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1

Targeted Nanogels: A Versatile Platform for Drug Delivery to Tumors  

PubMed Central

While nanoparticle-based drug delivery formulations can improve the effectiveness and safety of certain anti-cancer drugs, many drugs, due to their chemical composition, are unsuitable for nanoparticle loading. Here, we describe a targeted nanogel drug delivery platform that can 1) encapsulate a wide range of drug chemotypes including: biological, small molecule, and cytotoxic agents 2) display targeting ligands and polymeric coatings on the surface, 3) enhance drug retention within the nanogel core after photo-crosslinking, and 4) retain therapeutic activity after lyophilization allowing for long term storage. For therapeutic studies, we utilized integrin ?v?3-targeted lipid-coated nanogels with crosslinked human serum albumin in the core for carrying therapeutic cargoes. These particles exhibited potent activity in tumor cell viability assays with drugs of distinct chemotype including: paclitaxel, docetaxel, bortezomib, 17-AAG, sorafenib, sunitinib, bosutinib, and dasatinib. Treatment of orthotopic breast and pancreas tumors in mice with taxane-loaded nanogels produced a 15-fold improvement in anti-tumor activity relative to Abraxane by blocking both primary tumor growth and spontaneous metastasis. With a modifiable surface and core, the lipid-coated nanogel represents a platform technology that can be easily adapted for specific drug delivery applications to treat a wide range of malignant diseases. PMID:21518727

Murphy, Eric A.; Majeti, Bharat K.; Mukthavaram, Rajesh; Acevedo, Lisette M.; Barnes, Leo A.; Cheresh, David A.

2011-01-01

2

Polyelectrolyte Nanogels Decorated with Monoclonal Antibody for Targeted Drug Delivery  

PubMed Central

Novel surface-functionalized cross-linked nanogels were developed as a platform to allow conjugation of monoclonal antibodies (mAb) for targeted drug delivery. Well-defined diblock copolymers of poly(ethylene glycol)-b-poly(methacrylic acid) (PEG-b-PMA) with PEG terminal aldehyde functionality were synthesized by atom transfer radical polymerization (ATRP) and characterized by GPC and 1H NMR. These copolymers were used to prepare nanogels via condensation of PEG-b-PMA with Ca2+ ions into micelle-like aggregates, cross-linking of the PMA/Ca2+ cores and removal of Ca2+ ions. The resulting nanogels represent highly swollen spherical polyelectrolyte particles with free terminal aldehyde functionalities at the nonionic PEG chains. A reductive amination reaction between aldehyde groups and amino groups of mAb resulted in effective conjugation to the nanogels of mAb CC49 against tumor-associated glycoprotein 72 (TAG-72). The mAb retained the binding affinity to bovine submaxillary mucin after conjugation as shown by surface plasmon resonance (SPR). Therefore, aldehyde functionalized nanogels can be linked to mAb using a simple, one-step approach. They may have potential for targeted delivery of diagnostic and therapeutic agents to tumors. PMID:21503276

Nukolova, Nataliya V.; Yang, Zigang; Kim, Jong Oh; Kabanov, Alexander V.; Bronich, Tatiana K.

2010-01-01

3

LHRH-targeted nanogels as delivery system for cisplatin to ovarian cancer  

PubMed Central

Targeted drug delivery using multifunctional polymeric nanocarriers is a modern approach for cancer therapy. Our purpose was to prepare targeted nanogels for selective delivery of chemotherapeutic agent cisplatin to luteinizing hormone-releasing hormone (LHRH) receptor overexpressing tumor in vivo. Building blocks of such delivery systems consisted of innovative soft block copolymer nanogels with ionic cores serving as a reservoir for cisplatin (loading 35%) and a synthetic analog of LHRH conjugated to the nanogels via poly(ethylene glycol) spacer. Covalent attachment of (D-Lys6)-LHRH to nanogels was shown to be possible without loss in either the ligand binding affinity or the nanogel drug incorporation ability. LHRH-nanogel accumulation was specific to the LHRH-receptor positive A2780 ovarian cancer cells and not towards LHRH-receptor negative SKOV-3 cells. The LHRH-nanogel cisplatin formulation was more effective and less toxic than equimolar doses of free cisplatin or untargeted nanogels in the treatment of receptor-positive ovarian cancer xenografts in mice. Collectively, the study indicates that LHRH mediated nanogel-cisplatin delivery is a promising formulation strategy for therapy of tumors that express the LHRH receptor. PMID:23957812

Nukolova, Natalia V.; Oberoi, Hardeep S.; Zhao, Yi; Chekhonin, Vladimir P.; Kabanov, Alexander V.; Bronich, Tatiana K.

2013-01-01

4

Multifunctional quantum dot-polypeptide hybrid nanogel for targeted imaging and drug delivery  

NASA Astrophysics Data System (ADS)

A new type of multifunctional quantum dot (QD)-polypeptide hybrid nanogel with targeted imaging and drug delivery properties has been developed by metal-affinity driven self-assembly between artificial polypeptides and CdSe-ZnS core-shell QDs. On the surface of QDs, a tunable sandwich-like microstructure consisting of two hydrophobic layers and one hydrophilic layer between them was verified by capillary electrophoresis, transmission electron microscopy, and dynamic light scattering measurements. Hydrophobic and hydrophilic drugs can be simultaneously loaded in a QD-polypeptide nanogel. In vitro drug release of drug-loaded QD-polypeptide nanogels varies strongly with temperature, pH, and competitors. A drug-loaded QD-polypeptide nanogel with an arginine-glycine-aspartic acid (RGD) motif exhibited efficient receptor-mediated endocytosis in ?v?3 overexpressing HeLa cells but not in the control MCF-7 cells as analyzed by confocal microscopy and flow cytometry. In contrast, non-targeted QD-polypeptide nanogels revealed minimal binding and uptake in HeLa cells. Compared with the original QDs, the QD-polypeptide nanogels showed lower in vitro cytotoxicity for both HeLa cells and NIH 3T3 cells. Furthermore, the cytotoxicity of the targeted QD-polypeptide nanogel was lower for normal NIH 3T3 cells than that for HeLa cancer cells. These results demonstrate that the integration of imaging and drug delivery functions in a single QD-polypeptide nanogel has the potential for application in cancer diagnosis, imaging, and therapy.A new type of multifunctional quantum dot (QD)-polypeptide hybrid nanogel with targeted imaging and drug delivery properties has been developed by metal-affinity driven self-assembly between artificial polypeptides and CdSe-ZnS core-shell QDs. On the surface of QDs, a tunable sandwich-like microstructure consisting of two hydrophobic layers and one hydrophilic layer between them was verified by capillary electrophoresis, transmission electron microscopy, and dynamic light scattering measurements. Hydrophobic and hydrophilic drugs can be simultaneously loaded in a QD-polypeptide nanogel. In vitro drug release of drug-loaded QD-polypeptide nanogels varies strongly with temperature, pH, and competitors. A drug-loaded QD-polypeptide nanogel with an arginine-glycine-aspartic acid (RGD) motif exhibited efficient receptor-mediated endocytosis in ?v?3 overexpressing HeLa cells but not in the control MCF-7 cells as analyzed by confocal microscopy and flow cytometry. In contrast, non-targeted QD-polypeptide nanogels revealed minimal binding and uptake in HeLa cells. Compared with the original QDs, the QD-polypeptide nanogels showed lower in vitro cytotoxicity for both HeLa cells and NIH 3T3 cells. Furthermore, the cytotoxicity of the targeted QD-polypeptide nanogel was lower for normal NIH 3T3 cells than that for HeLa cancer cells. These results demonstrate that the integration of imaging and drug delivery functions in a single QD-polypeptide nanogel has the potential for application in cancer diagnosis, imaging, and therapy. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr03058c

Yang, Jie; Yao, Ming-Hao; Wen, Lang; Song, Ji-Tao; Zhang, Ming-Zhen; Zhao, Yuan-Di; Liu, Bo

2014-09-01

5

Near-Infrared Light-Responsive Core-Shell Nanogels for Targeted Drug Delivery  

PubMed Central

A near-infrared light-responsive drug delivery platform based on Au-Ag-nanorods (Au-Ag NRs) coated with DNA-crosslinked polymeric shells was constructed. DNA complementarity has been applied to develop a polyacrylamide-based sol-gel transition system to encapsulate anticancer drugs into the gel scaffold. The Au-Ag NR based nanogels can also be readily functionalized with targeting moieties, such as aptamers, for specific recognition of tumor cells. When exposed to NIR irradiation, the photothermal effect of the Au-Ag NRs leads to a rapid rise in the temperature of the surrounding gel, resulting in the fast release of the encapsulated payload with high controllability. In vitro study confirmed that aptamer functionalized nanogels can be used as drug carriers feasible for targeted drug delivery with remote control capability by NIR light with high spatial/temporal resolution. PMID:21542633

Kang, Huaizhi; Trondoli, Anna Carolina; Zhu, Guizhi; Chen, Yan; Chang, Ya-Jen; Liu, Haipeng; Huang, Yu-Fen; Zhang, Xiaoling; Tan, Weihong

2011-01-01

6

Polymer nanogels: a versatile nanoscopic drug delivery platform  

PubMed Central

In this review we put the spotlight on crosslinked polymer nanogels, a promising platform that has the characteristics of an “ideal” drug delivery vehicle. Some of the key aspects of drug delivery vehicle design like stability, response to biologically relevant stimuli, passive targeting, active targeting, toxicity and ease of synthesis are discussed. We discuss several delivery systems in this light and highlight some examples of systems, which satisfy some or all of these design requirements. In particular, we point to the advantages that crosslinked polymeric systems bring to drug delivery. We review some of the synthetic methods of nanogel synthesis and conclude with the diverse applications in drug delivery where nanogels have been fruitfully employed. PMID:22342438

Chacko, Reuben T.; Ventura, Judy; Zhuang, Jiaming; Thayumanavan, S.

2012-01-01

7

Nanogel-based carriers for topical delivery.  

E-print Network

??This thesis investigated the potential of multiple stimuli-responsive nanogels as carriers in topical drug administration, with a view to developing a multi-responsive topical delivery system.… (more)

Abu Samah, Nor Hayati.

2011-01-01

8

Folate-Decorated Nanogels for Targeted Therapy of Ovarian Cancer  

PubMed Central

Nanogels are comprised of swollen polymer networks and nearly 95 % water and can entrap diverse chemical and biological agents for cancer therapy with very high loading capacities. Here we use diblock copolymer poly(ethylene oxide)-b-poly(methacrylic acid) (PEO-b-PMA) to form nanogels with the desired degree of cross-linking. The nanogels are further conjugated to folic acid (FA) and loaded with different types of drugs (cisplatin, doxorubicin). For the first time we demonstrate a tumor-specific delivery and superior antitumor effect in vivo of an anti-cancer drug using these polyelectrolyte nanogels decorated with folate targeting groups. This reinforces the use of nanogels for the therapy of ovarian and other cancers, where folate receptor (FR) is over-expressed. PMID:21536326

Nukolova, Natalia V.; Oberoi, Hardeep S.; Cohen, Samuel M.; Kabanov, Alexander V.; Bronich, Tatiana K.

2011-01-01

9

Nanogel-based delivery of mycophenolic acid ameliorates systemic lupus erythematosus in mice  

PubMed Central

The ability to selectively inactivate immune cells with immunosuppressants is a much sought-after modality for the treatment of systemic lupus erythematosus and autoimmunity in general. Here, we designed and tested a novel nanogel drug delivery vehicle for the immunosuppressant mycophenolic acid (MPA). Treatment with MPA-loaded nanogels increased the median survival time (MST) of lupus-prone NZB/W F1 mice by 3 months with prophylactic use (MST was 50 weeks versus 38 weeks without treatment), and by 2 months when administered after the development of severe renal damage (MST after proteinuria onset was 12.5 weeks versus 4 weeks without treatment). Equivalent and greater doses of MPA administered in buffer were not efficacious. Nanogels had enhanced biodistribution to organs and association with immune cells. CD4-targeted nanogels yielded similar therapeutic results compared with nontargeted formulations, with protection from glomerulonephritis and decreases in IFN-?–positive CD4 T cells. DCs that internalized nanogels helped mediate immunosuppression, as they had reduced production of inflammatory cytokines such as IFN-? and IL-12. Our results demonstrate efficacy of nanogel-based lupus therapy and implicate a mechanism by which immunosuppression is enhanced, in part, by the targeting of antigen-presenting cells. PMID:23454752

Look, Michael; Stern, Eric; Wang, Qin A.; DiPlacido, Leah D.; Kashgarian, Michael; Craft, Joe; Fahmy, Tarek M.

2013-01-01

10

Polymeric nanogel formulations of nucleoside analogs  

PubMed Central

Nanogels are colloidal microgel carriers that have been introduced recently as a prospective drug delivery system for nucleotide therapeutics. The crosslinked protonated polymer network of nanogels binds oppositely charged drug molecules, encapsulating them into submicron particles with a core-shell structure. The nanogel network also provides a suitable template for chemical engineering, surface modification and vectorisation. This review reveals recent attempts to develop novel drug formulations of nanogels with antiviral and antiproliferative nucleoside analogs in the active form of 5?-triphosphates; discusses structural approaches to the optimisation of nanogel properties, and; discusses the development of targeted nanogel drug formulations for systemic administration. Notably, nanogels can improve the CNS penetration of nucleoside analogs that are otherwise restricted from passing across the blood–brain barrier. The latest findings reviewed here demonstrate an efficient intracellular release of nucleoside analogs, encouraging further applications of nanogel carriers for targeted drug delivery. PMID:17184158

Vinogradov, Serguei V

2008-01-01

11

ICAM-1 Targeted Nanogels Loaded with Dexamethasone Alleviate Pulmonary Inflammation  

PubMed Central

Lysozyme dextran nanogels (NG) have great potential in vitro as a drug delivery platform, combining simple chemistry with rapid uptake and cargo release in target cells with “stealth” properties and low toxicity. In this work, we study for the first time the potential of targeted NG as a drug delivery platform in vivo to alleviate acute pulmonary inflammation in animal model of LPS-induced lung injury. NG are targeted to the endothelium via conjugation with an antibody (Ab) directed to Intercellular Adhesion Molecule-1(ICAM-NG), whereas IgG conjugated NG (IgG-NG) are used for control formulations. The amount of Ab conjugated to the NG and distribution in the body after intravenous (IV) injection have been quantitatively analyzed using a tracer isotope-labeled [125I]IgG. As a proof of concept, Ab-NG are loaded with dexamethasone, an anti-inflammatory therapeutic, and the drug uptake and release kinetics are measured by HPLC. In vivo studies in mice showed that: i) ICAM-NG accumulates in mouse lungs (?120% ID/g vs ?15% ID/g of IgG-NG); and, ii) DEX encapsulated in ICAM-NG, but not in IgG-NG practically blocks LPS-induced overexpression of pro-inflammatory cell adhesion molecules including ICAM-1 in the pulmonary inflammation. PMID:25019304

Coll Ferrer, M. Carme; Shuvaev, Vladimir V.; Zern, Blaine J.; Composto, Russell J.; Muzykantov, Vladimir R.; Eckmann, David M.

2014-01-01

12

Methacrylic-based nanogels for the pH-sensitive delivery of 5-Fluorouracil in the colon  

PubMed Central

Methacrylic-based copolymers in drug-delivery systems demonstrate a pH-sensitive drug-releasing behavior in the colon. In this study, copolymers of methacrylic acid and 2-ethyl hexyl acrylate were prepared using a microemulsion polymerization technique. The purified copolymer was characterized by Fourier transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, and differential scanning calorimetry. 5-Fluorouracil (5-FU) was entrapped within methacrylic-based copolymers by a solvent evaporation method. The size of the nanogels formed was characterized by transmission electron microscopy and atomic force microscopy. In vitro drug-release studies using phosphate-buffered saline at different pH levels demonstrated the sustained release of 5-FU and its pH dependence. Cell proliferation assay of a human colon tumor colon cancer cell line (HCT-116) was performed and showed that the nanogels containing 5-FU exhibited considerable cytotoxicity in comparison with free 5-FU. Cell uptake of the nanogels was also monitored using confocal microscopy. Western blot analysis and flow cytometry studies confirmed that the nanogels could be successfully used as an efficient vector for pH-sensitive and controlled delivery of drugs specifically targeted to the colon. PMID:23172988

Ashwanikumar, N; Kumar, Nisha Asok; Nair, S Asha; Kumar, GS Vinod

2012-01-01

13

Soy protein/soy polysaccharide complex nanogels: folic acid loading, protection, and controlled delivery.  

PubMed

In this study, we developed a facile approach to produce nanogels via self-assembly of folic acid, soy protein, and soy polysaccharide. High-pressure homogenization was introduced to break down the original aggregates of soy protein, which benefits the binding of soy protein with soy polysaccharide and folic acid at pH 4.0. After a heat treatment that causes the soy protein denaturation and gelation, folic acid-loaded soy protein/soy polysaccharide complex nanogels were fabricated. The nanogels have a polysaccharide surface that makes the nanogels dispersible in acidic conditions where folic acid is insoluble and soy protein forms precipitates after heating. More importantly, the protein and polysaccharide can inhibit the reactions between dissolved oxygen and folic acid during UV irradiation. After the preparation and storage of the nanogels in the presence of heat, oxygen, and light in acidic conditions, most of the folic acid molecules in the nanogels remain in their natural structure and can be released rapidly at neutral pH, that is, in the intestine. Because most food and beverages are acidic, the nanogels are a suitable delivery system of folic acid in food and beverages. PMID:23758109

Ding, Xuzhe; Yao, Ping

2013-07-01

14

Modular ‘Click-in-Emulsion’ Bone-Targeted Nanogels  

E-print Network

A new class of nanogel demonstrates modular biodistribution and affinity for bone. Nanogels, ~70 nm in diameter and synthesized via an astoichiometric click-chemistry in-emulsion method, controllably display residual, free ...

Heller, Daniel A.

15

Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines  

NASA Astrophysics Data System (ADS)

Nanotechnology is an innovative method of freely controlling nanometre-sized materials. Recent outbreaks of mucosal infectious diseases have increased the demands for development of mucosal vaccines because they induce both systemic and mucosal antigen-specific immune responses. Here we developed an intranasal vaccine-delivery system with a nanometre-sized hydrogel (`nanogel') consisting of a cationic type of cholesteryl-group-bearing pullulan (cCHP). A non-toxic subunit fragment of Clostridium botulinum type-A neurotoxin BoHc/A administered intranasally with cCHP nanogel (cCHP-BoHc/A) continuously adhered to the nasal epithelium and was effectively taken up by mucosal dendritic cells after its release from the cCHP nanogel. Vigorous botulinum-neurotoxin-A-neutralizing serum IgG and secretory IgA antibody responses were induced without co-administration of mucosal adjuvant. Importantly, intranasally administered cCHP-BoHc/A did not accumulate in the olfactory bulbs or brain. Moreover, intranasally immunized tetanus toxoid with cCHP nanogel induced strong tetanus-toxoid-specific systemic and mucosal immune responses. These results indicate that cCHP nanogel can be used as a universal protein-based antigen-delivery vehicle for adjuvant-free intranasal vaccination.

Nochi, Tomonori; Yuki, Yoshikazu; Takahashi, Haruko; Sawada, Shin-Ichi; Mejima, Mio; Kohda, Tomoko; Harada, Norihiro; Kong, Il Gyu; Sato, Ayuko; Kataoka, Nobuhiro; Tokuhara, Daisuke; Kurokawa, Shiho; Takahashi, Yuko; Tsukada, Hideo; Kozaki, Shunji; Akiyoshi, Kazunari; Kiyono, Hiroshi

2010-07-01

16

A novel crosslinked hyaluronic acid nanogel for drug delivery.  

PubMed

An amphiphilic hyaluronic acid conjugate is successfully developed based on grafting a thiolated hydrophobic molecule to the polysaccharide backbone. The engineered conjugate is capable of assembling into nanostructures once dispersed in water, with average diameter of 80.2?±?0.4?nm (n?=?5), stable up to 6 months. The thiolated HyA conjugate is reticulated by dissulfide bond with a homofunctional crosslinker-1,4-Bis(3-[2-pyridyldithio]propionamido)butane (DPDPB). The drug loading efficiency of the reticulated and non-reticulated nanogel is accessed with two hydrophobic drugs, curcumin and simvastatin. Results suggest that crosslinked nanogel exhibit higher stability upon dilution and drug loading efficiency and proves to be a redox sensitive material. The nanogels hold great potential as stealth carriers of lipophilic drugs. PMID:25088667

Pedrosa, Sílvia Santos; Gonçalves, Catarina; David, Laurent; Gama, Miguel

2014-11-01

17

Bioreducible alginate-poly(ethylenimine) nanogels as an antigen-delivery system robustly enhance vaccine-elicited humoral and cellular immune responses.  

PubMed

Although polysaccharide nanogels have emerged as a novel antigen delivery system for vaccine development, whether modulating the redox sensitivity of nanogels could improve vaccine efficacy remains unclear. In the present study, we generated bioreducible cationic alginate-polyethylenimine (PEI) nanogels as a novel vaccine delivery system. Briefly, nanogels were prepared by the electrostatic interaction of negatively charged alginate sodium with branched PEI2k, followed by disulfide cross-linking to generate bioreducible nanogels (AP-SS). The AP-SS nanogels demonstrated great antigen-loading capacity and minimal cytotoxicity. The in vitro study showed that reducible AP-SS nanogels not only facilitated antigen uptake by mouse bone marrow dendritic cells (BMDCs), but also promoted intracellular antigen degradation and cytosolic release. Moreover, AP-SS nanogels significantly enhanced both MHC class I and II antigen presentation by BMDCs. Compared with the non-reducible nanogels, AP-SS nanogels more potently enhanced vaccine-induced antibody production and CD8+ T cell-mediated tumor cell lysis. Hence, the bioreducible alginate-PEI nanogels could serve as a potent adjuvant to improve vaccine-elicited humoral and cellular immune responses. PMID:23562637

Li, Ping; Luo, Zichao; Liu, Peng; Gao, Ningning; Zhang, Yijuan; Pan, Hong; Liu, Lanlan; Wang, Ce; Cai, Lintao; Ma, Yifan

2013-06-28

18

Design and engineering of nanogels for cancer treatment  

PubMed Central

Here, we provide a comprehensive insight into current advances in the use of nanogel-mediated chemotherapy for cancer treatment. Nanogels are composed of cross-linked three-dimensional polymer chain networks that are formed via covalent linkages or self-assembly processes. The porosity between the cross-linked networks of nanogels not only provides an ideal reservoir for loading drugs, oligonucleotides and imaging agents, but also protects them from environmental degradation and hazards. Here, we focus mainly on novel synthetic strategies and key considerations in the design of nanogel-based drug delivery systems for controlled and targeted cancer therapeutic applications. PMID:21414419

Yallapu, Murali Mohan; Jaggi, Meena; Chauhan, Subhash

2011-01-01

19

Biodistribution and renal clearance of biocompatible lung targeted poly(ethylene glycol) (PEG) nanogel aggregates.  

