聚合物胶束的制备

合成聚苹果酸苄基酯（PMLABz）和聚苹果酸（PMLA）,并以此为基础构建两种不同类型的聚合物胶束,通过合成PMLABz、PMLA、聚乙二醇-聚苹果酸-喜树碱-I（P1）和聚乙二醇-聚苹果酸-喜树碱-Ⅱ（P2）,动态透析法制备P1、P2胶束,并进行表征、筛选。为了进一步增强胶柬的细胞内摄作用和特定肿瘤细胞靶向性,用靶向分子叶酸修饰胶柬。结果表明,成功地制备出药物载体PMLABz、PMLA及共聚物P1、P2。P1是接枝共聚物,能够自组装成平均直径100nm星型胶束（载药量：11.2％,粒径：97．2±4．6nm,zeta电位：-18．5mV）;P2是嵌段共聚物．能够自组装成平均直径75nm的平头型胶束（载药量：20．5％,粒径：76．4±3．8nm,zeta电位：-16．4mv）：P1、P2胶柬形态圆整,粒径均匀,因此,P1、P2胶束是一种潜在的自组装给药体系。     

Nanoparticles for cellular drug delivery: mechanisms and factors influencing delivery

Polymeric nanoparticles have demonstrated enormous potential as cellular drug delivery vehicles. Nanoparticles improve drug's stability as well as its availability and retention at the target intracellular site of action. Therapeutic efficacy of nanoparticles can be further enhanced by conjugating specific ligands to nanoparticle surface. Ligand conjugation can also be used to favorably modify the intracellular disposition of nanoparticles. A number of ligands are available for this purpose; use of a specific ligand depends on the target cell, the material used for nanoparticle formulation, and the chemistry available for ligand-nanoparticle conjugation. Cellular drug delivery using nanoparticles is also affected by clearance through the reticuloendothelial system. In this paper, we review the recent progress on our understanding of physicochemical factors that affect the cellular uptake of nanoparticles and the different cellular processes that could be exploited to enhance nanoparticle uptake into cells.     

Design of novel sheet-shaped chitosan hydrogel for wound healing: A hybrid biomaterial consisting of both PEG-grafted chitosan and crosslinkable polymeric micelles acting as drug containers

In this study, we successfully prepared a novel “sheet-shaped” chitosan hydrogel for wound healing consisting of both PEG-g-chitosan and a crosslinkable polymeric micelle. The study's findings clarify that the PEG modification percentage (PMP) of PEG-g-chitosan increased proportionally as the weight ratio of PEG/chitosan increased. Furthermore, the positive second virial coefficient of PEG-g-chitosans from a Debye plot strongly suggests that the PEG modification greatly improved the solubility of the water-insoluble chitosan. Finally, the “sheet-shaped” “flexible” hydrogel formed by mixing solutions containing either PEG-g-chitosan with moderate PMP or polymeric micelles exhibited the highest storage modulus. The sheet itself exhibited an attractive feature insofar as polymeric micelles, which can act as drug containers facilitating the incorporation and the gradual release of drugs, are covalently immobilized in the polymeric network of the hydrogel. The results obtained in the present study show that the hybrid PEG-g-chitosan hydrogel containing crosslinkable polymeric micelles has the potential to address the need for novel functional biomaterials.     

PH-sensitive Dioctadecylamine-501 polymeric micelles for delivery of insulin

In this work, fluorescently labeled smart micelle copolymers which consist of Dioctadecylamine-501 (DODA-501) as the hydrophobic segment, N-isopropylacrylamide (NIPAAm) as well as acrylic acid (AAc) as the hydrophilic segments were prepared. These micelles showed both thermo- and pH-sensitive properties due to the nature properties of NIPAAm and AAc, respectively. The particle size of the prepared micelles ranged from 94 approximately 200 nm and was found to increase with DODA-501 concentration. The size of particles varied in different pH mediums or different temperatures suggesting these micelles were pH- and thermo-sensitive. The image of confocal laser scanning microscopy (CLSM) illustrates these micelles had the ability to encapsulate rhodamine solution. From CLSM observation, fluorescein isothiocyanate (FITC) expression was found on the surface of micelles indicating the target detecting ability of these micelles. In drug loading and release studies, these micelles had the ability to encapsulate insulin and its release was pH sensitive, being more rapid under intestinal fluid environment, but resisting the drug release at gastric fluid environment. Stability test indicates these micelles had good stability during storage. These results suggest the pH-sensitivity of the DODA-501 polymeric micelles may be an interesting candidate for oral drug delivery system.     

Bioerodible polymeric nanoparticles for targeted delivery of proteic drugs

Significant efforts are being devoted to develop nanotechnology for drug delivery, mainly because of the distinct advantages offered by nanometer-size polymeric systems. Moreover, targeted drug delivery can be obtained by polymer conjugation to biospecific ligands. The present investigation was aimed mainly at determining the targeting ability of hybrid nanoparticles based on synthetic polymer/protein hybrid matrices. These nanoparticles were designed for liver targeted release of proteic drugs with antiviral activity, such as alpha-interferon. Human serum albumin and the monoesters of alternating copolymers of maleic anhydride/alkyl vinyl ethers of oligo(ethylene glycol) were selected as proteic and synthetic components, respectively. Digalactosyl diacyl glycerol, a natural glycolipid selectively recognized by the asialofetuin receptor present on liver hepatocytes was used as active targeting agent. Nanoparticles of 100-300 nm average size were obtained by controlled coprecipitation method. Investigation of nanoparticle surface properties by spectroscopic analysis and by biological tests indicated that the synthesized nanoparticles do expose on their surface targeting moieties that selectively interact with liver hepatocytes receptors.