PubMed

A novel stabilized aggregated nanogel particle (SANP) drug delivery system was prepared for injectable passive lung targeting. Gel nanoparticles (GNPs) were synthesized by irreversibly cross-linking 8 Arm PEG thiol with 1,6-hexane-bis-vinylsulfone (HBVS) in phosphate buffer (PB, pH 7.4) containing 0.1% v/v Tween™ 80. Aggregated nanogel particles (ANPs) were generated by aggregating GNPs to micron-size, which were then stabilized (i.e., SANPs) using a PEG thiol polymer to prevent further growth-aggregation. The size of SANPs, ANPs and GNPs was analyzed using a Coulter counter and transmission electron microscopy (TEM). Stability studies of SANPs were performed at 37°C in rat plasma, phosphate buffered saline (PBS, pH 7.4) and PB (pH 7.4). SANPs were stable in rat plasma, PBS and PB over 7 days. SANPs were covalently labeled with HiLyte Fluor™ 750 (DYE-SANPs) to facilitate ex vivo imaging. Biodistribution of intravenous DYE-SANPs (30 ?m, 4 mg in 500 ?L PBS) in male Sprague-Dawley rats was compared to free HiLyte Fluor™ 750 DYE alone (1mg in 500 ?L PBS) and determined using a Xenogen IVIS® 100 Imaging System. Biodistribution studies demonstrated that free DYE was rapidly eliminated from the body by renal filtration, whereas DYE-SANPs accumulated in the lung within 30 min and persisted for 48 h. DYE-SANPs were enzymatically degraded to their original principle components (i.e., DYE-PEG-thiol and PEG-VS polymer) and were then eliminated from the body by renal filtration. Histological evaluation using H & E staining and broncho alveolar lavage (BAL) confirmed that these flexible SANPs were not toxic. This suggests that because of their flexible and non-toxic nature, SANPs may be a useful alternative for treating pulmonary diseases such as asthma, pneumonia, tuberculosis and disseminated lung cancer. PMID:23041417

Deshmukh, Manjeet; Kutscher, Hilliard L; Gao, Dayuan; Sunil, Vasanthi R; Malaviya, Rama; Vayas, Kinal; Stein, Stanley; Laskin, Jeffrey D; Laskin, Debra L; Sinko, Patrick J

2012-11-28

20

Skin permeating nanogel for the cutaneous co-delivery of two anti-inflammatory drugs.  

PubMed

The aim of this study was to develop an effective drug delivery system for the simultaneous topical delivery of two anti-inflammatory drugs, spantide II (SP) and ketoprofen (KP). To achieve this primary goal, we have developed a skin permeating nanogel system (SPN) containing surface modified polymeric bilayered nanoparticles along with a gelling agent. Poly-(lactide-co-glycolic acid) and chitosan were used to prepare bilayered nanoparticles (NPS) and the surface was modified with oleic acid (NPSO). Hydroxypropyl methyl cellulose (HPMC) and Carbopol with the desired viscosity were utilized to prepare the nanogels. The nanogel system was further investigated for in vitro skin permeation, drug release and stability studies. Allergic contact dermatitis (ACD) and psoriatic plaque like model were used to assess the effectiveness of SPN. Dispersion of NPSO in HPMC (SPN) produced a stable and uniform dispersion. In vitro permeation studies revealed increase in deposition of SP for the SP-SPN or SP+KP-SPN in the epidermis and dermis by 8.5 and 9.5 folds, respectively than SP-gel. Further, the deposition of KP for KP-SPN or SP+KP-SPN in epidermis and dermis was 9.75 and 11.55 folds higher, respectively than KP-gel. Similarly the amount of KP permeated for KP-SPN or SP+KP-SPN was increased by 9.92 folds than KP-gel. The ear thickness in ACD model and the expression of IL-17 and IL-23; PASI score and TEWL values in psoriatic plaque like model were significantly less (p < 0.001) for SPN compared to control gel. Our results suggest that SP+KP-SPN have significant potential for the percutaneous delivery of SP and KP to the deeper skin layers for treatment of various skin inflammatory disorders. PMID:22118820

Shah, Punit P; Desai, Pinaki R; Patel, Apurva R; Singh, Mandip S

2012-02-01

21

Skin permeating nanogel for the cutaneous co-delivery of two anti-inflammatory drugs  

PubMed Central

The aim of this study was to develop an effective drug delivery system for the simultaneous topical delivery of two anti-inflammatory drugs, spantide II (SP) and ketoprofen (KP). To achieve this primary goal we have developed a skin permeating nanogel system (SPN) containing surface modified polymeric bilayered nanoparticles along with a gelling agent. Poly-(lactide-co-glycolic acid) and chitosan were used to prepare bilayered nanoparticles (NPS) and the surface was modified with oleic acid (NPSO). Hydroxypropyl methyl cellulose (HPMC) and Carbopol with the desired viscosity were utilized to prepare the nanogels. The nanogel system was further investigated for in vitro skin permeation, drug release and stability studies. Allergic contact dermatitis (ACD) and psoriatic plaque like model were used to assess the effectiveness of SPN. Dispersion of NPSO in HPMC (SPN) produced a stable and uniform dispersion. In vitro permeation studies revealed increase in deposition of SP for the SP-SPN or SP+KP-SPN in the epidermis and dermis by 8.5 and 9.5 folds, respectively than SP-gel. Further, the deposition of KP for KP-SPN or SP+KP-SPN in epidermis and dermis was 9.75 and 11.55 folds higher, respectively than KP-gel. Similarly the amount of KP permeated for KP-SPN or SP+KP-SPN was increased by 9.92 folds than KP-gel. The ear thickness in ACD model and the expression of IL-17 and IL-23; PASI score and TEWL values in psoriatic plaque like model were significantly less (p<0.001) for SPN compared to control gel. Our results suggest that SP+KP-SPN have significant potential for the percutaneous delivery of SP and KP to the deeper skin layers for treatment of various skin inflammatory disorders. PMID:22118820

Shah, Punit; Desai, Pinaki; Patel, Apurva; Singh, Mandip

2011-01-01

22

A magnetic nanogel based on O-carboxymethylchitosan for antitumor drug delivery: synthesis, characterization and in vitro drug release.  

PubMed

This paper studied the synthesis, characterization and use of the magnetic chitosan nanogel for carrying meleimidic compounds. The hydrogel polymer was prepared using O-carboxymethylchitosan, which was crosslinked with epichlorohydrin for subsequent incorporation of iron oxide magnetic nanoparticles. The characterization revealed that the magnetic material comprises about 10% of the hydrogel. This material is comprised of magnetite and maghemite and exhibits ferro-ferrimagnetic behavior. The average particle size is 4.2 nm. There was high incorporation efficiency of maleimides in the magnetic nanogel. The release was of sustained character and there was a greater release when an external magnetic field was applied. The mathematical model that best explained the process of drug release by the magnetic hydrogel was that of Peppas-Sahlin. The magnetic nanogel proved to be an excellent candidate for use in drug-delivery systems. PMID:24647530

Demarchi, Carla Albetina; Debrassi, Aline; Buzzi, Fátima de Campos; Corrêa, Rogério; Filho, Valdir Cechinel; Rodrigues, Clovis Antonio; Nedelko, Nataliya; Demchenko, Pavlo; ?lawska-Waniewska, Anna; D?u?ewski, Piotr; Greneche, Jean-Marc

2014-05-21

23

Quantum dots loaded nanogels for low cytotoxicity, pH-sensitive fluorescence, cell imaging and drug delivery.  

PubMed

Nanogels (NGs) with drug tracking and delivery possess promising usage in clinical treatment. In this study, an available, low toxic and facile approach was developed to synthesize CdTe quantum dots loaded nanogels (QDs-NGs). The QDs-NGs retained the intrinsic pH sensitivity of the QDs with regard to the fluorescence intensity. The QDs-NGs were easily internalized by the cells as fluorescence probes, and acted as carriers for delivering methotrexate (MTX). The cellular uptake indicated that the QDs-NGs can protect QDs from decomposition in cytoplasm and retain the native fluorescence intensity. MTT assay demonstrated that the QDs-NGs greatly decreased the cytotoxicity of the QDs. The MTX loaded QDs-NGs exhibited slow release property in PBS buffer. Moreover, the MTX loaded QDs-NGs distinctly enhanced the availability of drug. The QDs-NGs are potential nanocarriers for the cell imaging and drug delivery. PMID:25659723

Li, Zhenshun; Xu, Wei; Wang, Yuntao; Shah, Bakht Ramin; Zhang, Chunlan; Chen, Yijie; Li, Yan; Li, Bin

2015-05-01

24

Preparation and evaluation of solid lipid nanoparticles based nanogel for dermal delivery of meloxicam.  

PubMed

The aim of the current investigation was to prepare and investigate the potential of solid lipid nanoparticles based gel (SLN-gel) for the dermal delivery of meloxicam (MLX). The meloxicam loaded SLN (MLX-SLN) gel was developed and characterized by means of photon correlation spectroscopy, rheometry, and differential scanning calorimetry to determine the physicochemical properties. The behavior of SLN gel on rat skin was evaluated in vitro using Franz diffusion cells to determine the skin permeation and penetration characteristics, in vivo on mice to determine the skin tolerance by histopathological examinations. The anti-inflammatory potential of SLN gel was assessed by carrageenan induced rat paw edema test. Biophysical studies including differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) were undertaken to study the interaction between the SLN gel and skin. MLX-SLN gel with nanometric particle size exhibited the controlled release abilities and simultaneously the potential to transport the drug to various skin layers. SLN gel displayed viscoelastic properties with predominantly elastic behavior and exhibited plastic flow. Biophysical studies elucidated the interaction between the SLN gel and stratum corneum (SC) lipids, and proposed the lipid bilayer fluidization as the possible mechanism for the increased penetration of meloxicam into skin. The nano-gel system showed marked anti-inflammatory activity and excellent skin tolerability. It can be concluded that SLN gel may be a promising delivery system for MLX in the treatment of inflammatory disorders. PMID:23994283

Khurana, S; Bedi, P M S; Jain, N K

2013-01-01

25

Development of a hybrid dextrin hydrogel encapsulating dextrin nanogel as protein delivery system.  

PubMed

Dextrin, a glucose polymer with low molecular weight, was used to develop a fully resorbable hydrogel, without using chemical initiators. Dextrin was first oxidized (oDex) with sodium periodate and then cross-linked with adipic acid dihidrazide, a nontoxic cross-linking molecule. Furthermore, a new bidimensional composite hydrogel, made of oxidized dextrin incorporating dextrin nanogels (oDex-nanogel), was also developed. The oDex hydrogels showed good mechanical properties and biocompatibility, allowing the proliferation of mouse embryo fibroblasts 3T3 cultured on top of the gel. The gelation time may be controlled selecting the concentrations of the polymer and reticulating agent. Both the oDex and oDex-nanogel hydrogels are biodegradable and present a 3-D network with a continuous porous structure. The obtained hybrid hydrogel enables the release of the dextrin nanogel over an extended period of time, paralleling the mass loss curve due to the degradation of the material. The dextrin nanogel allowed the efficient incorporation of interleukin-10 and insulin in the oDex hydrogel, providing a sophisticated system of controlled release. The new hydrogels present promising properties as an injectable carrier of bioactive molecules. Both proteins and poorly water-soluble low-molecular-weight drugs are efficiently encapsulated in the nanogel, which performs as a controlled release system entrapped in the hydrogel matrix. PMID:22288730

Molinos, Maria; Carvalho, Vera; Silva, Dina M; Gama, Francisco M

2012-02-13

26

A nanogel of on-site tunable pH-response for efficient anticancer drug delivery.  

PubMed

A smart, soft and small nanoparticulate drug carrier that can efficiently transport therapeutics into tumor cells to control the intracellular drug concentration will enable major advancements in cancer therapy. To facilitate a remote modulation of the intracellular pH-regulated drug release, we have designed a new class of pH-responsive chitosan-based nanogels (<200 nm) by the physical interpenetration of chitosan chains into a nonlinear poly(ethylene glycol) (nonlinear PEG) chain network. The resultant PEG-chitosan nanogels not only respond to the changes in environmental pH over the physiologically important range of 5.0-7.4, but - more importantly - also enable us to remotely modulate the pH response by external cooling/heating. The nanogel, as well as the nanogel loaded with a model anticancer drug 5-fluorouracil (5-FU), is capable of varying its surface charge from nearly neutral to positive around tumor extracellular pH (~6.0-6.2) to facilitate cell internalization. Subsequently, the significantly increased acidity in subcellular compartments (~5.0) can trigger 5-FU release from the endocytosed drug carriers. While this nanogel serving as a drug carrier exhibits a reduced toxicity in combined chemo-thermo treatments, it has shown significantly enhanced therapeutic efficacy in combined chemo-cryo treatments of the model B16F10 melanoma cells, indicating its great potential for cancer therapy. PMID:22906624

Zhou, Ting; Xiao, Chuanfu; Fan, Jiao; Chen, Shoumin; Shen, Jing; Wu, Weitai; Zhou, Shuiqin

2013-01-01

27

Cycloamylose-nanogel drug delivery system-mediated intratumor silencing of the vascular endothelial growth factor regulates neovascularization in tumor microenvironment.  

PubMed

RNAi enables potent and specific gene silencing, potentially offering useful means for treatment of cancers. However, safe and efficient drug delivery systems (DDS) that are appropriate for intra-tumor delivery of siRNA or shRNA have rarely been established, hindering clinical application of RNAi technology to cancer therapy. We have devised hydrogel polymer nanoparticles, or nanogel, and shown its validity as a novel DDS for various molecules. Here we examined the potential of self-assembled nanogel of cholesterol-bearing cycloamylose with spermine group (CH-CA-Spe) to deliver vascular endothelial growth factor (VEGF)-specific short interfering RNA (siVEGF) into tumor cells. The siVEGF/nanogel complex was engulfed by renal cell carcinoma (RCC) cells through the endocytotic pathway, resulting in efficient knockdown of VEGF. Intra-tumor injections of the complex significantly suppressed neovascularization and growth of RCC in mice. The treatment also inhibited induction of myeloid-derived suppressor cells, while it decreased interleukin-17A production. Therefore, the CH-CA-Spe nanogel may be a feasible DDS for intra-tumor delivery of therapeutic siRNA. The results also suggest that local suppression of VEGF may have a positive impact on systemic immune responses against malignancies. PMID:25283373

Fujii, Hidetaka; Shin-Ya, Masaharu; Takeda, Shigeo; Hashimoto, Yoshihide; Mukai, Sada-Atsu; Sawada, Shin-Ichi; Adachi, Tetsuya; Akiyoshi, Kazunari; Miki, Tsuneharu; Mazda, Osam

2014-12-01

28

Hyaluronic acid-based nanogel-drug conjugates with enhanced anticancer activity designed for the targeting of CD44-positive and drug-resistant tumors.  

PubMed

Many drug-resistant tumors and cancer stem cells (CSC) express elevated levels of CD44 receptor, a cellular glycoprotein binding hyaluronic acid (HA). Here, we report the synthesis of nanogel-drug conjugates based on membranotropic cholesteryl-HA (CHA) for efficient targeting and suppression of drug-resistant tumors. These conjugates significantly increased the bioavailability of poorly soluble drugs with previously reported activity against CSC, such as etoposide, salinomycin, and curcumin. The small nanogel particles (diameter 20-40 nm) with a hydrophobic core and high drug loads (up to 20%) formed after ultrasonication and demonstrated a sustained drug release following the hydrolysis of biodegradable ester linkage. Importantly, CHA-drug nanogels demonstrated 2-7 times higher cytotoxicity in CD44-expressing drug-resistant human breast and pancreatic adenocarcinoma cells compared to that of free drugs and nonmodified HA-drug conjugates. These nanogels were efficiently internalized via CD44 receptor-mediated endocytosis and simultaneous interaction with the cancer cell membrane. Anchoring by cholesterol moieties in the cellular membrane after nanogel unfolding evidently caused more efficient drug accumulation in cancer cells compared to that in nonmodified HA-drug conjugates. CHA-drug nanogels were able to penetrate multicellular cancer spheroids and displayed a higher cytotoxic effect in the system modeling tumor environment than both free drugs and HA-drug conjugates. In conclusion, the proposed design of nanogel-drug conjugates allowed us to significantly enhance drug bioavailability, cancer cell targeting, and the treatment efficacy against drug-resistant cancer cells and multicellular spheroids. PMID:23547842

Wei, Xin; Senanayake, Thulani H; Warren, Galya; Vinogradov, Serguei V

2013-04-17

29

Therapeutic Effect of Nanogel-Based Delivery of Soluble FGFR2 with S252W Mutation on Craniosynostosis  

PubMed Central

Apert syndrome is an autosomal dominantly inherited disorder caused by missense mutations in fibroblast growth factor receptor 2 (FGFR2). Surgical procedures are frequently required to reduce morphological and functional defects in patients with Apert syndrome; therefore, the development of noninvasive procedures to treat Apert syndrome is critical. Here we aimed to clarify the etiological mechanisms of craniosynostosis in mouse models of Apert syndrome and verify the effects of purified soluble FGFR2 harboring the S252W mutation (sFGFR2IIIcS252W) on calvarial sutures in Apert syndrome mice in vitro. We observed increased expression of Fgf10, Esrp1, and Fgfr2IIIb, which are indispensable for epidermal development, in coronal sutures in Apert syndrome mice. Purified sFGFR2IIIcS252W exhibited binding affinity for fibroblast growth factor (Fgf) 2 but also formed heterodimers with FGFR2IIIc, FGFR2IIIcS252W, and FGFR2IIIbS252W. Administration of sFGFR2IIIcS252W also inhibited Fgf2-dependent proliferation, phosphorylation of intracellular signaling molecules, and mineralization of FGFR2S252W-overexpressing MC3T3-E1 osteoblasts. sFGFR2IIIcS252W complexed with nanogels maintained the patency of coronal sutures, whereas synostosis was observed where the nanogel without sFGFR2S252W was applied. Thus, based on our current data, we suggest that increased Fgf10 and Fgfr2IIIb expression may induce the onset of craniosynostosis in patients with Apert syndrome and that the appropriate delivery of purified sFGFR2IIIcS252W could be effective for treating this disorder. PMID:25003957

Yokota, Masako; Kobayashi, Yukiho; Morita, Jumpei; Suzuki, Hiroyuki; Hashimoto, Yoshihide; Sasaki, Yoshihiro; Akiyoshi, Kazunari; Moriyama, Keiji

2014-01-01

30

Curcumin encapsulated pH sensitive gelatin based interpenetrating polymeric network nanogels for anti cancer drug delivery.  

PubMed

Interpenetrating polymeric network nanogels (IPN-NGs) composed of natural gelatin biological protein macromolecules and poly(acrylamidoglycolic acid) were produced by simple free radical emulsion polymerization. The developed IPN-NGs were characterized by Fourier-transform infra-red spectroscopy to confirm the formation of NGs. The hydrophobic curcumin drug was loaded successfully into these NGs using an in-situ method. The curcumin-encapsulated NGs were well dispersed in aqueous solutions and showed good bioavailability. Curcumin was dispersed molecularly in the IPN-NGs, which was confirmed by differential scanning calorimetry and X-ray diffraction. The NGs exhibited pH sensitive properties according to dynamic light scattering and the zeta size potentials. Transmission electron microscopy revealed the NGs to be spherical, approximately 100nm in size. The encapsulation efficiency of these IPN-NGs drug formulations ranged from 42 to 48%. In addition, the release of curcumin from the NGs was examined in phosphate buffer medium. The cytotoxicity of the IPN-NGs was studied using in vitro cultures of fibroblasts and a colorectal cancer cell line. The results suggest that the newly developed pH sensitive gelatin-poly(acrylamidoglycolic acid)-curcumin NGs can be applied for colorectal cancer drug delivery applications. PMID:25528297

Madhusudana Rao, K; Krishna Rao, K S V; Ramanjaneyulu, G; Ha, Chang-Sik

2015-01-30

31

Magnetic and pH dual responsive core-shell hybrid nanogels: a single nano-object for pH-dependent magnetic manipulation, fluorescent pH-sensing, and drug delivery  

SciTech Connect

Remotely optical sensing and drug delivery using an environmentally-guided magnetically-driven hybrid nanogel particle could allow for medical diagnostics and treatment. Such multifunctional hybrid nanogels (<200 nm) were prepared through the first synthesis of magnetic Ni NPs, followed by a moderate growth of fluorescent metallic Ag on the surface of Ni NPs, and then a coverage of a pH-responsive copolymer gel shell of poly(ethylene glycol-co-methacrylic acid) [p(EG-MAA)] onto the Ni-Ag bimetallic NP cores (18 {+-} 5 nm). The introduction of the pH-responsive p(EG-MAA) gel shell onto the magnetic and fluorescent Ni-Ag NPs makes the polymer-bound Ni-Ag NPs responsive to pH over the physiologically important range 5.0-7.4. The hybrid nanogels can adapt to surrounding pH and regulate the sensitivity in response to external magnetic field (such as a small magnet of 0.1 T), resulting in the accumulation of the hybrid nanogels within the duration from hours to a few seconds as the pH value decreases from 7.4 to 5.0. The pH-dependent magnetic response characteristic of the hybrid nanogels were further integrated with the pH change to fluorescent signal transduction and pH-regulated anticancer drug (a model drug 5-fluorouracil) delivery functions. The hybrid nanogels can overcome cellular barriers to enter the intracellular region and light up the mouse melanoma B16F10 cells. The multiple responsive hybrid nanogel that can be manipulated in tandem endogenous and exogenous activation should enhance our ability to address the complexity of biological systems.

Wu, Weitai [City University of New York (CUNY); Shen, Jing [City University of New York (CUNY); Gai, Zheng [ORNL; Hong, Kunlun [ORNL; Banerjeea, Probal [City University of New York (CUNY); Zhou, Shuiqin [City University of New York (CUNY)

2011-01-01

32

Aptamers for Targeted Drug Delivery  

PubMed Central

Aptamers are a class of therapeutic oligonucleotides that form specific three-dimensional structures that are dictated by their sequences. They are typically generated by an iterative screening process of complex nucleic acid libraries employing a process termed Systemic Evolution of Ligands by Exponential Enrichment (SELEX). SELEX has traditionally been performed using purified proteins, and cell surface receptors may be challenging to purify in their properly folded and modified conformations. Therefore, relatively few aptamers have been generated that bind cell surface receptors. However, improvements in recombinant fusion protein technology have increased the availability of receptor extracellular domains as purified protein targets, and the development of cell-based selection techniques has allowed selection against surface proteins in their native configuration on the cell surface. With cell-based selection, a specific protein target is not always chosen, but selection is performed against a target cell type with the goal of letting the aptamer choose the target. Several studies have demonstrated that aptamers that bind cell surface receptors may have functions other than just blocking receptor-ligand interactions. All cell surface proteins cycle intracellularly to some extent, and many surface receptors are actively internalized in response to ligand binding. Therefore, aptamers that bind cell surface receptors have been exploited for the delivery of a variety of cargoes into cells. This review focuses on recent progress and current challenges in the field of aptamer-mediated delivery.

Ray, Partha; White, Rebekah R.

2010-01-01

33

Liposomes interiorly thickened with thermosensitive nanogels as novel drug delivery systems.  

PubMed

The fundamental structure of liposomes suffers from drawbacks of physical instability. To overcome this problem, the hypothesis of this study was to thicken the liposomal interior by incorporating thermosensitive in situ gel. The so called gelliposomes (GLs) were prepared by a thin-film method using poloxamer solutions as interior aqueous phase. Interior thermosensitive gelation was proved by observation of sustained dissolving of the poloxamer gel after destroying the lipid bilayers with Triton X-100; structural transformation as observed under optical microscopy in a heating-cooling circle also proved the fact of interior gelling. The sol-gel transition temperatures of GLs were in good correlation with those of the bulk poloxamer solution counterparts, which could be easily tailored by adjusting the concentration and ratio of poloxamer 407 (P407) to poloxamer 188 (P188). Membrane anisotropy measurement indicated increased membrane rigidity. In vitro release of the model drug cytosine arabinoside from GLs showed sustained release characteristics for at least one week with typical biphasic kinetics. Study on storage stability and protection against the destroying effect by membrane destroyers indicated improved physical stability in comparison with conventional liposomes. In situ evading of phagocytic uptake by macrophages was observed for GLs, which however should be attributed to the effect of exteriorly adsorbed poloxamers. In conclusion, GLs present distinct characteristics to be used as potential drug delivery systems. PMID:23872301

Zhang, Bei; Chen, Jian; Lu, Yi; Qi, Jianping; Wu, Wei

2013-10-15

34

Targeted Drug Delivery in Pancreatic Cancer  

PubMed Central

Effective drug delivery in pancreatic cancer treatment remains a major challenge. Because of the high resistance to chemo and radiation therapy, the overall survival rate for pancreatic cancer is extremely low. Recent advances in drug delivery systems hold great promise for improving cancer therapy. Using liposomes, nanoparticles, and carbon nanotubes to deliver cancer drugs and other therapeutic agents such as siRNA, suicide gene, oncolytic virus, small molecule inhibitor and antibody has been a success in recent pre-clinical trials. However, how to improve the specificity and stability of the delivered drug using ligand or antibody directed delivery represent a major problem. Therefore, developing novel, specific, tumor-targeted drug delivery systems is urgently needed for this terrible disease. This review summarizes the current progress on targeted drug delivery in pancreatic cancer, and provides important information on potential therapeutic targets for pancreatic cancer treatment. PMID:19853645

Yu, Xianjun; Zhang, Yuqing; Chen, Changyi; Yao, Qizhi; Li, Min

2009-01-01

35

Biocompatibility of a self-assembled Glycol Chitosan nanogel.  

PubMed

The research of chitosan-based nanogel for biomedical applications has grown exponentially in the last years; however, its biocompatibility is still insufficiently reported. Hence, the present work provides a thorough study of the biocompatibility of a glycol chitosan (GC) nanogel. The obtained results showed that GC nanogel induced slight decrease on metabolic activity of RAW, 3T3 and HMEC cell cultures, although no effect on cell membrane integrity was verified. The nanogel does not promote cell death by apoptosis and/or necrosis, exception made for the HMEC cell line challenged with the higher GC nanogel concentration. Cell cycle arrest on G1 phase was observed only in the case of RAW cells. Remarkably, the nanogel is poorly internalized by bone marrow derived macrophages and does not trigger the activation of the complement system. GC nanogel blood compatibility was confirmed through haemolysis and whole blood clotting time assays. Overall, the results demonstrated the safety of the use of the GC nanogel as drug delivery system. PMID:25482991

Pereira, Paula; Pedrosa, Sílvia S; Correia, Alexandra; Lima, Cristovão F; Olmedo, Mercedes Peleteiro; González-Fernández, Africa; Vilanova, Manuel; Gama, Francisco M

2014-12-01

36

IFE Target Fabrication, Delivery, and Cost Estimates  

E-print Network

IFE Target Fabrication, Delivery, and Cost Estimates N. B. Alexander, L. Brown, D. Callahan, P degrees... SOMBRERO 3-D model for neutronics analysisLaser Fusion HIF - HYLIFE-II ZFE #12;An initial cost analysis has been done for an "nth-of-a-kind" IFE target manufacturing Goodin, D.T., et al, "A cost

37

Tumor-Targeted Drug Delivery with Aptamers  

PubMed Central

Cancer is one of the leading causes of death around the world. Tumor-targeted drug delivery is one of the major areas in cancer research. Aptamers exhibit many desirable properties for tumor-targeted drug delivery, such as ease of selection and synthesis, high binding affinity and specificity, low immunogenicity, and versatile synthetic accessibility. Over the last several years, aptamers have quickly become a new class of targeting ligands for drug delivery applications. In this review, we will discuss in detail about aptamer-based delivery of chemotherapy drugs (e.g. doxorubicin, docetaxel, daunorubicin, and cisplatin), toxins (e.g. gelonin and various photodynamic therapy agents), and a variety of small interfering RNAs. Although the results are promising which warrants enthusiasm for aptamer-based drug delivery, tumor homing of aptamer-based conjugates after systemic injection has only been achieved in one report. Much remains to be done before aptamer-based drug delivery can reach clinical trials and eventually the day-to-day management of cancer patients. Therefore, future directions and challenges in aptamer-based drug delivery are also discussed. PMID:21838687

Zhang, Yin; Hong, Hao; Cai, Weibo

2011-01-01

38

Nanoparticles for intracellular-targeted drug delivery  

NASA Astrophysics Data System (ADS)

Nanoparticles (NPs) are very promising for the intracellular delivery of anticancer and immunomodulatory drugs, stem cell differentiation biomolecules and cell activity modulators. Although initial studies in the area of intracellular drug delivery have been performed in the delivery of DNA, there is an increasing interest in the use of other molecules to modulate cell activity. Herein, we review the latest advances in the intracellular-targeted delivery of short interference RNA, proteins and small molecules using NPs. In most cases, the drugs act at different cellular organelles and therefore the drug-containing NPs should be directed to precise locations within the cell. This will lead to the desired magnitude and duration of the drug effects. The spatial control in the intracellular delivery might open new avenues to modulate cell activity while avoiding side-effects.

Paulo, Cristiana S. O.; Pires das Neves, Ricardo; Ferreira, Lino S.

2011-12-01

39

Magnetizable implants for targeted drug delivery  

NASA Astrophysics Data System (ADS)

The capability to deliver high effective dosages to specific sites in the human body has become the holy grail of drug delivery research. Drugs with proven effectiveness under in vitro investigation often reach a major roadblock under in vivo testing due to a lack of an effective delivery strategy. In addition, many clinical scenarios require delivery of agents that are therapeutic at the desired delivery point, but otherwise systemically toxic. This project proposes a method for targeted drug delivery by applying high magnetic field gradients within the body to an injected superparamagnetic colloidal fluid carrying a drug, with the aid of modest uniform magnetic field. The design involves patterning of endovascular implants, such as coronary stents, with soft magnetic coatings capable of applying high local magnetic field gradients within the body. Examination of the feasibility of the design has been focused around the treatment of coronary restenosis following angioplasty. Drug-eluting stents, which have debuted in hospitals over the past two years, have thus far reduced restenosis rates to below 10%. Our local drug delivery system is a viable alternative or enhancement to drug-eluting stents, offering increased clinician control of dose size, the ability to treat a site repeatedly, and a wide array of applications for treatment of other pathologies. The theoretical models, parallel plate and pipe flow analysis, and cell culture models presented give insight into the use of micron and sub-micron scale magnetic particles for site-specific delivery of pharmaceuticals and magnetically labeled cells.

Forbes, Zachary Graham

40

Targeted drug delivery via the folate receptor  

Microsoft Academic Search

The folate receptor is a highly selective tumor marker overexpressed in greater than 90% of ovarian carcinomas. Two general strategies have been developed for the targeted delivery of drugs to folate receptor-positive tumor cells: by coupling to a monoclonal antibody against the receptor and by coupling to a high affinity ligand, folic acid. First, antibodies against the folate receptor, including

Jennifer Sudimack; Robert J Lee

2000-01-01

41

Macromolecules in drug delivery Macromolecular targeting agents, carriers, and drugs  

E-print Network

Macromolecules in drug delivery Macromolecular targeting agents, carriers, and drugs 1gauthier@emt.inrs.ca #12;Why macromolecules in drug delivery? 2gauthier@emt.inrs.ca Classic chemotherapy Drug delivery? Targeting A carrier for small drugs A release mechanism (if necessary) Protection of drug cargo #12;How? 3

Barthelat, Francois

42

Targeted estrogen delivery reverses the metabolic syndrome  

PubMed Central

We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1–targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1–estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases. PMID:23142820

Finan, Brian; Yang, Bin; Ottaway, Nickki; Stemmer, Kerstin; Müller, Timo D; Yi, Chun-Xia; Habegger, Kirk; Schriever, Sonja C; García-Cáceres, Cristina; Kabra, Dhiraj G; Hembree, Jazzminn; Holland, Jenna; Raver, Christine; Seeley, Randy J; Hans, Wolfgang; Irmler, Martin; Beckers, Johannes; de Angelis, Martin Hrab?; Tiano, Joseph P; Mauvais-Jarvis, Franck; Perez-Tilve, Diego; Pfluger, Paul; Zhang, Lianshan; Gelfanov, Vasily; DiMarchi, Richard D; Tschöp, Matthias H

2013-01-01

43

Multifunctional Magnetic Nanoparticles for Targeted Delivery  

PubMed Central

A major problem associated with therapy is the inability to deliver pharmaceuticals to a specific site of the body without causing nonspecific toxicity. Development of magnetic nanoparticles and techniques for their safe transport and concentration in specific sites in the body would constitute a powerful tool for gene/drug therapy in vivo. Furthermore, drug delivery in vitro could improve further if the drugs were modified with antibodies, proteins or ligands. For in vivo experiments, magnetic nanoparticles were conjugated with plasmid DNA expressing GFP and then coated with chitosan. These particles were injected into mice through tail vein and directed to heart and kidney by means of external magnets of 25 gauss or 2kA –kA/m. These particles were concentrated in the lungs, heart, and kidney of mice and the expression of GFP in these sites were monitored. The expression of GFP in specific locations was visualized by whole-body fluorescent imaging and the concentration of these particles in the designated body locations was confirmed by transmission electron microscopy. In another model system, we used atrial natriuretic peptide (ANP) and Carcino Embryonic Antigen (CEA) antibodies coupled to the chitosan coated magnetic nanoparticles to target cells in vitro. The present work demonstrates that a simple external magnetic field is all that is necessary to target a drug to a specific site inside the body without the need to functionalize the nanoparticles. However, the option to use magnetic targeting with external magnets on functionalized nanoparticles could prove as a more efficient means of drug delivery. PMID:19446653

Kumar, Arun; Jena, Prasanna K.; Behera, Sumita; Lockey, Richard F.; Mohapatra, Subhra; Mohapatra, Shyam

2012-01-01

44

Nanogels based on alginic aldehyde and gelatin by inverse miniemulsion technique: synthesis and characterization.  

PubMed

Nanogels were developed from alginic aldehyde and gelatin by an inverse miniemulsion technique. Stable inverse miniemulsions were prepared by sonication of noncontinuous aqueous phase (mixture of alginic aldehyde and gelatin) in a continuous organic phase (Span 20 dissolved in cyclohexane). Cross-linking occurred between alginic aldehyde (AA) and gelatin (gel) in the presence of borax by Schiff's base reaction during the formation of inverse miniemulsion. The effects of surfactant (Span 20) concentration, volume of the aqueous phase and AA/gel weight ratio on the size of the alginic aldehyde-gelatin (AA-gel) nanoparticles were studied. Nanogels were characterized by DLS, FT-IR spectroscopy, TGA, SEM and TEM. DLS, TEM and SEM studies demonstrated nanosize and spherical morphology of the nanogels. Hemocompatibility and in vitro cytocompatibility analyses of the nanogels proved their nontoxicity. The results indicated the potential of the present nanogel system as a candidate for drug- and gene-delivery applications. PMID:25563951

Sarika, P R; Anil Kumar, P R; Raj, Deepa K; James, Nirmala Rachel

2015-03-30

45

Hydrophobically modified biodegradable poly(ethylene glycol) copolymers that form temperature-responsive Nanogels.  

PubMed

Biodegradable copolymers consisting of a hydrophilic poly[l-aspartic acid-alt-poly(ethylene glycol)] (poly(l-Asp-alt-PEG)) backbone and hydrophobic capryl units as side chains were synthesized. The amphiphilic copolymer was found to form nanosized hydrogel particles (nanogels) of approximately 15 nm in size by self-assembly at 20 degrees C in aqueous media, and the nanogel solutions displayed phase-transition in response to temperature. The transition of the nanogel solution was reversible and tunable in the range from 19 to 55 degrees C by variation of the amounts of capryl units introduced and the solution concentration. The nanogels were gradually degraded within days in a phosphate buffer solution (PBS) at 37 degrees C. Temperature-responsive biodegradable nanogel systems consisting of biocompatible PEG may have potential utility for high biocompatibility temperature-responsive nanodevices such as microreactor systems, molecular-chaperones, and drug delivery vehicles. PMID:19705882

Nagahama, Koji; Hashizume, Mihoko; Yamamoto, Hidetoshi; Ouchi, Tatsuro; Ohya, Yuichi

2009-09-01

46

Hypoxia-targeted siRNA delivery.  

PubMed

Altered vasculature and the resultant chaotic tumor blood flow lead to the appearance in fast-growing tumors of regions with gradients of oxygen tension and acute hypoxia (less than 1.4% oxygen). Due to its roles in tumorigenesis and resistance to therapy, hypoxia represents a problem in cancer therapy. Insufficient delivery of therapeutic agents to the hypoxic regions in solid tumors is recognized as one of the causes of resistance to therapy. This led to the development of hypoxia imaging agents, and the use of hypoxia-activated anticancer prodrugs. Here we show the first example of the hypoxia-induced siRNA uptake and silencing using a nanocarrier consisting of polyethyleneglycol?2000, azobenzene, polyethyleneimine?(PEI)(1.8?kDa), and 1,2-dioleyl-sn-glycero-3-phosphoethanolamine (DOPE) units (the nanocarrier is referred to as PAPD), where azobenzene imparts hypoxia sensitivity and specificity. We report hypoxia-activated green fluorescent protein (GFP) silencing in vitro and its downregulation in GFP-expressing tumors after intravenous administration. The proposed nanoformulation represents a novel tumor-environment-responsive modality for cancer targeting and siRNA delivery. PMID:24554550

Perche, F; Biswas, S; Wang, T; Zhu, L; Torchilin, V P

2014-03-24

47

Cellular Uptake and Intracellular Cargo Release From Dextran Based Nanogel Drug Carriers.  

PubMed

Nanogels (NG) hold great promise as a drug delivery platform. In this work, we examine the potential of lysozyme-dextran nanogels (LDNG) as drug carriers in vitro using two cell lines: a model target tissue, human umbilical cord vein endothelial cells (HUVEC) and a model of the mononuclear phagocyte system (phorbol 12-myristate 13-acetate (PMA)-stimulated THP-1 cells). The LDNG (?100?nm) were prepared with rhodamine-label dextran (LRDNG) via Maillard reaction followed by heat-gelation reaction and were loaded with a fluorescent probe, 5-hexadecanoylaminofluorescein (HAF), as a mock drug. Epifluorescence microscopy confirmed rapid uptake of LRDNG by HUVEC. Although LysoTracker Green staining indicated a lysosomal fate for LRDNG, the mock drug cargo (HAF) diffused extensively inside the cell within 15?min. Flow cytometry and confocal microscopy indicated slow uptake of LRDNG in PMA-stimulated THP-1 cells, with only 41% of cells containing LRDNG after 24?h exposure. Finally, 24?h exposure to LRDNG did not affect the viability of either cell type at the dose studied (20??g/ml). At a higher dose (200??g/ml), LRDNG resulted in a marked loss of viability of HUVEC and THP-1, measuring 30% and 38%, respectively. Collectively, our results demonstrate the great potential of LRDNG as a drug delivery platform, combining simple production, rapid uptake and cargo release in target cells with "stealth" properties and low cytotoxicity. PMID:23917337

Carme Coll Ferrer, M; Sobolewski, Peter; Composto, Russell J; Eckmann, David M

2013-02-01

48

Progress in Aptamer-Mediated Drug Delivery Vehicles for Cancer Targeting and Its Implications in Addressing Chemotherapeutic Challenges  

PubMed Central

Aptamers are novel oligonucleotides with flexible three-dimensional configurations that recognize and bind to their cognate targets, including tumor surface receptors, in a high-affinity and highly specific manner. Because of their unique intrinsic properties, a variety of aptamer-mediated nanovehicles have been developed to directionally transport anti-cancer drugs to tumor sites to minimize systemic cytotoxicity and to enhance permeation by these tumoricidal agents. Despite advances in the selection and synthesis of aptamers and in the conjugation and self-assembly of nanotechnologies, current chemotherapy and drug delivery systems face great challenges. These challenges are due to the limitations of aptamers and vehicles and because of complicated tumor mechanisms, including heterogeneity, anti-cancer drug resistance, and hypoxia-induced aberrances. In this review, we will summarize current approaches utilizing tumor surface hallmarks and aptamers and their roles and mechanisms in therapeutic nanovehicles targeting tumors. Delivery forms include nanoparticles, nanotubes, nanogels, aptamer-drug conjugates, and novel molecular trains. Moreover, the obstacles posed by the aforementioned issues will be highlighted, and possible solutions will be acknowledged. Furthermore, future perspectives will be presented, including cutting-edge integration with RNA interference nanotechnology and personalized chemotherapy, which will facilitate innovative approaches to aptamer-based therapeutics. PMID:25057317

Zhu, Jie; Huang, He; Dong, Shiwu; Ge, Liang; Zhang, Yuan

2014-01-01

49

Toward Intracellular Targeted Delivery of Cancer Therapeutics  

PubMed Central

A number of anti-cancer drugs have their targets localized to particular intracellular compartments. These drugs reach the targets mainly through diffusion, dependent on biophysical and biochemical forces that allow cell penetration. This means that both cancer cells and normal cells will be subjected to such diffusion; hence many of these drugs, like chemotherapeutics, are potentially toxic and the concentration achieved at the site of their action is often suboptimal. The same relates to radiation that indiscriminately affects normal and diseased cells. However, nature-designed systems enable compounds present in the extracellular environment to end up inside the cell and even travel to more specific intracellular compartments. For example, viruses and bacterial toxins can more or less specifically recognize eukaryotic cells, enter these cells, and direct some protein portions to designated intracellular areas. These phenomena have led to creative thinking, such as employing viruses or bacterial toxins for cargo delivery to cells and, more specifically, to cancer cells. Proteins can be genetically engineered in order to not only mimic what viruses and bacterial toxins can do, but also to add new functions, extending or changing the intracellular routes. It is possible to make conjugates or, more preferably, single-chain proteins that recognize cancer cells and deliver cargo inside the cells, even to the desired subcellular compartment. These findings offer new opportunities to deliver drugs/labels only to cancer cells and only to their site of action within the cells. The development of such dual-specificity vectors for targeting cancer cells is an attractive and potentially safer and more efficacious way of delivering drugs. We provide examples of this approach for delivering brain cancer therapeutics, using a specific biomarker on glioblastoma tumor cells. PMID:22671766

Pandya, Hetal; Debinski, Waldemar

2013-01-01

50

J Drug Target . Author manuscript Targeted delivery of a proapoptotic peptide to tumors in vivo  

E-print Network

J Drug Target . Author manuscript Page /1 10 Targeted delivery of a proapoptotic peptide to tumors of perfectly controlled, targeted drug delivery systems. Author Keywords drug vectorization ; cancer ; integrin for tumour imaging and drug targeting. We designed the molecule RAFT-(c -RGDfK- ) , a constrained

Boyer, Edmond

51

Janus nanogels of PEGylated Taxol and PLGA-PEG-PLGA copolymer for cancer therapy  

NASA Astrophysics Data System (ADS)

Nanogels are promising carriers for the delivery of anti-cancer drugs for cancer therapy. We report in this study on a Janus nanogel system formed by mixing a prodrug of Taxol (PEGylated Taxol) and a copolymer of PLGA-PEG-PLGA. The Janus nanogels have good stability over months in aqueous solutions and the freeze-dried powder of nanogels can be re-dispersed instantly in aqueous solutions. The Janus nanogels show an enhanced inhibition effect on tumor growth in a mice breast cancer model probably due to the enhanced uptake of the nano-sized materials by the EPR effect. What is more, the nanogels can also serve as physical carriers to co-deliver other anti-cancer drugs such as doxorubicin to further improve the anti-cancer efficacy. The results obtained from H&E staining and TUNEL assay also support the observation of tumor growth inhibition. These results suggest the potential of this novel delivery system for cancer therapy.Nanogels are promising carriers for the delivery of anti-cancer drugs for cancer therapy. We report in this study on a Janus nanogel system formed by mixing a prodrug of Taxol (PEGylated Taxol) and a copolymer of PLGA-PEG-PLGA. The Janus nanogels have good stability over months in aqueous solutions and the freeze-dried powder of nanogels can be re-dispersed instantly in aqueous solutions. The Janus nanogels show an enhanced inhibition effect on tumor growth in a mice breast cancer model probably due to the enhanced uptake of the nano-sized materials by the EPR effect. What is more, the nanogels can also serve as physical carriers to co-deliver other anti-cancer drugs such as doxorubicin to further improve the anti-cancer efficacy. The results obtained from H&E staining and TUNEL assay also support the observation of tumor growth inhibition. These results suggest the potential of this novel delivery system for cancer therapy. Electronic supplementary information (ESI) available: Synthesis and characterization of compounds, dynamic time sweep, H&E result and body weight change of mice. See DOI: 10.1039/c3nr02937a

Wei, Jun; Wang, Huaimin; Zhu, Meifeng; Ding, Dan; Li, Dongxia; Yin, Zhinan; Wang, Lianyong; Yang, Zhimou

2013-09-01

52

Giant Fullerenes for Target Specific Drug Delivery  

NASA Astrophysics Data System (ADS)

Carbon nano-structures, such as giant fullerenes, have a great potential for biological and medical applications. Most of the previous research is dedicated to investigate the use of fullerenes as vehicles for carrying medication which is chemisorbed on the outside surface of the fullerenes. In contrast, using fullerenes as an enclosure was largely abandoned due to the high strength of the carbon-carbon bonds which has been perceived to prevent the rupturing of the fullerene to release their cargo. We performed atomistic computations based on classical force fields that will address this perception. Specifically we explore the physics and chemistry of OH functionalized carbon based giant fullerenes with diameters from 0.72 nm (60 atoms) to 5.7 nm (3840 atoms). The preliminary results show that OH functionalization on these fullerenes is not only viable but also provides a pH sensitive release mechanism. Furthermore our current results show that carbon-carbon bonds can be broken in low energy biological environments in the presence of a flow induced strain field. These insights may have implications for target specific drug delivery in general and cancer treatment in particular.

Courtney, Robert; Kiefer, Boris

2013-03-01

53

Nanoparticle-based targeted drug delivery  

PubMed Central

Nanotechnology could be defined as the technology that has allowed for the control, manipulation, study, and manufacture of structures and devices in the “nanometer” size range. These nano-sized objects, e.g., “nanoparticles”, take on novel properties and functions that differ markedly from those seen from items made of identical materials. The small size, customized surface, improved solubility, and multi-functionality of nanoparticles will continue to open many doors and create new biomedical applications. Indeed, the novel properties of nanoparticles offer the ability to interact with complex cellular functions in new ways. This rapidly growing field requires cross-disciplinary research and provides opportunities to design and develop multifunctional devices that can target, diagnose, and treat devastating diseases such as cancer. This article presents an overview of nanotechnology for the biologist and discusses the attributes of our novel XPclad© nanoparticle formulation that has shown efficacy in treating solid tumors, for single dose vaccination, and oral delivery of therapeutic proteins. PMID:19186176

Singh, Rajesh; Lillard, James W.

2009-01-01

54

Nanogel for dermal application of the triterpenoids isolated from Ganoderma lucidum (GLT) for frostbite treatment.  

PubMed

Abstract Objective: The purpose of this study was to formulate stable Ganoderma lucidum (GLT) nanogels suitable for topical delivery with a view to improve the therapeutic effect for frostbite. Methods: GLT nanosuspensions were formulated using the high-pressure homogenization technique and then suitably gelled for characterized. In order to confirm the advantages of GLT nanogel for dermal application, skin permeation studies in vitro and pharmacodynamic evaluation in vivo were studied and compared with GLT-carbopol gel. Results: The particle size analysis and SEM studies revealed that GLT nanosuspensions were still stably kept their particle size after suitably gelled by carbopol preparation. The drug content, pH, and spreadability of the GLT nanogel was found to be 99.23?±?1.8%, 6.07?±?0.1, and 26.42 (g·cm)/s, which were within acceptable limits. In vitro permeation studies through rat skin indicated that the amount of GLT permeated through skin of GLT nanogel after 24?h was higher than GLT-carbopol gel, and GLT nanogel increased the accumulative amount of GLT in epidermis five times than GLT-carbopol gel. No oedema and erythema were observed after administration of GLT nanogel on the rabbits' skin. Pharmacodynamic study showed that GLT nanogel was more effective than GLT-carbopol gel in treatment of frostbite. Conclusion: The GLT nanogel possess superior therapeutic effect for frostbite compared with the GLT-carbopol gel, which indicates that nanogels are eligible for the use as a suitable nanomedicine for dermal delivery of poorly soluble drugs such as GLT. PMID:24963753

Shen, Cheng-Ying; Xu, Ping-Hua; Shen, Bao-de; Min, Hong-Yan; Li, Xiao-Rong; Han, Jin; Yuan, Hai-Long

2014-06-25

55

Expert Review Functionalized Micellar Systems for Cancer Targeted Drug Delivery  

E-print Network

Expert Review Functionalized Micellar Systems for Cancer Targeted Drug Delivery Damon Sutton,1, and general use of micelles as drug delivery systems (4Y13). The purpose of this review is to provide stability, ability to solubilize water insoluble anticancer drugs, and prolonged blood circulation times

Gao, Jinming

56

Colon targeted delivery systems: review of polysaccharides for encapsulation and delivery.  

PubMed

Colon-targeted delivery of bioactives has recently gained importance in addressing specific needs in the therapy of colon-based diseases. Many approaches have been attempted for the development of colon-specific delivery systems, with not much success in the past. Recent research into the utilization of the metabolic activity and the colonic microenvironment in the lower gastrointestinal tract has attained great value in the design of novel colon-targeted delivery systems based on natural biodegradable polymers. In the current article, special emphasis has been placed on polysaccharide systems, with minimal chemical modification, that have been exploitedfor colon targeting. These polysaccharide based encapsulation and targeted delivery systems are envisaged to have an immense potential for the development of food/nutraceutical formulations for colon-based diseases, including colorectal cancer. PMID:16047493

Kosaraju, Shantha L

2005-01-01

57

Subcellular targeting strategies for drug design and delivery  

Microsoft Academic Search

Many drug targets are localized to particular subcellular compartments, yet current drug design strategies are focused on bioavailability and tissue targeting and rarely address drug delivery to specific intracellular compartments. Insights into how the cell traffics its constituents to these different cellular locations could improve drug design. In this Review, we explore the fundamentals of membrane trafficking and subcellular organization,

Lawrence Rajendran; Hans-Joachim Knölker; Kai Simons

2010-01-01

58

Polymer- and liposome-based nanoparticles in targeted drug delivery.  

PubMed

This review focuses on polymer- and liposome-based nanoparticles used in targeted delivery of bioactive molecules, from drugs to siRNA to pDNA. The perspective centers around commercial and clinical successes, and a rationalization of these successes. Microparticulate systems are not covered, and only those applications that truly utilize the advantages of nano size are covered. "Stealth" systems dominate in this review, as most of the clinical successes are for passive targeting rather than for active targeting of tissue. The relevance of nano size to gene delivery is also discussed with relevant examples. PMID:20515826

Venkatraman, Subbu S; Ma, Lwin Lwin; Natarajan, Jayaganesh V; Chattopadhyay, Sujay

2010-01-01

59

Application of nanogel systems in the administration of local anesthetics  

PubMed Central

Nanogels are robust nanoparticles that could be used to deliver active drug compounds in controlled drug delivery applications. This review discusses the design, synthesis, loading, and release of local anesthetics using polymeric nanoparticles produced via various types of polymerization techniques. The strategy of using layer-by-layer approach to control the burst release of procaine hydrochloride (PrHy; a local anesthetic drug of the amino ester group) is described and discussed. PMID:22915875

Tan, Jeremy PK; Tan, Maureen BH; Tam, Michael KC

2010-01-01

60

Targeted delivery systems for biological therapies of inflammatory diseases.  

PubMed

Introduction: Inflammatory diseases, including autoimmune diseases and autoinflammatory diseases, are characterized by the imbalance of pro-inflammatory cytokines and anti-inflammatory cytokines. Targeted systems allow for specific delivery and sustained release of biological agents to inflamed tissues and macrophages, hence reducing their side effects. Areas covered: This review discusses various targeting strategies for biological therapies of inflammatory diseases, with a focus on modulating macrophage functional polarization from an M1 to M2 phenotype. Furthermore, recent advances in the development of targeted delivery systems for gene therapy against inflammatory diseases including liposomal therapeutics, polymeric nanoparticles and microspheres, and multi-compartmental delivery systems are summarized. Expert opinion: Molecular advances have uncovered various targets for biological therapies against inflammatory diseases. Despite substantial promise, the potential translation from the bench to the clinic is limited due to poor systemic stability of the delivery systems, low tissue distribution, and safety concerns. In order to develop clinically translatable targeted delivery systems, thorough evaluation of the efficacy and toxicity in relevant animal models and in different inflammatory diseases is needed. In addition, issues related to long-term storage stability, scale-up and manufacturing of the systems need to be addressed. PMID:25366552

Tran, Thanh-Huyen; Amiji, Mansoor M

2014-11-01

61

Functionalized nanosystems for targeted mitochondrial delivery.  

PubMed

Mitochondrial dysfunction including oxidative stress and DNA mutations underlies the pathology of various diseases including Alzheimer's disease and diabetes, necessitating the development of mitochondria targeted therapeutic agents. Nanotechnology offers unique tools and materials to target therapeutic agents to mitochondria. As discussed in this paper, a variety of functionalized nanosystems including polymeric and metallic nanoparticles as well as liposomes are more effective than plain drug and non-functionalized nanosystems in delivering therapeutic agents to mitochondria. Although the field is in its infancy, studies to date suggest the superior therapeutic activity of functionalized nanosystems for treating mitochondrial defects. PMID:22138492

Durazo, Shelley A; Kompella, Uday B

2012-03-01

62

Cell-Specific Aptamer-Mediated Targeted Drug Delivery  

PubMed Central

Nucleic acid aptamers are in vitro-selected small, single-stranded DNA or RNA oligonucleotides that can specifically recognize their target on the basis of their unique 3-dimensional structures. Recent advances in the development of escort aptamers to deliver and enhance the efficacy of other therapeutic agents have drawn enthusiasm in exploiting cell-type-specific aptamers as drug delivery vehicles. This review mainly focuses on the recent developments of aptamer-mediated targeted delivery systems. We also place particular emphasis on aptamers evolved against cell membrane receptors and possibilities for translation to clinical applications. PMID:21182455

Zhou, Jiehua

2011-01-01

63

Thermoresponsive nanogels for prolonged duration local anesthesia  

PubMed Central

Nanogels based on poly(N-isopropylacrylamide) are attractive vehicles for prolonged duration local anesthesia because of their tunable size, number of functional groups, thermoresponsiveness, and their anionic charge. Nerve block durations of up to nine hours were achieved using acrylic acid-loaded nanogels loaded with bupivacaine. Increasing the anionic charge density of the nanogels or (for more highly acid-functionalized nanogels) decreasing the nanogel size facilitated longer duration anesthetic release. Small (<300 nm diameter) nanogels formed dense aggregates upon injection in vivo and induced only mild inflammatory responses, while large (>500 nm diameter) nanogels typically remained as liquid-like residues in vivo and induced more severe inflammatory reactions. PMID:22732383

Hoare, Todd; Young, Stuart; Lawlor, Michael W.; Kohane, Daniel S.

2012-01-01

64

Thermoresponsive nanogels for prolonged duration local anesthesia.  

PubMed

Nanogels based on poly(N-isopropylacrylamide) are attractive vehicles for prolonged duration local anesthesia because of their tunable size, number of functional groups, thermoresponsiveness and anionic charge. Nerve block durations of up to 9h were achieved using acrylic acid-loaded nanogels loaded with bupivacaine. Increasing the anionic charge density of the nanogels or (for more highly acid-functionalized nanogels) decreasing the nanogel size facilitated longer duration of anesthetic release. Small (<300 nm diameter) nanogels formed dense aggregates upon injection in vivo and induced only mild inflammatory responses, while large (>500 nm diameter) nanogels typically remained as liquid-like residues in vivo and induced more severe inflammatory reactions. PMID:22732383

Hoare, Todd; Young, Stuart; Lawlor, Michael W; Kohane, Daniel S

2012-10-01

65

Liposomes surface conjugated with human hemoglobin target delivery to macrophages  

PubMed Central

Current strategies to deliver therapeutic molecules to specific cell and tissue types rely on conjugation of antibodies and other targeting ligands directly to the therapeutic molecule itself or its carrier. This work describes a novel strategy to deliver therapeutic molecules into macrophages that takes advantage of the native hemoglobin (Hb) scavenging activity of plasma haptoglobin (Hp) and the subsequent uptake of the Hb-Hp complex into macrophages via CD163 receptor mediated endocytosis. The drug delivery system described in this work consists of hemoglobin decorated liposomes that can encapsulate any therapeutic molecule of interest, in this case the model fluorescent dye calcein was used in this study. The results of this study clearly demonstrate that this delivery system is specific towards macrophages and demonstrates the feasibility of using this approach in targeted drug delivery. PMID:22012493

Zhang, Ning; Palmer, Andre F.

2012-01-01

66

Targeted Delivery of Radioprotective Agents to Mitochondria  

PubMed Central

Adverse effects of ionizing radiation are mediated through reactive oxygen and nitrogen species. Mitochondria are the principal source of these species in the cell and play an important role in irradiation-induced apoptosis. The use of free radical scavengers and nitric oxide synthase inhibitors has proven to protect normal tissues and, in some cases, to sensitize tumor tissues to radiation damage. Dual molecules that combine radical-scavenging and NOS-inhibitory functions may be particularly effective. Drugging strategies that target mitochondria can enhance the effectiveness of such agents, in comparison to systemic administration, and circumvent side effects. PMID:19144902

Zabbarova, Irina; Kanai, Anthony

2010-01-01

67

Self-Assembling Peptide Amphiphiles for Targeted Drug Delivery  

NASA Astrophysics Data System (ADS)

The systemic delivery of therapeutics is currently limited by off-target side effects and poor drug uptake into the cells that need to be treated. One way to circumvent these issues is to target the delivery and release of therapeutics to the desired location while limiting systemic toxicity. Using self-assembling peptide amphiphiles (PAs), this work has investigated supramolecular nanostructures for the development of targeted therapies. Specifically, the research has focused on the interrelationships between presentation of targeting moeities and the control of nanostructure morphology in the context of systemic delivery for targeting cancer and vascular injuries. The self-assembly region of the PA was systematically altered to achieve control of nanostructure widths, from 100 nm to 10 nm, by the addition of valine-glutamic acid dimers into the chemical structure, subsequently increasing the degree of nanostructure twist. For the targeting of tumors, a homing PA was synthesized to include a dimeric, cyclic peptide sequence known to target the cancer-specific, death receptor 5 (DR5) and initiate apoptosis through the oligomerization of DR5. This PA presented a multivalent display of DR5-binding peptides, resulting in improved binding affinity measured by surface plasmon resonance. The DR5-targeting PA also showed enhanced efficacy in both in vitro and in vivo tumor models relative to non-targeted controls. Alternative modifications to the PA-based antitumor therapies included the use of a cytotoxic, membrane-lytic PA coassembled with a pegylated PA, which showed enhanced biodistribution and in vivo activity after coassembly. The functionalization of the hydrophobic core was also accomplished through the encapsulation of the chemotherapy camptothecin, which was shown to be an effective treatment in vivo. Additionally, a targeted PA nanostructure was designed to bind to the site of vascular intervention by targeting collagen IV. Following balloon angioplasty, targeted PA nanofibers showed enhanced binding by fluorescence relative to spherical micelles with the same targeting sequence, demonstrating the importance of nanostructure shape for vascular binding. Nitric oxide was functionalized onto the PA nanostructure through the S-nitrosylation (SNO) of a cysteine residue. Two weeks after vascular injury, the SNO-functionalized, targeted nanofibers showed significantly decreased levels of restenosis. In all treatment methods described, the control of multivalency through the tuning of supramolecular structure was essential to achieve optimal binding. Understanding the role of dynamic, supramolecular structures for the systemic delivery of peptide therapeutics should be an important focus of future work.

Moyer, Tyson

68

Tetraspecific ligand for tumor-targeted delivery of nanomaterials.  

PubMed

The polygenetic nature of most cancers emphasizes the necessity of cancer therapies that target multiple essential signaling pathways. However, there is a significant paucity of targeting ligands with multi-specificities for targeted delivery of biomaterials. To address this unmet need, we generated a tetraspecific targeting ligand that recognizes four different cancer biomarkers, including VEGFR2, ?v?3 integrin, EGFR, and HER2 receptors, which have been implicated in numerous malignant tumors. The tetraspecific targeting ligand was constructed by sequentially connecting four targeting ligand subunits via flexible linkers, yielding a fusion protein that can be highly expressed in Escherichia coli and readily purified to near homogeneity. Surface Plasmon Resonance (SPR), Bio-Layer Interferometry (BLI) studies and extensive cellular binding analyses indicated that all the targeting ligand subunits in the tetraspecific fusion protein recognized their target receptors proximately to the corresponding monospecific ligands. The resulting tetraspecific targeting ligand was applied for the delivery of nanomaterials such as gold nanoparticles (AuNPs) for targeted hyperthermic killing of various cancer cell lines with biomarkers of interest expressed. We demonstrate that the tetraspecific ligand can be facilely introduced on the surface of AuNPs and efficient target-dependent killing of cancer cells can be achieved only when the AuNPs are conjugated with the tetraspecific ligand. Significantly, the tetraspecific ligand simultaneously interacts with more than one receptors, such as EGFR and HER2 receptors, when they are expressed on the surface of the same cell, as demonstrated by in vitro binding assays and cell binding analyses. Our results demonstrate that the tetraspecific ligand, through multivalency and synergistic binding, can be readily used to generate various 'smart' biomaterials with greatly broadened tumor targeting range for simultaneous targeting of multiple signaling pathways on many different cancer types. PMID:24786763

Kim, Dongwook; Friedman, Adam D; Liu, Rihe

2014-07-01

69

Targeted Decationized Polyplexes for siRNA Delivery.  

PubMed

The applicability of small interfering RNA (siRNA) in future therapies depends on the availability of safe and efficient carrier systems. Ideally, siRNA delivery requires a system that is stable in the circulation but upon specific uptake into target cells can rapidly release its cargo into the cytoplasm. Previously, we evaluated a novel generation of carrier systems ("decationized" polyplexes) for DNA delivery, and it was shown that folate targeted decationized polyplexes had an excellent safety profile and showed intracellular triggered release upon cell specific uptake. Targeted decationized polyplexes consist of a core of disulfide cross-linked poly(hydroxypropyl methacrylamide) (pHPMA) stably entrapping nucleic acids and a shell of poly(ethylene glycol) (PEG) decorated with folate molecules. In the present study, the applicability of folate targeted decationized polyplexes for siRNA delivery was investigated. This required optimization of the carrier system particularly regarding the cross-linking density of the core of the polyplexes. Stable and nanosized siRNA decationized polyplexes were successfully prepared by optimizing the cross-link density of their core. Upon incubation in human plasma, a significant portion of siRNA remained entrapped in the decationized polyplexes as determined by fluorescence correlation spectroscopy (FCS). When tested in a folate receptor overexpressing cell line stably expressing luciferase, Skov3-luc, sequence specific gene silencing was observed. As expected, neither interference on the intrinsic luciferase expression nor on the cell metabolic activity (determined by XTT) was induced by the free-polymer or the siRNA polyplexes. In conclusion, targeted decationized polyplexes are safe and stable carriers that interact with the targeted cells and rapidly disassemble upon cell entry making them promising siRNA delivery systems. PMID:25384057

Novo, Luís; Takeda, Kaori M; Petteta, Tamara; Dakwar, George R; van den Dikkenberg, Joep B; Remaut, Katrien; Braeckmans, Kevin; van Nostrum, Cornelus F; Mastrobattista, Enrico; Hennink, Wim E

2015-01-01

70

Pharmacytes: an ideal vehicle for targeted drug delivery.  

PubMed

An ideal nanotechnology-based drug delivery system is a pharmacyte--a self-powered, computer-controlled medical nanorobot system capable of digitally precise transport, timing, and targeted delivery of pharmaceutical agents to specific cellular and intracellular destinations within the human body. Pharmacytes may be constructed using future molecular manufacturing technologies such as diamond mechanosynthesis which are currently being investigated theoretically using quantum ab initio and density-functional computational methods. Pharmacytes will have many applications in nanomedicine such as initiation of apoptosis in cancer cells and direct control of cell signaling processes. PMID:17048481

Freitas, Robert A

2006-01-01

71

Targeted Liposomal Drug Delivery to Monocytes and Macrophages  

PubMed Central

As the role of monocytes and macrophages in a range of diseases is better understood, strategies to target these cell types are of growing importance both scientifically and therapeutically. As particulate carriers, liposomes naturally target cells of the mononuclear phagocytic system (MPS), particularly macrophages. Loading drugs into liposomes can therefore offer an efficient means of drug targeting to MPS cells. Physicochemical properties including size, charge and lipid composition can have a very significant effect on the efficiency with which liposomes target MPS cells. MPS cells express a range of receptors including scavenger receptors, integrins, mannose receptors and Fc-receptors that can be targeted by the addition of ligands to liposome surfaces. These ligands include peptides, antibodies and lectins and have the advantages of increasing target specificity and avoiding the need for cationic lipids to trigger intracellular delivery. The goal for targeting monocytes/macrophages using liposomes includes not only drug delivery but also potentially a role in cell ablation and cell activation for the treatment of conditions including cancer, atherosclerosis, HIV, and chronic inflammation. PMID:21512579

Kelly, Ciara; Jefferies, Caroline; Cryan, Sally-Ann

2011-01-01

72

Nanostructured materials for selective recognition and targeted drug delivery  

NASA Astrophysics Data System (ADS)

Selective recognition requires the introduction of a molecular memory into a polymer matrix in order to make it capable of rebinding an analyte with a very high specificity. In addition, targeted drug delivery requires drug-loaded vesicles which preferentially localize to the sites of injury and avoid uptake into uninvolved tissues. The rapid evolution of nanotechnology is aiming to fulfill the goal of selective recognition and optimal drug delivery through the development of molecularly imprinted polymeric (MIP) nanoparticles, tailor-made for a diverse range of analytes (e.g., pharmaceuticals, pesticides, amino acids, etc.) and of nanostructured targeted drug carriers (e.g., liposomes and micelles) with increased circulation lifetimes. In the present study, PLGA microparticles containing multilamellar vesicles (MLVs), and MIP nanoparticles were synthesized to be employed as drug carriers and synthetic receptors respectively.

Kotrotsiou, O.; Kotti, K.; Dini, E.; Kammona, O.; Kiparissides, C.

2005-01-01

73

A Fluorescent Responsive Hybrid Nanogel for Closed-Loop Control of Glucose  

PubMed Central

Background The concept of closed-loop control of glucose, in which continuous glucose sensing is coupled to a fully automated insulin delivery device, without human input, has been an attractive idea for diabetes management. This study presents a new class of hybrid nanogels that can integrate glucose sensing and glucose-responsive insulin release into a single nano-object. Methods Zinc oxide@poly[N-isopropylacrylamide (NIPAM)-acrylamide (AAm)- 2-aminomethyl-5-fluorophenylboronic acid (FPBA)] hybrid nanogels were synthesized and investigated for size, morphology, volume phase transition, photoluminescence properties, and in vitro insulin release under different glucose concentrations. Glucose sensing was performed both in phosphate-buffered saline (PBS) and in blood samples. The insulin release in PBS of varying glucose levels, as well as a stepwise treatment between two glucose levels (126.0 and 270.0 mg/dl), was performed to test the glucose-responsive insulin release ability of the hybrid nanogels. Results Zinc oxide@poly(NIPAM-AAm-FPBA) hybrid nanogels can sensitively and selectively detect glucose in highly reproducible fluorescent signals over the clinically relevant glucose concentration range of 18?540 mg/dl. The glucose-responsive volume phase transition of the nanogels can further regulate the release of the preloaded insulin. The insulin release from the nanogels exhibits the slowest rate (~5% released in 76 h) at a normal glucose level (108.0 mg/dl) but becomes quicker and quicker as the glucose increases to higher and higher levels. Conclusions The rationally designed hybrid nanogel can optically signal the glucose level with high sensitivity and selectivity and simultaneously regulate the insulin release rate in response to the glucose reading, which shows a promising concept toward the development of a miniaturized closed-loop glycemic control system. PMID:22920816

Wu, Weitai; Chen, Shoumin; Hu, Yumei; Zhou, Shuiqin

2012-01-01

74

Targeted Delivery of Multicomponent Cargos to Cancer via Nanoporous Particle-Supported Lipid Bilayers  

E-print Network

1 Targeted Delivery of Multicomponent Cargos to Cancer via Nanoporous Particle-Supported Lipid the SLB 24 5. Delivery of siRNA Cocktails via SP94-Targeted Protocells 25 Supplementary Figure 13 SP94 apoptosis of HCC within 24 hours 28 6. Delivery of Protein Toxins via SP94-Targeted Protocells 29

Brinker, C. Jeffrey

75

Multifunctional Inorganic Nanoparticles for Imaging, Targeting, and Drug Delivery  

PubMed Central

Drug delivery, magnetic resonance and fluorescence imaging, magnetic manipulation, and cell targeting are simultaneously possible using a multifunctional mesoporous silica nanoparticle. Superparamagnetic iron oxide nanocrystals were encapsulated inside mesostructured silica spheres that were labeled with fluorescent dye molecules and coated with hydrophilic groups to prevent aggregation. Water-insoluble anticancer drugs were delivered into human cancer cells; surface conjugation with cancer-specific targeting agents increased the uptake into cancer cells relative to that in non-cancerous fibroblasts. The highly versatile multifunctional nanoparticles could potentially be used for simultaneous imaging and therapeutic applications. PMID:19206485

Liong, Monty; Lu, Jie; Kovochich, Michael; Xia, Tian; Ruehm, Stefan G.; Nel, Andre E.; Tamanoi, Fuyuhiko; Zink, Jeffrey I.

2009-01-01

76

In vivo targeted delivery of nanoparticles for theranosis.  

PubMed

Therapy and diagnosis are two major categories in the clinical treatment of disease. Recently, the word "theranosis" has been created, combining the words to describe the implementation of these two distinct pursuits simultaneously. For successful theranosis, the efficient delivery of imaging agents and drugs is critical to provide sufficient imaging signal or drug concentration in the targeted disease site. To achieve this purpose, biomedical researchers have developed various nanoparticles composed of organic or inorganic materials. However, the targeted delivery of these nanoparticles in animal models and patients remains a difficult hurdle for many researchers, even if they show useful properties in cell culture condition. In this Account, we review our strategies for developing theranostic nanoparticles to accomplish in vivo targeted delivery of imaging agents and drugs. By applying these rational strategies, we achieved fine multimodal imaging and successful therapy. Our first strategy involves physicochemical optimization of nanoparticles for long circulation and an enhanced permeation and retention (EPR) effect. We accomplished this result by testing various materials in mouse models and optimizing the physical properties of the materials with imaging techniques. Through these experiments, we developed a glycol chitosan nanoparticle (CNP), which is suitable for angiogenic diseases, such as cancers, even without an additional targeting moiety. The in vivo mechanism of this particle was examined through rationally designed experiments. In addition, we evaluated and compared the biodistribution and target-site accumulation of bare and drug-loaded nanoparticles. We then focus on the targeting moieties that bind to cell surface receptors. Small peptides were selected as targeting moieties because of their stability, low cost, size, and activity per unit mass. Through phage display screening, the interleukin-4 receptor binding peptide was discovered, and we combined it with our nanoparticles. This product accumulated efficiently in atherosclerotic regions or tumors during both imaging and therapy. We also developed hyaluronic acid nanoparticles that can bind efficiently to the CD44 antigen receptors abundant in many tumor cells. Their delivery mechanism is based on both physicochemical optimization for the EPR effect and receptor-mediated endocytosis by their hyaluronic acid backbone. Finally, we introduce the stimuli-responsive system related to the chemical and biological changes in the target disease site. Considering the relatively low pH in tumors and ischemic sites, we applied pH-sensitive micelle to optical imaging, magnetic resonance imaging, anticancer drug delivery, and photodynamic therapy. In addition, we successfully evaluated the in vivo imaging of enzyme activity at the target site with an enzyme-specific peptide sequence and CNPs. On the basis of these strategies, we were able to develop self-assembled nanoparticles for in vivo targeted delivery, and successful results were obtained with them in animal models for both imaging and therapy. We anticipate that these rational strategies, as well as our nanoparticles, will be applied in both the diagnosis and therapy of many human diseases. These theranostic nanoparticles are expected to greatly contribute to optimized therapy for individual patients as personalized medicine, in the near future. PMID:21851104

Koo, Heebeom; Huh, Myung Sook; Sun, In-Cheol; Yuk, Soon Hong; Choi, Kuiwon; Kim, Kwangmeyung; Kwon, Ick Chan

2011-10-18

77

Multiscale Modeling of Functionalized Nanocarriers in Targeted Drug Delivery  

PubMed Central

Targeted drug delivery using functionalized nanocarriers (NCs) is a strategy in therapeutic and diagnostic applications. In this paper we review the recent development of models at multiple length and time scales and their applications to targeting of antibody functionalized nanocarriers to antigens (receptors) on the endothelial cell (EC) surface. Our mesoscale (100 nm-1 ?m) model is based on phenomenological interaction potentials for receptor-ligand interactions, receptor-flexure and resistance offered by glycocalyx. All free parameters are either directly determined from independent biophysical and cell biology experiments or estimated using molecular dynamics simulations. We employ a Metropolis Monte Carlo (MC) strategy in conjunction with the weighted histogram analysis method (WHAM) to compute the free energy landscape (potential of mean force or PMF) associated with the multivalent antigen-antibody interactions mediating the NC binding to EC. The binding affinities (association constants) are then derived from the PMF by computing absolute binding free energy of binding of NC to EC, taking into account the relevant translational and rotational entropy losses of NC and the receptors. We validate our model predictions by comparing the computed binding affinities and PMF to a wide range of experimental measurements, including in vitro cell culture, in vivo endothelial targeting, atomic force microscopy (AFM), and flow chamber experiments. The model predictions agree closely and quantitatively with all types experimental measurements. On this basis, we conclude that our computational protocol represents a quantitative and predictive approach for model driven design and optimization of functionalized NCs in targeted vascular drug delivery. PMID:22116782

Liu, Jin; Bradley, Ryan; Eckmann, David M.; Ayyaswamy, Portonovo S.; Radhakrishnan, Ravi

2011-01-01

78

Chlorotoxin Labeled Magnetic Nanovectors for Targeted Gene Delivery to Glioma  

PubMed Central

Glioma accounts for 80% of brain tumors, and currently remains one of the most lethal forms of cancers. Gene therapy could potentially improve the dismal prognosis of patients with glioma, but this treatment modality has not yet reached the bedside from the laboratory due to the lack of safe and effective gene delivery vehicles. In this study we investigate targeted gene delivery to C6 glioma cells in a xenograft mouse model using chlorotoxin (CTX) labeled nanoparticles. The developed nanovector consists of an iron oxide nanoparticle core, coated with a copolymer of chitosan, polyethylene glycol (PEG) and polyethylenimine (PEI). Green fluorescent protein (GFP) encoding DNA was bound to these nanoparticles, and CTX was then attached using a short PEG linker. Nanoparticles without CTX were also prepared as a control. Mice bearing C6 xenograft tumors were injected intravenously with the DNA bound nanoparticles. Nanoparticle accumulation in the tumor site was monitored using magnetic resonance imaging and analyzed by histology, and GFP gene expression was monitored through Xenogen IVIS fluorescence imaging and confocal fluorescence microscopy. Interestingly, the CTX did not affect the accumulation of nanoparticles at the tumor site, but specifically enhanced their uptake into cancer cells as evidenced by higher gene expression. These results indicate that this targeted gene delivery system may potentially improve treatment outcome of gene therapy for glioma and other deadly cancers. PMID:20731441

Kievit, Forrest M.; Veiseh, Omid; Fang, Chen; Bhattarai, Narayan; Lee, Donghoon; Ellenbogen, Richard G.; Zhang, Miqin

2010-01-01

79

Fabrication and characterization of sol-gel based nanoparticles for drug delivery  

NASA Astrophysics Data System (ADS)

Nanogels are cross linked polymeric sol-gel based nanoparticles that offer an interior network for incorporation and protection of biomolecules, exhibiting unique advantages for polymer based delivery systems. We have successfully synthesized stable sol-gel nanoparticles by means of [a] silicification reactions using cationic peptides like polylysine as gelating agents, and [b] lyophilization of sol-gels. Macromolecules such as Hemoglobin and Glucose Oxidase and small molecules such as Sodium Nitroprusside (SNP) and antibiotics were encapsulated within the nanogels. We have used transmission electron microscopy, dynamic light scattering, zeta potential analysis, and spectroscopy to perform a physicochemical characterization of the nanogels resulting from the two approaches. Our studies have indicated that the nanogel encapsulated proteins and small molecules remain intact, stable and functional. A Hydrogen Peroxide (H2O2) and Nitric Oxide (NO) generating drug carrier was synthesized using these nanogels and the effect of generation of H2O2 from Glucose Oxidase encapsulated nanogels and NO from SNP encapsulated nanogels was tested on E.coli. The results show that the nanoparticles exert antimicrobial activity against E.Coli, in addition NO generating nanogels potentiated H2O2 generating nanogels induced killing. These data suggest that these NO and H2O2 releasing nanogels have the potential to serve as a novel class of antimicrobials for the treatment of multidrug resistant bacteria. The unique properties of these protein/drug incorporated nanogels raise the prospect of fine tailoring to specific applications such as drug delivery and bio imaging.

Yadav, Reeta

80

Improved Biochemical Strategies for Targeted Delivery of Taxoids  

PubMed Central

Paclitaxel (Taxol ®) and docetaxel (Taxotere ®) are very important anti-tumor drugs in clinical use for cancer. However, their clinical utility is limited due to systemic toxicity, low solubility and inactivity against drug resistant tumors. To improve chemotherapeutic levels of these drugs, it would be highly desirable to design strategies which bypass the above limitations. In this respect various prodrug and drug targeting strategies have been envisioned either to improve oral bioavailability or tumor specific delivery of taxoids. Abnormal properties of cancer cells with respect to normal cells have guided in designing of these protocols. This review article records the designed biochemical strategies and their biological efficacies as potential taxoid chemotherapeutics. PMID:17419065

Ganesh, Thota

2008-01-01

81

Integrated nanoplasmonic-nanofluidic biosensors with targeted delivery of analytes  

NASA Astrophysics Data System (ADS)

Performances of the biosensors are often limited by the depletion zones created around the sensing area which impede the effective analyte transport. To overcome this limitation, we propose and demonstrate a nanoplasmonic-nanofluidic sensor enabling targeted delivery of analytes to the sensor surface with dramatic improvements in mass transport efficiency. Our sensing platform is based on extraordinary light transmission effect in suspended plasmonic nanoholes. This scheme allows three-dimensional control of the fluidic flow by connecting separate layers of microfluidic channels through plasmonic/nanofluidic holes. To implement the proposed sensor platform, we also introduce a lift-off free nanofabrication method.

Yanik, Ahmet Ali; Huang, Min; Artar, Alp; Chang, Tsung-Yao; Altug, Hatice

2010-01-01

82

Bioresponsive nanohydrogels based on HEAA and NIPA for poorly soluble drugs delivery.  

PubMed

Environmentally sensitive hydrogels have gained considerable attention in recent years as one of the most promising drug delivery systems. In the present study, two new formulations of pH and temperature stimuli-responsive nanogels (NGs) based on poly-N-isopropylacrylamide (NIPA), N-hydroxyethyl acrylamide (HEAA) and tert-butyl 2-acrylamidoethyl carbamate (2AAECM) were synthesized and evaluated for passive targeting of paclitaxel (PTX). Nanogels were prepared by microemulsion polymerization method using N-methylenebis(acrylamide) (NMBA) as crosslinking agent. TEM images and DLS results showed nanosized spherical hydrogels. FTIR spectra confirmed the synthesis of nanogels by radical polymerization among vinyl groups of monomers. The PTX loading capacity, encapsulation efficiency and in vitro release were analyzed by HPLC. The cumulative release profile of the PTX-loaded nanohydrogels within 144h showed a faster drug release at acid pH (pH 5), similar to those observed at lysosome compartment, whereas a fewer PTX amount was released from NGs at pH similar to plasma levels. Cellular uptake assays revealed rapid penetration and intracellular accumulation of those nanogels in MCF7, HeLa and T47D cells after 48h incubation. MTT assays showed cell viability dependence on concentration and time incubation. Finally, the PTX effect on cell viability showed a G2/M cell arrest after using PTX-loaded NGs and pure PTX. PMID:24813784

Pérez, Elena; Martínez, Ana; Teijón, César; Teijón, Jose M; Blanco, M Dolores

2014-08-15

83

Synergistic Antitumor Activity from Two-Stage Delivery of Targeted Toxins and Endosome-Disrupting Nanoparticles  

E-print Network

Plant-derived Type I toxins are candidate anticancer therapeutics requiring cytosolic delivery into tumor cells. We tested a concept for two-stage delivery, whereby tumor cells precoated with an antibody-targeted gelonin ...

Su, Xingfang

84

Amphoteric hyaluronic acid derivative for targeting gene delivery.  

PubMed

The study aimed to develop an amphoteric hyaluronic acid (HA) derivative with polyethyleneimine (PEI) chains (HAP) for gene delivery to overcome the disadvantages of PEI as gene carrier including the cytotoxicity caused by excess of positive charge, non-special interaction and aggregation in the blood, and non-target gene delivery. The HAP was synthesized by an imine reaction between periodate-oxidized HA and PEI. The HAP/DNA complex was prepared, and its characterization was investigated. The size of complex with higher molecular weight HA in PBS was about 200 nm at optimal charge ratio. No apparent aggregation among the particles was observed. The HAPs also showed high protection of DNA from nuclease, better dissociation of DNA from the complex and lower cytotoxicity. It also exhibited higher transfection efficiency in HepG2 cells than the PEI/DNA complex. Among all complexes, the HAP50/DNA complex was especially found to be most efficient, yielding comparable transfection efficiency with that of Lipofectamine/DNA lipoplexes. Moreover, the HAP-IR820 obviously accumulated in tumor after i.v. administration as compared to the PEI-IR820, which indicated that the HAP could assist the DNA targeting to the tumor. Therefore, HAP should be a promising non-viral gene vector. PMID:20864163

Yao, Jing; Fan, Ying; Du, Ronghui; Zhou, Jianping; Lu, Yun; Wang, Wei; Ren, Jin; Sun, Xiaojing

2010-12-01

85

Shell-crosslinked hyaluronic acid nanogels for live monitoring of hyaluronidase activity in vivo.  

PubMed

A hyaluronidase (HAdase) has been noticed as a potential drug target as well as prognostic marker because of its close associations with tumor invasion, metastasis, and angiogenesis. Accordingly, precise monitoring of HAdase activity in vivo seems to be crucial not only for the evaluation of HAdase activity but also for non-invasive molecular imaging. In our study, we propose a new organic, near-infrared fluorescence imaging probe, indocyanine green (ICG)-based stimuli-responsive fluorescence probe for selective imaging of HAdases with appreciable signal-to-noise (S/N) ratios in serum and in vivo. Shell-crosslinked hyaluronic acid (HA) nanogels (sc-nanogels) are generated via a reducible covalent linkage which incorporate ICG derivatives. The ICG-embeded HA nanogels via shell-crosslinking have preferable properties for ideal selective imaging and detection of HAdase activity in vivo. The sc-nanogels exhibit prominent chemical stability against external light, greatly control background signals in serum, and small size compared to use of self-assembled ICG-based carriers. Collapsed ICG in the hydrogel core is selectively disentangled by HAdase treatment for selective near-infrared imaging without unwanted background signal. The newly designed sc-nanogels may have great potential to serve as probes for improved selective imaging of HAdase-associated diseases in clinics as well as HAdase-activity screening in vivo. PMID:24505028

Kim, Jihyun; Chong, Youhoon; Mok, Hyejung

2014-06-01

86

Pharmaceutical approaches to colon targeted drug delivery systems  

Microsoft Academic Search

Purpose. Although oral delivery has become a widely accepted route of administration of therapeutic drugs, the gastrointestinal tract presents several formidable barriers to drug delivery. Colonic drug delivery has gained increased importance not just for the delivery of the drugs for the treatment of local diseases associated with the colon but also for its potential for the delivery of proteins

M. K. Chourasia; S. K. Jain

87

Potential of magnetic nanoparticles for targeted drug delivery  

PubMed Central

Nanoparticles (NPs) play an important role in the molecular diagnosis, treatment, and monitoring of therapeutic outcomes in various diseases. Their nanoscale size, large surface area, unique capabilities, and negligible side effects make NPs highly effective for biomedical applications such as cancer therapy, thrombolysis, and molecular imaging. In particular, nontoxic superparamagnetic magnetic NPs (MNPs) with functionalized surface coatings can conjugate chemotherapeutic drugs or be used to target ligands/proteins, making them useful for drug delivery, targeted therapy, magnetic resonance imaging, transfection, and cell/protein/DNA separation. To optimize the therapeutic efficacy of MNPs for a specific application, three issues must be addressed. First, the efficacy of magnetic targeting/guidance is dependent on particle magnetization, which can be controlled by adjusting the reaction conditions during synthesis. Second, the tendency of MNPs to aggregate limits their therapeutic use in vivo; surface modifications to produce high positive or negative charges can reduce this tendency. Finally, the surface of MNPs can be coated with drugs which can be rapidly released after injection, resulting in targeting of low doses of the drug. Drugs therefore need to be conjugated to MNPs such that their release is delayed and their thermal stability enhanced. This chapter describes the creation of nanocarriers with a high drug-loading capacity comprised of a high-magnetization MNP core and a shell of aqueous, stable, conducting polyaniline derivatives and their applications in cancer therapy. It further summarizes some newly developed methods to synthesize and modify the surfaces of MNPs and their biomedical applications. PMID:24198498

Yang, Hung-Wei; Hua, Mu-Yi; Liu, Hao-Li; Huang, Chiung-Yin; Wei, Kuo-Chen

2012-01-01

88

Potential of magnetic nanoparticles for targeted drug delivery.  

PubMed

Nanoparticles (NPs) play an important role in the molecular diagnosis, treatment, and monitoring of therapeutic outcomes in various diseases. Their nanoscale size, large surface area, unique capabilities, and negligible side effects make NPs highly effective for biomedical applications such as cancer therapy, thrombolysis, and molecular imaging. In particular, nontoxic superparamagnetic magnetic NPs (MNPs) with functionalized surface coatings can conjugate chemotherapeutic drugs or be used to target ligands/proteins, making them useful for drug delivery, targeted therapy, magnetic resonance imaging, transfection, and cell/protein/DNA separation. To optimize the therapeutic efficacy of MNPs for a specific application, three issues must be addressed. First, the efficacy of magnetic targeting/guidance is dependent on particle magnetization, which can be controlled by adjusting the reaction conditions during synthesis. Second, the tendency of MNPs to aggregate limits their therapeutic use in vivo; surface modifications to produce high positive or negative charges can reduce this tendency. Finally, the surface of MNPs can be coated with drugs which can be rapidly released after injection, resulting in targeting of low doses of the drug. Drugs therefore need to be conjugated to MNPs such that their release is delayed and their thermal stability enhanced. This chapter describes the creation of nanocarriers with a high drug-loading capacity comprised of a high-magnetization MNP core and a shell of aqueous, stable, conducting polyaniline derivatives and their applications in cancer therapy. It further summarizes some newly developed methods to synthesize and modify the surfaces of MNPs and their biomedical applications. PMID:24198498

Yang, Hung-Wei; Hua, Mu-Yi; Liu, Hao-Li; Huang, Chiung-Yin; Wei, Kuo-Chen

2012-01-01

89

Targeted drug delivery and enhanced intracellular release using functionalized liposomes  

NASA Astrophysics Data System (ADS)

The ability to target cancer cells using an appropriate drug delivery system can significantly reduce the associated side effects from cancer therapies and can help in improving the overall quality of life, post cancer survival. Integrin alpha5beta1 is expressed on several types of cancer cells, including colon cancer and plays an important role in tumor growth and metastasis. Thus, the ability to target the integrin alpha 5beta1 using an appropriate drug delivery nano-vector can significantly help in inhibiting tumor growth and reducing tumor metastasis. The work in this thesis focuses on designing and optimizing, functionalized stealth liposomes (liposomes covered with polyethylene glycol (PEG)) that specifically target the integrin alpha5beta1. The PEG provides a steric barrier allowing the liposomes to circulate in the blood for longer duration and the functionalizing moiety, PR_b peptide specifically recognizes and binds to integrin alpha5beta1 expressing cells. The work demonstrates that by optimizing the amount of PEG and PR_b on the liposomal interface, nano-vectors can be engineered that bind to CT26.WT colon cancer cells in a specific manner and internalize through alpha 5beta1-mediated endocytosis. To further improve the efficacy of the system, PR_b functionalized pH-sensitive stealth liposomes that exhibit triggered release under mild acidic conditions present in endocytotic vesicles were designed. The study showed that PR_b functionalized pH-sensitive stealth liposomes, undergo destabilization under mildly acidic conditions and incorporation of the PR_b peptide does not significantly affect the pH-sensitivity of the liposomes. PR_b functionalized pH-sensitive stealth liposomes bind to CT26.WT colon carcinoma cells that express integrin alpha5beta 1, undergo cellular internalization, and release their load intracellularly in a short period of time as compared to other formulations. PR_b-targeted pH-sensitive stealth liposomes encapsulating 5-fluorouracil (5-FU) show significantly higher cytotoxicity than the PR_b-targeted inert stealth liposomes and the non-targeted stealth liposomes (both pH-sensitive and inert). The studies demonstrated that optimized PR_b functionalized pH sensitive liposomes have the potential to deliver a payload, such as chemotherapeutic agents, directly to colon cancer cells in an efficient and specific manner.

Garg, Ashish

90

Annexin A5 Molecular Imaging Targeted Drug Delivery  

E-print Network

Ó The Author(s) 2010. This article is published with open access at Springerlink.com Abstract Cells are able to execute apoptosis by activating series of specific biochemical reactions. One of the most prominent characteristics of cell death is the externalization of phosphatidylserine (PS), which in healthy cells resides predominantly in the inner leaflet of the plasma membrane. These features have made PS-externalization a well-explored phenomenon to image cell death for diagnostic purposes. In addition, it was demonstrated that under certain conditions viable cells express PS at their surface such as endothelial cells of tumor blood vessels, stressed tumor cells and hypoxic cardiomyocytes. Hence, PS has become a potential target for therapeutic strategies aiming at Targeted Drug Delivery. In this review we highlight the biomarker PS and various PS-binding compounds that have been employed to target PS for diagnostic purposes. We emphasize the 35 kD human protein annexin A5, that has been developed as a Molecular Imaging agent to measure cell death in vitro, and non-invasively in vivo in animal models and in patients with cardiovascular diseases and cancer. Recently focus has shifted from diagnostic towards therapeutic applications employing annexin A5 in strategies to deliver drugs to cells that express PS at their surface.

Kristof Schutters; Chris Reutelingsperger; K. Schutters; C. Reutelingsperger; C. Reutelingsperger

2010-01-01

91

Cubosomes as targeted drug delivery systems - a biopharmaceutical approach.  

PubMed

Cubosomes are reversed bicontinuous cubic phases and possess unique physicochemical properties. These special systems are receiving much attention for the delivery of various hydrophilic, hydrophobic and amphiphilic drugs with enhanced bioavailability and high loading capacity. A wide variety of drugs are applicable for cubosome formulation for various routes of delivery. The lipids used in cubosome formulation are more stable and offer stability to the formulation during shelf-life. The article reviews about the back ground, techniques of cubosome preparation such as high pressure homogenization, probe ultrasonication and automated cubosome preparation; and also methods of cubosomes preparation such as top down, bottom up and other methods with pictorial presentation. This article emphasizes the phase transition and also targeted approaches of cubosomes. The characterization studies for cubosomes such as cryo transmission electron microscopy, differential scanning calorimetry and scanning electron microscopy followed by in-vitro and in-vivo evaluation studies of cubosomes were explained with appropriate examples. Recent applications of cubosomes were explained with reference to flurbiprofen, odorranalectin, diazepam and dexamethasone. The advantages, disadvantages and limitations of cubosomal technology were emphasized. PMID:24836404

Lakshmi, Naga M; Yalavarthi, Prasanna R; Vadlamudi, Harini C; Thanniru, Jyotsna; Yaga, Gowri; K, Haritha

2014-01-01

92

PECAM-targeted delivery of SOD inhibits endothelial inflammatory response  

PubMed Central

Elevated generation of reactive oxygen species (ROS) by endothelial enzymes, including NADPH-oxidase, is implicated in vascular oxidative stress and endothelial proinflammatory activation involving exposure of vascular cell adhesion molecule-1 (VCAM-1). Catalase and superoxide dismutase (SOD) conjugated with antibodies to platelet/endothelial cell adhesion molecule 1 (PECAM-1) bind specifically to endothelium and inhibit effects of corresponding ROS, H2O2, and superoxide anion. In this study, anti-PECAM/SOD, but not anti-PECAM/catalase or nontargeted enzymes, including polyethylene glycol (PEG)-SOD, inhibited 2- to 3-fold VCAM expression caused by tumor necrosis factor (TNF), interleukin-1?, and lipopolysaccharide. Anti- PECAM/SOD, but not nontargeted counterparts, accumulated in vascular endothelium after intravenous injection, localized in endothelial endosomes, and inhibited by 70% lipopolysaccharide-caused VCAM-1 expression in mice. Anti-PECAM/SOD colocalized with EEA-1-positive endothelial vesicles and quenched ROS produced in response to TNF. Inhibitors of NADPH oxidase and anion channel ClC3 blocked TNF-induced VCAM expression, affirming that superoxide produced and transported by these proteins, respectively, mediates inflammatory signaling. Anti-PECAM/SOD abolished VCAM expression caused by poly(I:C)-induced activation of toll-like receptor 3 localized in intracellular vesicles. These results directly implicate endosomal influx of superoxide in endothelial inflammatory response and suggest that site-specific interception of this signal attained by targeted delivery of anti-PECAM/SOD into endothelial endosomes may have anti-inflammatory effects.—Shuvaev, V. V., Han, J., Yu, K. J., Huang, S., Hawkins, B. J., Madesh, M., Nakada, M., and Muzykantov, V. R. PECAM-targeted delivery of SOD inhibits endothelial inflammatory response. PMID:20876216

Shuvaev, Vladimir V.; Han, Jingyan; Yu, Kevin J.; Huang, Shaohui; Hawkins, Brian J.; Madesh, Muniswamy; Nakada, Marian; Muzykantov, Vladimir R.

2011-01-01

93

Cationic Nanogels Based On Diethylaminoethyl Methacrylate  

PubMed Central

The effect of polymer composition and polymerization parameters such as comonomers, crosslinking ratio, and polymerization method, on the surface characteristics, surface chemistry, and swelling response of crosslinked 2-(diethylaminoethyl methacrylate) (DEAEM) and polyethylene glycol monoethyl ether monomethacrylate (PEGMMA) nanogels was studied. A novel inverse-emulsion polymerization method was developed, which formed latex nanoparticles on the order of 100–400 nm. The properties of these nanogels were compared to microparticles synthesized via solution polymerization. The new polymerization method allowed the incorporation of PEG surface tethers of lengths 400 Da up to 2000 Da. Surface tethers successfully decreased the ?-potential of these nanogels from 70 mV to 30 mV in acidic conditions and from ?60 mV to 2 mV in basic media. Nanogels swelled from 100 nm in basic media to 800 nm in acidic media due to the protonation of the tertiary amine on DEAEM. PMID:20436948

Marek, Steve R.; Conn, Charles A.; Peppas, Nicholas A.

2010-01-01

94

Synthetic Aptamer-Polymer Hybrid Constructs for Programmed Drug Delivery into Specific Target Cells  

E-print Network

Synthetic Aptamer-Polymer Hybrid Constructs for Programmed Drug Delivery into Specific Target Cells effective drug delivery with fewer side effects.8,9 The systems that have made the greatest progress. They achieve this by performing a coordinated series of complex functions, resulting in delivery that is far

Akhmedov, Azer

95

Polypropylene nanogel: “Myth or reality”  

NASA Astrophysics Data System (ADS)

The objective of this work is the investigation of the nanogel and microgel formation in modified PP. The modified PP in pellets was synthesized by gamma irradiation of pristine PP under a crosslinking atmosphere of acetylene in dose of 5, 12.5 and 20 kGy, followed by thermal treatment for radical recombination and annihilation of the remaining radicals. The thin film gel of the polypropylenes was obtained by extraction in boiling xylene for period of 12 h at 138 °C, followed by decantation in beaker at room temperature of 25 °C with the total volatilization of the xylene and deposition of dried material film on glass substrate under agitation by Settling process. The thin film gel formed of pristine PP and modified PP (i.e., irradiated) was characterized using scanning electron microscopy (SEM), field emission scanning electron microscopy (FESEM) and differential scanning calorimetry (DSC). The PP morphology indicated the nanogels and microgel formation with increase of spherulitic concentration and crystallinity at dose of 12.5 kGy.

Oliani, W. L.; Parra, D. F.; Riella, H. G.; Lima, L. F. C. P.; Lugao, A. B.

2012-09-01

96

Magnetically responsive microparticles for targeted drug and radionuclide delivery.  

SciTech Connect

We are currently investigating the use of magnetic particles--polymeric-based spheres containing dispersed magnetic nanocrystalline phases--for the precise delivery of drugs via the human vasculature. According to this review, meticulously prepared magnetic drug targeting holds promise as a safe and effective method of delivering drugs to specific organ, tissue or cellular targets. We have critically examined the wide range of approaches in the design and implementation of magnetic-particle-based drug delivery systems to date, including magnetic particle preparation, drug encapsulation, biostability, biocompatibility, toxicity, magnetic field designs, and clinical trials. However, we strongly believe that there are several limitations with past developments that need to be addressed to enable significant strides in the field. First, particle size has to be carefully chosen. Micrometer-sized magnetic particles are better attracted over a distance than nanometer sized magnetic particles by a constant magnetic field gradient, and particle sizes up to 1 {micro}m show a much better accumulation with no apparent side effects in small animal models, since the smallest blood vessels have an inner diameter of 5-7 {micro}m. Nanometer-sized particles <70 nm will accumulate in organ fenestrations despite an effective surface stabilizer. To be suitable for future human applications, our experimental approach synthesizes the magnetic drug carrier according to specific predefined outcome metrics: monodisperse population in a size range of 100 nm to 1.0 {micro}m, non-toxic, with appropriate magnetic properties, and demonstrating successful in vitro and in vivo tests. Another important variable offering possible improvement is surface polarity, which is expected to prolong particle half-life in circulation and modify biodistribution and stability of drugs in the body. The molecules in the blood that are responsible for enhancing the uptake of particles by the reticuloendothelial system (RES) prefer to associate with hydrophobic surfaces. Accordingly, we will tackle this challenge by modifying the particles with hydrophilic coatings such as PEG or poloxamer (co-polymers containing hydrophobic polyoxypropylene segments and repetitive polyoxyethylene hydrophilic groups), which have a proven ability to mask recognition by the RES. Modeling is needed to help optimize the performance of targeted magnetic-particle delivery, enhance its medicinal value, and expedite its medical application. To this end, scientists at Argonne National Laboratory, working with The University of Chicago and Cleveland Clinic Hospital, are working on an effective magnetic drug targeting system based on custom magnetic field designs coupled to a three-dimensional imaging platform that addresses all associated physical and theoretical problems. Furthermore, while our clinical trial results are encouraging with regard to the tolerance and applicability of the system, more improvements must be made with respect to future study designs and systems being used. Given the technical hurdles in developing this potentially important technology, we believe we have made great progress and that we have a strong developmental plan.

Kaminski, M. D.; Ghebremeskel, A. N.; Nunez, L.; Kasza, K. E.; Chang, F.; Chien, T.-H.; Fisher, P. F.; Eastman, J. A.; Rosengart, A. J.; McDonald, L.; Xie, Y.; Johns, L.; Pytel, P.; Hafeli, U. O.

2004-02-16

97

Charge-conversional and reduction-sensitive poly(vinyl alcohol) nanogels for enhanced cell uptake and efficient intracellular doxorubicin release.  

PubMed

Charge-conversional and reduction-sensitive polyvinyl alcohol (PVA) nanogels were developed for efficient cancer treatment by enhanced cell uptake and intracellular triggered doxorubicin (DOX) release. These PVA nanogels were prepared in a straightforward manner by inverse nanoprecipitation via "click" reaction with an average diameter of 118nm. The introduction of COOH into the PVA nanogels efficiently improved the DOX encapsulation due to the electrostatic interaction. The in vitro release result showed that the decrease of electrostatic interaction between COOH and DOX under a mimicking endosomal pH, in combination with the cleavage of the intervening disulfide bonds in response to a high glutathione (GSH) concentration led to a fast and complete release of DOX. Furthermore, confocal laser scanning microscopy (CLSM) revealed that the ultra pH-sensitive terminal groups allowed nanogels to reverse their surface charge from negative to positive under a tumor extracellular pH (6.5-6.8) which facilitated cell internalization. MTT assays and real time cell analysis (RTCA) showed that these DOX-loaded charge-conversional and reducible PVA nanogels had much better cell toxicity than DOX-loaded non-charge-conversional or reduction-insensitive PVA nanogels following 48h of incubation. These novel charge-conversional and stimuli-responsive PVA nanogels are highly promising for targeted intracellular anticancer drug release. PMID:25445693

Chen, Wei; Achazi, Katharina; Schade, Boris; Haag, Rainer

2014-11-20

98

Role of nanotechnology in targeted drug delivery and imaging: a concise review  

Microsoft Academic Search

The use of nanotechnology in drug delivery and imaging in vivo is a rapidly expanding field. The emphases of this review are on biophysical attributes of the drug delivery and imaging platforms as well as the biological aspects that enable targeting of these platforms to injured and diseased tissues and cells. The principles of passive and active targeting of nanosized

Otilia M. Koo; Israel Rubinstein; Hayat Onyuksel

2005-01-01

99

Electrospun Nanofibers of Guar Galactomannan for Targeted Drug Delivery  

NASA Astrophysics Data System (ADS)

Guar galactomannan is a biodegradable polysaccharide used widely in the food industry but also in the cosmetics, pharmaceutical, oil drilling, textile and paper industries. Guar consists of a mannose backbone and galactose side groups that are both susceptible to enzyme degradation, a unique property that can be explored for targeted drug delivery especially since those enzymes are naturally secreted by the microflora in human colon. The present study can be divided into three parts. In the first part, we discuss ways to modify guar to produce nanofibers by electrospinning, a process that involves the application of an electric field to a polymer solution or melt to facilitate production of fibers in the sub-micron range. Nanofibers are currently being explored as the next generation of drug carriers due to its many advantages, none more important than the fact that nanofibers are on a size scale that is a fraction of a hair's width and have large surface-to-volume ratio. The incorporation and controlled release of nano-sized drugs is one way in which nanofibers are being utilized in drug delivery. In the second part of the study, we explore various methods to crosslink guar nanofibers as a means to promote water-resistance in a potential drug carrier. The scope and utility of water-resistant guar nanofibers can only be fully appreciated when subsequent drug release studies are carried out. To that end, the third part of our study focuses on understanding the kinetics and diffusion mechanisms of a model drug, Rhodamine B, through moderately-swelling (crosslinked) hydrogel nanofibers in comparison to rapidly-swelling (non-crosslinked) nanofibers. Along the way, our investigations led us to a novel electrospinning set-up that has a unique collector designed to capture aligned nanofibers. These aligned nanofiber bundles can then be twisted to hold them together like yarn. From a practical standpoint, these yarns are advantageous because they come freely suspended and without any attached support. As composites of aligned nanofibers, yarns potentially combine the inherent advantages of nanofibers with the strength and pliability of larger sized fibers. As such, we became interested in exploring the potential of nanofiber yarns as drug carriers. Our study evolved to accommodate comparative studies between the behavior of traditional nonwoven mats and nanofiber yarns. Throughout the process, we sought to answer the bigger question: Can guar galactomannan nanofibers be used as a new biodegradable platform for drug delivery?

Chu, Hsiao Mei Annie

2011-12-01

100

Buparvaquone loaded solid lipid nanoparticles for targeted delivery in theleriosis  

PubMed Central

Background: Buparvaquone (BPQ), a hydroxynaphthoquinone derivative, has been investigated for the treatment of many infections and is recommended as the gold standard for the treatment of theileriosis. Theileriosis, an intramacrophage infection is localized mainly in reticuloendotheileial system (RES) organs. The present study investigates development of solid lipid nanoparticles (SLN) of BPQ for targeted delivery to the RES. Materials and Methods: BPQ SLN was prepared using melt method by adding a molten mixture into aqueous Lutrol F68 solution (80°C). Larger batches were prepared up to 6 g of BPQ with GMS: BPQ, 2:1. SLN of designed size were obtained using ultraturrax and high pressure homogenizer. A freeze and thaw study was used to optimize type and concentration of cryoprotectant with Sf: Mean particle size, Si: Initial particle size <1.3. Differential scanning calorimetry (DSC), powder X-ray diffraction (XRD) and scanning electron microscope (SEM) study was performed on optimized formulation. Formulation was investigated for in vitro serum stability, hemolysis and cell uptake study. Pharmacokinetic and biodistribution study was performed in Holtzman rat. Results: Based on solubility in lipid; glyceryl monostearate (GMS) was selected for preparation of BPQ SLN. Batches of BPQ SLN were optimized for average particle size and entrapment efficiency at <100 mg solid content. A combination of Solutol HS-15 and Lutrol F68 at 2% w/v and greater enabled the desired Sf/Si < 1.3. Differential scanning calorimetry and powder X-ray diffraction revealed decrease in crystallinity of BPQ in BPQ SLN while, scanning electron microscope revealed spherical morphology. BPQ SLN revealed good stability at 4°C and 25°C. Low hemolytic potential (<8%) and in vitro serum stability up to 5 h was observed. Cytotoxicity of SLN to the U937 cell was low. The macrophage cell line revealed high (52%) uptake of BPQ SLN in 1 h suggesting the potential to RES uptake. SLN revealed longer circulation and biodistrbution study confirmed high RES uptake (75%) in RES organs like liver lung spleen etc. Conclusion: The high RES uptake suggests BPQ SLN as a promising approach for targeted and improved delivery in theileriosis. PMID:24459400

Soni, Maheshkumar P.; Shelkar, Nilakash; Gaikwad, Rajiv V.; Vanage, Geeta R.; Samad, Abdul; Devarajan, Padma V.

2014-01-01

101

Development of novel drug delivery prototypes devices for targeted delivery drug therapy at the molecular level in aqueous media.  

PubMed

A novel approach in target specific molecular prototype drug delivery system concerns the attempt to employ radical affording substances (RAS) or radical quenching substances (RQS) as prodrugs able to produce irreversible damage on the desired target and therefore to stimulate cellular apoptosis. However, radical species generated can react quickly within the chemical environment prior to reaching its proper site of action. In this short communication, we report our investigations towards developing two alternative novel, simple, flexible and effective drug delivery systems that provide optimal dosage of drugs precisely where and when needed and therefore achieve and sustain a complex delivery profile. We have demonstrated the application of two effective molecular prototype delivery systems able to harness free radical reactivity within the laboratory where biological processes can be studied and controlled, leading to the prevention of disease and the development of new treatments for disease states mediated by free radicals. PMID:21843149

George, Roy; Oberhozer, Theunis Gerhardus; Perchyonok, Victoria Tamara

2011-09-01

102

Transporter targeted gatifloxacin prodrugs: Synthesis, permeability, and topical ocular delivery  

PubMed Central

Purpose To design and synthesize prodrugs of gatifloxacin targeting OCT, MCT, and ATB (0, +) transporters and to identify a prodrug with enhanced delivery to the back of the eye. Method Dimethylamino-propyl, carboxy-propyl, and amino-propyl(2-methyl) derivatives of gatifloxacin (GFX), DMAP-GFX, CP-GFX, and APM-GFX, were designed and synthesized to target OCT, MCT, and ATB (0, +) transporters, respectively. LC-MS method was developed to analyze drug and prodrug levels in various studies. Solubility and Log D (pH 7.4) were measured for prodrugs and the parent drug. Permeability of the prodrugs was determined in cornea, conjunctiva, and sclera-choroidretinal pigment epitheluim (SCRPE) and compared with gatifloxacin using Ussing chamber assembly. Permeability mechanisms were elucidated by determining the transport in the presence of transporter specific inhibitors. 1-Methyl-4-phenylpyridinium iodide (MPP+), nicotinic acid sodium salt, and ?-methyl-DL-tryptophan were used to inhibit OCT, MCT, and ATB (0, +) transporters, respectively. A prodrug selected based on in vitro studies was administered as an eye drop to pigmented rabbits and the delivery to various eye tissues including vitreous humor was compared with gatifloxacin dosing. Results DMAP-GFX exhibited 12.8-fold greater solubility than GFX. All prodrugs were more lipophilic, with the measured Log D (pH 7.4) values ranging from 0.05 to 1.04, when compared to GFX (Log D: -1.15). DMAP-GFX showed 1.4-, 1.8-, and 1.9-fold improvement in permeability across cornea, conjunctiva, as well as SCRPE when compared to GFX. Moreover, it exhibited reduced permeability in the presence of MPP+ (competitive inhibitor of OCT), indicating OCT-mediated transport. CP-GFX showed 1.2-, 2.3- and 2.5-fold improvement in permeability across cornea, conjunctiva and SCRPE, respectively. In the presence of nicotinic acid (competitive inhibitor of MCT), permeability of CP-GFX was reduced across conjunctiva. However, cornea and SCRPE permeability of CP-GFX was not affected by nicotinic acid. APM-GFX did not show any improvement in permeability when compared to GFX across cornea, conjunctiva, and SCRPE. Based on solubility and permeability, DMAP-GFX was selected for in vivo studies. DMAP-GFX showed 3.6- and 1.95-fold higher levels in vitreous humor and CRPE compared to that of GFX at 1 hour after topical dosing. In vivo conversion of DMAP-GFX prodrug to GFX was quantified in tissues isolated at 1 hour after dosing. Prodrug-to-parent drug ratio was 8, 70, 24, 21, 29, 13, 55, and 60 % in cornea, conjunctiva, iris-ciliary body, aqueous humor, sclera, CRPE, retina, and vitreous humor, respectively. Conclusions DMAP-GFX prodrug enhanced solubility, Log D, as well as OCT mediated delivery of gatifloxacin to the back of the eye. PMID:23003105

Vooturi, Sunil K.; Kadam, Rajendra S.; Kompella, Uday B.

2013-01-01

103

HSA nanocapsules functionalized with monoclonal antibodies for targeted drug delivery.  

PubMed

The chronic autoimmune disorder rheumatoid arthritis (RA) affects millions of adults and children every year. Chronically activated macrophages secreting enzymes and inflammatory cytokines play a key role in RA. Distinctive marker molecules on the macrophage surface could be used to design a targeted drug delivery device for the treatment of RA without affecting healthy cells and tissues. Here, different methods for covalent attachment of antibodies (mAb) recognizing MHC class II molecules found on macrophages onto human serum albumin (HSA) nanocapsules were compared. HSA nanocapsules were prepared with a hydrodynamic diameter of 500.7 ± 9.4 nm and a narrow size distribution as indicated by a polydispersity index (PDI) of 0.255 ± 0.024. This was achieved by using a sonochemical process avoiding toxic cross linking agents and emulsifiers. Covalent binding of mAb on the surface of HSA nanocapsules was realized using polyethyleneglycol (PEG)3000 as spacer molecule. The presence of mAb was confirmed by confocal laser scanning microscopy (CLSM) and enzyme-linked immunosorbent assay (ELISA). Specific binding of mAb-HSA nanocapsules to MHC class II molecules on antigen-presenting cells was demonstrated by flow cytometry analysis. PMID:24157344

Rollett, Alexandra; Reiter, Tamara; Ohradanova-Repic, Anna; Machacek, Christian; Cavaco-Paulo, Artur; Stockinger, Hannes; Guebitz, Georg M

2013-12-15

104

PECAM-targeted delivery of SOD inhibits endothelial inflammatory response.  

PubMed

Elevated generation of reactive oxygen species (ROS) by endothelial enzymes, including NADPH-oxidase, is implicated in vascular oxidative stress and endothelial proinflammatory activation involving exposure of vascular cell adhesion molecule-1 (VCAM-1). Catalase and superoxide dismutase (SOD) conjugated with antibodies to platelet/endothelial cell adhesion molecule 1 (PECAM-1) bind specifically to endothelium and inhibit effects of corresponding ROS, H(2)O(2), and superoxide anion. In this study, anti-PECAM/SOD, but not anti-PECAM/catalase or nontargeted enzymes, including polyethylene glycol (PEG)-SOD, inhibited 2- to 3-fold VCAM expression caused by tumor necrosis factor (TNF), interleukin-1?, and lipopolysaccharide. Anti- PECAM/SOD, but not nontargeted counterparts, accumulated in vascular endothelium after intravenous injection, localized in endothelial endosomes, and inhibited by 70% lipopolysaccharide-caused VCAM-1 expression in mice. Anti-PECAM/SOD colocalized with EEA-1-positive endothelial vesicles and quenched ROS produced in response to TNF. Inhibitors of NADPH oxidase and anion channel ClC3 blocked TNF-induced VCAM expression, affirming that superoxide produced and transported by these proteins, respectively, mediates inflammatory signaling. Anti-PECAM/SOD abolished VCAM expression caused by poly(I:C)-induced activation of toll-like receptor 3 localized in intracellular vesicles. These results directly implicate endosomal influx of superoxide in endothelial inflammatory response and suggest that site-specific interception of this signal attained by targeted delivery of anti-PECAM/SOD into endothelial endosomes may have anti-inflammatory effects. PMID:20876216

Shuvaev, Vladimir V; Han, Jingyan; Yu, Kevin J; Huang, Shaohui; Hawkins, Brian J; Madesh, Muniswamy; Nakada, Marian; Muzykantov, Vladimir R

2011-01-01

105

Temperature- and redox-directed multiple self assembly of poly(N-isopropylacrylamide) grafted dextran nanogels.  

PubMed

Poly(N-isopropylacrylamide) (PNIPAAm) grafted dextran nanogels with dodecyl and thiol end groups have been synthesized by RAFT process. Dodecyl-terminated polymers (DexPNI) can be readily dissolved in water and further self assemble into ordered stable nanostructures through direct noncovalent interactions at room temperature. SEM, AFM and DLS measurements confirm the formation of spherical nanogels at hundred-nanometer scales. The elevation of environment temperature will indirectly result in the formation of collapsed nanostructures due to the LCST phase transition of PNIPAAm side chains. Turbidimetry results show that the phase transition behaviors of DexPNI are greatly dependent on PNIPAAm chain length and polymer concentration: increasing PNIPAAm chain length and polymer concentration both lead to lower LCSTs and sharper phase transitions. Moreover, the dodecyl-terminated polymers can transform into thiol-terminated versions by aminolysis of trithiocarbonate groups, and further into chemical (disulfide) cross-linked versions (SS-DexPNI) by oxidation. SS-DexPNI nanogels have "doubled" chain length of PNIPAAm, and hence sharper phase transitions. In situ DLS measurements of the evolution of hydrodynamic radius attest that the self assembly of SS-DexPNI nanogels can be selectively directed by the change in either external temperature or redox potential. These nanogels thus are promising candidates for triggered intracellular delivery of encapsulated cargo. We can also expect that the polymer can be noncovalently (by dodecyl end groups) or covalently (by thiol end groups) coated on a series of nanomaterials (e.g., carbon nanotubes, graphene, gold nanomaterials) to build a variety of novel smart, and robust nanomaterials. PMID:21648004

Lv, Weipeng; Liu, Shuoqi; Feng, Wenqian; Qi, Junjie; Zhang, Guoliang; Zhang, Fengbao; Fan, Xiaobin

2011-07-15

106

Near-infrared light-triggered, targeted drug delivery to cancer cells by aptamer gated nanovehicles.  

PubMed

A novel cell-targeting, near-infrared light-responsive drug delivery platform based on mesoporous silica-coated gold nanorods that are surface-functionalized with aptamer DNA is constructed. Aptamer DNA is used as both capping and targeting agent. In vitro studies show the feasibility of using this nanocarrier for targeted and noninvasive remote controlled drug delivery and photothermal therapy. PMID:22539076

Yang, Xinjian; Liu, Xia; Liu, Zhen; Pu, Fang; Ren, Jinsong; Qu, Xiaogang

2012-06-01

107

Engineering targeted proteins for intracellular delivery of biotherapeutics  

E-print Network

Biotherapeutics have revolutionized medicine with their ability to achieve unprecedented molecular recognition and mediate complex biological responses. The intracellular delivery of biotherapeutics is an unmet scientific ...

Pirie, Christopher M

2011-01-01

108

Exploring targeted pulmonary delivery for treatment of lung cancer  

PubMed Central

Lung cancer is the most malignant cancer today. The treatment of lung cancer continues to be a challenge for oncologists. The direct delivery of chemotherapeutic agents to the lungs could represent a novel therapeutic approach for patients with pulmonary metastases. The large alveolar surface area, the low thickness of the epithelial barrier, and an extensive vascularization make the pulmonary route an ideal route for administration of oncolytics. This paper reviews the research performed over the last and current decades on the delivery of various oncolytics for pulmonary delivery for the treatment of lung cancer. Inhaled drug delivery devices in cancer therapy are also discussed in the present manuscript. PMID:23799201

Goel, Amit; Baboota, Sanjula; Sahni, Jasjeet K; Ali, Javed

2013-01-01

109

Abstract --This paper studies the use of the innovative concept of MRI-targeted drug delivery platform for robotic  

E-print Network

Abstract -- This paper studies the use of the innovative concept of MRI-targeted drug delivery by external magnetic fields. I. INTRODUCTION Drug delivery of chemotherapy agents using aerosolized liposomes for intravascular targeted drug delivery and proved that targeting to specific lesions could be achieved by locating

Mavroidis, Constantinos

110

The ability of retention, drug release and rheological properties of nanogel bioadhesives based on cellulose derivatives.  

PubMed

The rheological and drug release behavior of biopolymer nanocomposite gels based on the cellulose derivatives, formulated as the bioadhesive drug delivery platforms, were investigated. The bioadhesive gel is composed of the microcrystalline cellulose, sodium carboxymethyl cellulose and phosphate buffered saline (pH?=?7.4 at 20?°C) as the dissolution and release medium. The reinforcing nanofillers such as MMT-clay, fumed porous silica and porous starch were used as additives in the nanogel bioadhesive. The constant steady state viscosities of this nanogels upon incorporation of various nanofillers into the systems is the sign of structural stability. Hence, this system is suitable for use in the controlled drug delivery systems in contact with the biological tissues. Based on the rheological measurements, the shear flow properties (i.e. zero shear viscosity and yield stress) were influenced by the concentration of polymers and nanoparticles. The results indicate that the nonlinear rheological data are fitted properly by the Giesekus model. Furthermore, the results showed that the nonlinear viscoelastic parameters (? and ?) are highly affected by the biogel and nanoparticles concentrations. Finally, the drug release was measured, and the results indicated that the biopolymer-clay nanocomposites have appropriate release pattern as the release is better controlled compared to the other nanogel formulations. PMID:24160773

Keshavarz, M; Kaffashi, B

2014-12-01

111

Functionalized polymersomes with outlayered polyelectrolyte gels for potential tumor-targeted delivery of multimodal therapies and MR imaging.  

PubMed

A novel tumor-targeting polymersome carrier system capable of delivering magnetic resonance imaging (MRI) and chemotherapy is presented in this study. The doxorubicin (DOX)-loaded magnetic polymersomes were first attained by the self-assembly of lipid-containing copolymer, poly(acrylic acid-co-distearin acrylate), in aqueous solution containing citric acid-coated superparamagnetic iron oxide nanoparticles (SPIONs), and followed by DOX loading via electrostatic attraction. To further functionalize these artificial vesicles with superior in vivo colloidal stability, pH-tunable drug release and active tumor-targeting, chitosan and poly(?-glutamic acid-co-?-glutamyl oxysuccinimide)-g-poly(ethyleneglycol)-folate (FA) were deposited in sequence onto the assembly outer surfaces. The interfacial nanogel layers via complementary electrostatic interactions and in-situ covalent cross-linking were thus produced. These nanogel-caged polymersomes (NCPs) show excellent anti-dilution and serum proteins-repellent behaviors. Triggerable release of the encapsulated DOX was governed by dual external stimuli, pH and temperature. When these theranostic NCPs were effectively internalized by HeLa cells via FA receptor-mediated endocytosis and then exposed to high frequency magnetic fields (HFMF), the combined effects of both pH and magnetic hyperthermia-triggered drug release and thermo-therapy resulted in greater cytotoxicity than the treatment by DOX alone. By virtue of the SPION clustering effect in the assembly inner aqueous compartments, the SPION/DOX-loaded NCPs displayed an r? relaxivity value (255.2 F emM?¹ S?¹) higher than Resovist (183.4 F emM?¹ S?¹), a commercial SPION-based T? contrast agent. The high magnetic relaxivity of the tumor-targeting NCPs coupled with their enhanced cellular uptake considerably promoted the MRI contrast of targeted cancer cells. These results demonstrate the great potential of the FA-decorated SPION/DOX-loaded NCPs as an advanced cancer theranostic nanodevice. PMID:23562635

Chiang, Wen-Hsuan; Huang, Wen-Chia; Chang, Chien-Wen; Shen, Ming-Yin; Shih, Zong-Fu; Huang, Yi-Fong; Lin, Sung-Chyr; Chiu, Hsin-Cheng

2013-06-28

112

Multifunctional magnetic silica nanotubes for MR imaging and targeted drug delivery.  

PubMed

A multifunctional drug delivery vehicle consisting of a tubular shaped silica host, a compact superparamagnetic iron oxide nanoparticle layer and a hyaluronic acid surface coating was developed as a theranostic platform, for in vivo MR imaging and magnetically guided/cancer targeted drug delivery. PMID:25656155

Huang, Liang; Ao, Lijiao; Wang, Wei; Hu, Dehong; Sheng, Zonghai; Su, Wu

2015-02-17

113

Near Infrared-Sensitive Nanoparticles for Targeted Drug Delivery  

E-print Network

The invasive nature and undesirable side-effects related to conventional cancer therapy, such as surgery and chemotherapy, have led to the development of novel drug delivery systems (DDS). A minimally invasive DDS using ...

Tan, Mei Chee

114

Nano to micro delivery systems: targeting angiogenesis in brain tumors  

PubMed Central

Treating brain tumors using inhibitors of angiogenesis is extensively researched and tested in clinical trials. Although anti-angiogenic treatment holds a great potential for treating primary and secondary brain tumors, no clinical treatment is currently approved for brain tumor patients. One of the main hurdles in treating brain tumors is the blood brain barrier - a protective barrier of the brain, which prevents drugs from entering the brain parenchyma. As most therapeutics are excluded from the brain there is an urgent need to develop delivery platforms which will bypass such hurdles and enable the delivery of anti-angiogenic drugs into the tumor bed. Such delivery systems should be able to control release the drug or a combination of drugs at a therapeutic level for the desired time. In this mini-review we will discuss the latest improvements in nano and micro drug delivery platforms that were designed to deliver inhibitors of angiogenesis to the brain. PMID:20932320

2010-01-01

115

NEST Scientific Report 2007-2009 Nanotechnology for intracellular delivery and targeting of drugs, nanoreporters  

E-print Network

NEST Scientific Report 2007-2009 Nanotechnology for intracellular delivery and targeting of drugs to the Collaborators A. Albanese L. Albertazzi F. Beltram R. Bizzarri F. Cardarelli F. Salomone #12;Nanotechnology

Abbondandolo, Alberto

116

Cell-mediated Delivery and Targeted Erosion of Noncovalently Crosslinked Hydrogels  

NASA Technical Reports Server (NTRS)

A method for targeted delivery of therapeutic compounds from hydrogels is presented. The method involves administering to a cell a hydrogel in which a therapeutic compound is noncovalently bound to heparin.

Kiick, Kristi L. (Inventor); Yamaguchi, Nori (Inventor)

2013-01-01

117

Quantification of Mesenchymal Stem Cell (MSC) Delivery to a Target Site Using In Vivo Confocal Microscopy  

E-print Network

The ability to deliver cells to appropriate target tissues is a prerequisite for successful cell-based therapy. To optimize cell therapy it is therefore necessary to develop a robust method of in vivo cell delivery ...

Mortensen, Luke J.

118

A Nonpolycationic Fully Proteinaceous Multiagent System for Potent Targeted Delivery of siRNA  

E-print Network

Protein-based methods of targeted short-interfering RNA (siRNA) delivery have the potential to solve some of the problems faced by nanoparticle-based methods, such as poor pharmacokinetics and biodistribution, low tumor ...

Liu, David V.

119

The role of HER2 in cancer therapy and targeted drug delivery  

PubMed Central

HER2 is highly expressed in a significant proportion of breast cancer, ovarian cancer, and gastric cancer. Since the discovery of its role in tumorigenesis, HER2 has received great attention in cancer research during the past two decades. Successful development of the humanized monoclonal anti-HER2 antibody (Trastuzumab) for the treatment of breast cancer further spurred scientists to develop various HER2 specific antibodies, dimerization inhibitors and kinase inhibitors for cancer therapy. On the other hand, the high expression of HER2 and the accessibility of its extracellular domain make HER2 an ideal target for the targeted delivery of anti-tumor drugs as well as imaging agents. Although there is no natural ligand for HER2, various artificial ligands targeting HER2 have been developed and applied in various targeted drug delivery systems. The emphasis of this review is to elucidate the roles of HER2 in cancer therapy and targeted drug delivery. The structure and signal pathway of HER2 will be briefly described. The role of HER2 in tumorigenesis and its relationship with other tumor markers will be discussed. For the HER2 targeted cancer therapy, numerous strategies including the blockage of receptor dimerization, inhibition of the tyrosine kinase activity, and interruption of the downstream signal pathway will be summarized. For the targeted drug delivery to HER2 positive tumor cells, various targeting ligands and their delivery systems will be described in details. PMID:20385184

Tai, Wanyi; Mahato, Rubi; Cheng, Kun

2010-01-01

120

Oligoperoxide Based Physically Detectable Nanocomposites for Cell Targeting, Visualization and Treatment  

NASA Astrophysics Data System (ADS)

Novel promising routes for the obtaining luminescent, magnetic, plasmon resonance capable nanocomposites as well as drug delivery systems are proposed and studied. These routes are based on the synthesis and application of original type of functional oligoperoxides, their coordinating complexes of transition including rare earth metal cations for controlled synthesis of block, comb-like or nanogel oligoelectrolytes as well as for template synthesis of functional polymer and polymer-mineral nanoparticles. Developed nanoscale delivery systems were tested as medicines for cancer administration in vitro and in vivo. Physically detectable lectin-conjugated nanocomposites were studied as biomarkers for pathological cell targeting and visualization.

Zaichenko, A.; Mitina, N.; Shevchuk, O.; Shapoval, O.; Boiko, N.; Bilyy, R.; Stoika, R.; Voloshinovskii, A.; Horak, D.

2010-10-01

121

Nanostructured lipid carriers and their current application in targeted drug delivery.  

PubMed

In the last few decades, various drug-delivery technologies have emerged and a fascinating part of this has been the development of nanoscale drug delivery devices. Nanoparticles (NPs) and other colloidal drug-delivery systems modify the kinetics, drug distribution in the body and release profile of an associated drug. Nanostructured lipid carriers (NLCs) have been reported to be an alternative system to emulsions, liposomes, microparticles, solid lipid nanoparticles (SLNs) and their polymeric counterparts due to their numerous advantages. This paper basically reviews the types of NLCs, mechanism of skin penetration, stability related issues along with their production techniques, characterisation and applications towards targeted drug delivery. PMID:24813223

Jaiswal, Piyush; Gidwani, Bina; Vyas, Amber

2014-05-01

122

Calcium-crosslinked LABL-TAT complexes effectively target gene delivery to ICAM-1 expressing cells  

PubMed Central

Targeted gene delivery using non-viral vectors is a highly touted scheme to reduce the potential for toxic or immunological side effects by reducing dose. In previous reports, TAT polyplexes with DNA have shown relatively poor gene delivery. The transfection efficiency has been enhanced by condensing TAT/DNA complexes to a small particle size using calcium. To explore the targetability of these condensed TAT complexes, LABL peptide targeting intercellular cell-adhesion molecule-1 (ICAM-1) was conjugated to TAT peptide using a polyethylene glycol (PEG) spacer. PEGylation reduced the transfection efficiency of TAT, but TAT complexes targeting ICAM-1 expressing cells regained much of the lost transfection efficiency. Targeted block peptides properly formulated with calcium offer promise for gene delivery to ICAM-1 expressing cells at sites of injury or inflammation. PMID:21473630

Khondee, Supang; Baoum, Abdulgader; Siahaan, Teruna J.; Berkland, Cory

2014-01-01

123

Battling with environments: drug delivery to target tissues with particles and functional biomaterials  

PubMed Central

Recent years have seen a growing interest in drug-delivery technology as an enabling tool for complicated pharmacological activities. At the same time, this field has faced as many ideas into clinical benefits. The Laboratory for Therapeutic Particles and Biomaterials Engineering at Purdue University (IN, USA) has striven to identify the current challenges in drug delivery and find solutions through the design of new drug-delivery systems. We develop new inhalable formulations for drug and gene delivery for cystic fibrosis patients, simple particle platforms for inhalable drug delivery, anion-resistant nonviral gene vectors, tumor-targeted nanoparticle systems, and hydrogel-based therapeutics. Through expanded collaborations with researchers in medicine and related disciplines, we strive to contribute to advancing the drug delivery field in a clinically relevant manner. PMID:21339855

Yeo, Yoon

2011-01-01

124

Solid lipid nanoparticles for targeted brain drug delivery  

Microsoft Academic Search

The present review discusses the potential use of solid lipid nanoparticles for brain drug targeting purposes. The state of the art on surfactant-coated poly(alkylcyanoacrylate) nanoparticles specifically designed for brain targeting is given by emphasizing the transfer of this technology to solid lipid matrices. The available literature on solid lipid nanoparticles and related carriers for brain drug targeting is revised as

Paolo Blasi; Stefano Giovagnoli; Aurélie Schoubben; Maurizio Ricci; Carlo Rossi

2007-01-01

125

Cell Penetrating and Cell Targeting Peptides in Drug Delivery (revised version) Eric Vivs*, Julien Schmidt and Andr Plegrin.  

E-print Network

1 Cell Penetrating and Cell Targeting Peptides in Drug Delivery (revised version) Eric Vivès-penetrating peptide, cell-targeting peptide, cell delivery, drug. Abstract During the last decade, the potential of peptides for drug delivery into cells has been highlighted by the discovery of several cell

Paris-Sud XI, Université de

126

Ferri-liposomes as an MRI-visible drug-delivery system for targeting tumours and their  

E-print Network

Ferri-liposomes as an MRI-visible drug-delivery system for targeting tumours-invasively monitor drug delivery in vivo. We also visualize the targeting of the tumour microenvironment by the drug substantially reduced the size of the tumour compared with systemic delivery of the same drug. C ancer

Bogyo, Matthew

127

Cell targeted gene delivery system based on modified pectin  

Technology Transfer Automated Retrieval System (TEKTRAN)

Citrus pectin modified with various amine groups have been studied for its potential as a novel non-viral gene delivery carrier. The modified cationic pectin was able to condense DNA and mediate transfection in a cell type specific manner. The modified pectin seems to be a promising carrier, attra...

128

Polymeric nanofibers: targeted gastro-retentive drug delivery systems.  

PubMed

Abstract Background: Conventional oral dosage forms exhibit poor/low bioavailability due to incomplete release of drug and short residence time at the absorption site. Gastro-retentive drug delivery system (GRDDS) is particularly used to improve bioavailability of the drugs, which have narrow absorption window down in the levels of gastrointestinal tract and also to treat local disorders. Purpose: The purpose of this review is to describe the utility of the nanofibers as gastro-retentive dosage form. From last few decades, formulation scientists have put extensive efforts to develop suitable gastro-retentive drug delivery system, which is appropriate for commercialization. Current approaches used for preparation of gastro-retentive drug delivery system offers limited functional features to control the floating behavior. Recently, an extensive research has been developed to improve the gastric residence time by using nanofibers, which ultimately leads to the increased bioavailability of the drug. Multiple functional features and unique properties of nanofibers improve its gastro retention. Conclusion: Nanofiber system provides stomach-specific drug release for longer duration; moreover, increased local action of the drug due to prolonged contact time with the gastric mucosa. Thus, the nanofiber system promises to be the potential approach for gastric retention drug delivery system. PMID:25268275

Malik, Rafi; Garg, Tarun; Goyal, Amit K; Rath, Goutam

2014-09-30

129

Implications of nanoscale based drug delivery systems in delivery and targeting tubulin binding agent, noscapine in cancer cells.  

PubMed

Noscapine, a tubulin binding anticancer agent undergoing Phase I/II clinical trials, inhibits tumor growth in nude mice bearing human xenografts of breast, lung, ovarian, brain, and prostrate origin. The analogues of noscapine like 9-bromonoscapine (EM011) are 5 to 10-fold more active than parent compound, noscapine. Noscapinoids inhibit the proliferation of cancer cells that are resistant to paclitaxel and epothilone. Noscapine also potentiated the anticancer activity of doxorubicin in a synergistic manner against triple negative breast cancer (TNBC). However, physicochemical and pharmacokinetic (ED50˜300-600 mg/kg bodyweight) limitations of noscapine present hurdle in development of commercial anticancer formulations. Therefore, objectives of the present review are to summarize the chemotherapeutic potential of noscapine and implications of nanoscale based drug delivery systems in enhancing the therapeutic efficacy of noscapine in cancer cells. We have constructed noscapine-enveloped gelatin nanoparticles, NPs and poly (ethylene glycol) grafted gelatin NPs as well as inclusion complex of noscapine in ?-cyclodextrin (?-CD) and evaluated their physicochemical characteristics. The Fe3O4 NPs were also used to incorporate noscapine in its polymeric nanomatrix system where molecular weight of the polymer governed the encapsulation efficiency of drug. The enhanced noscapine delivery using ?PAR-targeted optical-MR imaging trackable NPs offer a great potential for image directed targeted delivery of noscapine. Human Serum Albumin NPs (150-300 nm) as efficient noscapine drug delivery systems have also been developed for potential use in breast cancer. PMID:22571485

Chandra, Ramesh; Madan, Jitender; Singh, Prashant; Chandra, Ankush; Kumar, Pradeep; Tomar, Vartika; Dass, Sujata K

2012-12-01

130

Magnetic/NIR-thermally responsive hybrid nanogels for optical temperature sensing, tumor cell imaging and triggered drug release.  

PubMed

The paper demonstrates a class of multifunctional core-shell hybrid nanogels with fluorescent and magnetic properties, which have been successfully developed for simultaneous optical temperature sensing, tumor cell imaging and magnetic/NIR-thermally responsive drug carriers. The as-synthesized hybrid nanogels were designed by coating bifunctional nanoparticles (BFNPs, fluorescent carbon dots embedded in the porous carbon shell and superparamagnetic iron oxide nanocrystals clustered in the core) with a thermo-responsive poly(N-isopropylacrylamide-co-acrylamide) [poly(NIPAM-AAm)]-based hydrogel as the shell. The BFNPs in hybrid nanogels not only demonstrate excellent photoluminescence (PL) and photostability due to the fluorescent carbon dots embedded in the porous carbon shell, but also has targeted drug accumulation potential and a magnetic-thermal conversion ability due to the superparamagnetic iron oxide nanocrystals clustered in the core. The thermo-responsive poly(NIPAM-AAm)-based gel shell can not only modify the physicochemical environment of the BFNPs core to manipulate the fluorescence intensity for sensing the variation of the environmental temperature, but also regulate the release rate of the loaded anticancer drug (curcumin) by varying the local temperature of environmental media. In addition, the carbon layer of BFNPs can adsorb and convert the NIR light to heat, leading to a promoted drug release under NIR irradiation and improving the therapeutic efficacy of drug-loaded hybrid nanogels. Furthermore, the superparamagnetic iron oxide nanocrystals in the core of BFNPs can trigger localized heating using an alternating magnetic field, leading to a phase change in the polymer gel to trigger the release of loaded drugs. Finally, the multifunctional hybrid nanogels can overcome cellular barriers to enter the intracellular region and light up the mouse melanoma B16F10 cells. The demonstrated hybrid nanogels would be an ideal system for the biomedical applications due to their excellent optical properties, magnetic properties, high drug loading capacity and responsive drug release behavior. PMID:25243783

Wang, Hui; Yi, Jinhui; Mukherjee, Sumit; Banerjee, Probal; Zhou, Shuiqin

2014-11-01

131

Protein engineering for targeted delivery of radionuclides to tumors  

E-print Network

Traditional cancer treatment strategies include systemic chemotherapy, external beam radiation, and surgical excision. Chemotherapy is nonspecific, and targets all rapidly dividing cells. External beam radiation and surgery ...

Orcutt, Kelly Davis

2010-01-01

132

Nanomicellar carriers for targeted delivery of anticancer agents  

PubMed Central

Clinical application of anticancer drugs is limited by problems such as low water solubility, lack of tissue-specificity and toxicity. Formulation development represents an important approach to these problems. Among the many delivery systems studied, polymeric micelles have gained considerable attention owing to ease in preparation, small sizes (10–100 nm), and ability to solubilize water-insoluble anticancer drugs and accumulate specifically at the tumors. This article provides a brief review of several promising micellar systems and their applications in tumor therapy. The emphasis is placed on the discussion of the authors’ recent work on several nanomicellar systems that have both a delivery function and antitumor activity, named dual-function drug carriers. PMID:24341817

Zhang, Xiaolan; Huang, Yixian; Li, Song

2014-01-01

133

Nanogel formation from dilute solutions of clickable elastin-like recombinamers and its dependence on temperature: two fractal gelation modes.  

PubMed

Diluted, complementary, click-reactive elastin-like recombinamer (ELR) solutions have been prepared and mixed at two different temperatures, one below and one above the characteristic transition temperature (Tt) of these chemically modified ELRs. FTIR measurements, size, aspect ratio, zeta potential, and microrheological measurements have been carried out on the nanostructures formed under these dilute conditions as a way to better understand the relationship between the final macroscopic properties of ELR-based hydrogels and the molecular conditions governing the initial stages of the chemical cross-linking process that occurs, especially its dependence on the preparation temperature relative to Tt. As a result, two different fractal modes of gel formation have been found at the two temperatures studied (above and below Tt). Thus, when the reaction mixture is prepared below Tt, essentially one-dimensional linear nanogels with a high aspect ratio are obtained. In contrast, 3D nanogels are formed above Tt, with spherical shapes predominating. These different structures seem to reflect the two molecular organizations of the single components of the mixture under these conditions, namely extended chains below Tt and a spherical arrangement above Tt. In addition to the interest in these nanogels as models for understanding the formation of microscopic structures and differential macroscopic properties under more conventional hydrogel-formation conditions, these nanogels are of interest because of their thermoresponsiveness and biocompatibility, which provide them with potential uses for drug delivery and other biomedical applications in living systems. PMID:25068707

González de Torre, Israel; Quintanilla, Luis; Pinedo-Martín, Guillermo; Alonso, Matilde; Rodríguez-Cabello, José Carlos

2014-08-27

134

Local delivery of nitric oxide: targeted delivery of therapeutics to bone and connective tissues  

PubMed Central

Non-invasive treatment of injuries and disorders affecting bones and connective tissue is a significant challenge facing the medical community. A treatment route that has recently been proposed is nitric oxide (NO) therapy. Nitric oxide plays several roles in physiology with many conditions lacking adequate levels of NO. As NO is a radical, localized delivery via NO donors is essential to promoting biological activity. Herein, we review current literature related to therapeutic NO delivery in the treatment of bone, skin and tendon repair. PMID:22433782

Nichols, Scott P.; Storm, Wesley L.; Koh, Ahyeon; Schoenfisch, Mark H.

2012-01-01

135

Magnetic Targeted Delivery of Dexamethasone Acetate across the Round Window Membrane in Guinea Pigs  

PubMed Central

Hypothesis Magnetically susceptible PLGA nanoparticles will effectively target the round window membrane (RWM) for delivery of dexamethasone-acetate (Dex-Ac) to the scala tympani. Background Targeted delivery of therapeutics to specific tissues can be accomplished using different targeting mechanisms. One technology includes iron oxide nanoparticles, susceptible to external magnetic fields. If a nanocomposite composed of biocompatible polymer (PLGA), magnetite, and Dex-Ac can be pulled into and across the mammalian RWM, drug delivery can be enhanced. Method In vitro targeting and release kinetics of PLGA-magnetite-Dex-Ac nanoparticles first were measured using a RWM model. Next, these optimized nanocomposites were targeted to the RWM by filling the niche in anesthetized guinea pigs. A permanent magnet was placed opposite the RWM for 1 hour. Cochlear soft tissues, perilymph, and RWM were harvested after euthanasia and steroid levels were measured using HPLC. Results Membrane transport, in vitro, proved optimal targeting using a lower particle magnetite concentration (1 versus 5 or 10 mg/ml). In vivo targeted PLGA-magnetite-Dex-Ac particles had an average size of 482.8 ± 158 nm (DLS) and an average zeta potential ?19.9 ± 3.3 mV. In 1 hour, there was significantly increased cochlear targeted delivery of Dex or Dex-Ac, compared with diffusion alone. Conclusion Superparamagnetic PLGA-magnetite-Dex-Ac nanoparticles under an external magnetic field (0.26 mT) for 1 hour significantly increased Dex-Ac delivery to the inner ear. The RWM was not completely permeated and also became loaded with nanocomposites, indicating that delivery to the cochlea would continue for weeks by PLGA degradation and passive diffusion. PMID:23187928

Du, Xiaoping; Chen, Kejian; Kuriyavar, Satish; Kopke, Richard D.; Grady, Brian P.; Bourne, David H.; Li, Wei; Dormer, Kenneth J.

2012-01-01

136

Conceptual design report for the University of Rochester cryogenic target delivery system  

SciTech Connect

The upgrade of the Omega laser at the University of Rochester's Laboratory for Laser Energetics (UR/LLE) will result in a need for large targets filled with D[sub 2] or Dt and maintained at cryogenic temperatures. This mandates a cryogenic target delivery system capable of filling, layering, characterizing and delivering cryogenic targets to the Omega Upgrade target chamber. The program goal is to design, construct, and test the entire target delivery system by June 1996. When completed (including an operational demonstration), the system will be shipped to Rochester for reassembly and commissioning in time for the Omega Upgrade cryogenic campaign, scheduled to start in 1998. General Atomics has been assigned the task of developing the conceptual design for the cryogenic target delivery system. Design and fabrication activities will be closely coordinated with the University of Rochester, Lawrence Livermore National laboratory (LLNL) and Los Alamos National Laboratory (LANL), drawing upon their knowledge base in fuel layering and cryogenic characterization. The development of a target delivery system for Omega could also benefit experiments at Lawrence Livermore National Laboratory and the other ICF Laboratories in that the same technologies could be applied to NOVA, the National Ignition Facility or the future Laboratory Microfusion Facility.

Fagaly, R.L.; Alexander, N.B.; Bourque, R.F.; Dahms, C.F.; Lindgren, J.R.; Miller, W.J. (General Atomics, San Diego, CA (United States)); Bittner, D.N.; Hendricks, C.D. (W.J. Schafer Associates, Livermore, CA (United States))

1993-05-01

137

Conceptual design report for the University of Rochester cryogenic target delivery system  

SciTech Connect

The upgrade of the Omega laser at the University of Rochester`s Laboratory for Laser Energetics (UR/LLE) will result in a need for large targets filled with D{sub 2} or Dt and maintained at cryogenic temperatures. This mandates a cryogenic target delivery system capable of filling, layering, characterizing and delivering cryogenic targets to the Omega Upgrade target chamber. The program goal is to design, construct, and test the entire target delivery system by June 1996. When completed (including an operational demonstration), the system will be shipped to Rochester for reassembly and commissioning in time for the Omega Upgrade cryogenic campaign, scheduled to start in 1998. General Atomics has been assigned the task of developing the conceptual design for the cryogenic target delivery system. Design and fabrication activities will be closely coordinated with the University of Rochester, Lawrence Livermore National laboratory (LLNL) and Los Alamos National Laboratory (LANL), drawing upon their knowledge base in fuel layering and cryogenic characterization. The development of a target delivery system for Omega could also benefit experiments at Lawrence Livermore National Laboratory and the other ICF Laboratories in that the same technologies could be applied to NOVA, the National Ignition Facility or the future Laboratory Microfusion Facility.

Fagaly, R.L.; Alexander, N.B.; Bourque, R.F.; Dahms, C.F.; Lindgren, J.R.; Miller, W.J. [General Atomics, San Diego, CA (United States); Bittner, D.N.; Hendricks, C.D. [W.J. Schafer Associates, Livermore, CA (US)

1993-05-01

138

Lipid-Coated Nanoscale Coordination Polymers for Targeted Delivery of Antifolates to Cancer Cells  

PubMed Central

Nanoscale coordination polymers (NCPs) have been demonstrated as an interesting platform for drug delivery, as they possess many advantages over small-molecule chemotherapeutics, such as high payloads, lower systemic toxicity, tunability, and enhanced tumor uptake. Existing formulations for the delivery of methotrexate (MTX), an antifolate cancer drug, have very low drug loadings. Herein, we report the incorporation of MTX as a building block in an NCP formulation with exceptionally high drug loadings (up to 79.1 wt%) and the selective delivery of the NCP to cancer cells. Encapsulation of the NCP in a functionalized lipid bilayer allows for targeted delivery and controlled release to cancer cells. A phosphor can be doped into the NCPs for monitoring particle uptake by optical imaging. The lipid-coated and anisamide-targeted NCPs have superior in vitro efficacy against acute lymphoblastic leukemia cells when compared to free drug. PMID:24288587

Huxford, Rachel C.; deKrafft, Kathryn E.; Boyle, William S.; Liu, Demin

2013-01-01

139

New Lipid and Glycolipid-Based Nanosystems for Targeted Gene Delivery: Cholenims, Glycoclips, Glycolipids and Chitosan  

Microsoft Academic Search

Cationic lipid vesicles and polypeptides represent common non-viral gene delivery systems for in vitro and in vivo applications.\\u000a New non-viral vectors for targeted gene delivery, namely, mono-, di- and tricholesterol derivatives of oligoethyleneimine,\\u000a glycolipids and chitosan derivatives are reported in this chapter. Testing of genotoxicity, cytotoxicity and gene transfer\\u000a activity against transformed monolayer and suspension cell cultures is carried out

R. I. Zhdanov; E. V. Bogdanenko; T. V. Zarubina; S. I. Dominova; G. G. Krivtsov; A. S. Borisenko; A. S. Bogdanenko; G. A. Serebrennikova; Yu. L. Sebyakin; V. V. Vlassov

140

Aptamer-targeted DNA nanostructures for therapeutic delivery.  

PubMed

DNA-based nanostructures have been widely used in various applications due to their structural diversity, programmability, and uniform structures. Their intrinsic biocompatibility and biodegradability further motivates the investigation of DNA-based nanostructures as delivery vehicles. Incorporating AS1411 aptamers into DNA pyramids leads to enhanced intracellular uptake and selectively inhibits the growth of cancer cells, achieved without the use of transfection reagents. Furthermore, aptamer-displaying pyramids are found to be substantially more resistant to nuclease degradation than single-stranded aptamers. These findings, along with their modularity, reinforce the potential of DNA-based nanostructures for therapeutic applications. PMID:24739136

Charoenphol, Phapanin; Bermudez, Harry

2014-05-01

141

PR_b-targeted delivery of tumor necrosis factor-a by polymersomes for the treatment of prostate cancer  

E-print Network

PR_b-targeted delivery of tumor necrosis factor-a by polymersomes for the treatment of prostate. In this study we design and assess peptide functionalized polymer vesicles, or polymersomes, self assembled from of these PR_b-targeted polymersomes show great promise for the targeted delivery of therapeutics. Introduction

Kokkoli, Efie

142

Challenges in design and characterization of ligand-targeted drug delivery systems  

PubMed Central

Targeting of therapeutic agents to molecular markers expressed on the surface of cells requiring clinical intervention holds promise to improve specificity of delivery, enhancing therapeutic effects while decreasing potential damage to healthy tissues. Drug targeting to cellular receptors involved in endocytic transport facilitates intracellular delivery, a requirement for a number of therapeutic goals. However, after several decades of experimental design, there is still considerable controversy on the practical outcome of drug targeting strategies. The plethora of factors contributing to the relative efficacy of targeting makes the success of these approaches hardly predictable. Lack of fully specific targets, along with selection of targets with spatial and temporal expression well aligned to interventional requirements, pose difficulties to this process. Selection of adequate sub-molecular target epitopes determines accessibility for anchoring of drug conjugates and bulkier drug carriers, as well as proper signaling for uptake within the cell. Targeting design must adapt to physiological variables of blood flow, disease status, and tissue architecture by accommodating physicochemical parameters such as carrier composition, functionalization, geometry, and avidity. In many cases, opposite features need to meet a balance, e.g., sustained circulation versus efficient targeting, penetration through tissues versus uptake within cells, internalization within endocytic compartment to avoid efflux pumps versus accessibility to molecular targets within the cytosol, etc. Detailed characterization of these complex physiological factors and design parameters, along with a deep understanding of the mechanisms governing the interaction of targeted drugs and carriers with the biological environment, are necessary steps toward achieving efficient drug targeting systems. PMID:22709588

Muro, Silvia

2012-01-01

143

Dendritic polymer-based nanodevices for targeted drug delivery applications  

NASA Astrophysics Data System (ADS)

Dendrimers and hyperbranched polymers are unimolecular micellar nanostructures, characterized by globular shape ( ˜ 20 nm) and large density of functional groups at periphery. The tailorable end groups make them ideal for conjugation with drugs, ligands, and imagining agents, making them an attractive molecular nanodevices for drug delivery. Compared to linear polymers and nanoparticles, these nanodevices enter cells rapidly, carrying drugs and delivering them inside cells. Performance of nanodevices prepared for asthma and cancer drug delivery will be discussed. Our conjugation procedure produced very high drug payloads. Dendritic polymer-drug conjugates were very effective in transporting methotrexate (a chemotherapy drug) into both sensitive (CCRF-CEM cell line) and resistant cell line (CEM-MTX). The conjugate nanodevice was 3 times more effective than free drug in the sensitive line, and 9 times more effective in the resistant cell line (based on IC50). The physics of cell entry and drug release from these nanodevices are being investigated. The conjugates appear to enter cells through endocytosis, with the rate of entry dependent on end-group, molecular weight, the pH of the medium, and the cancerous nature of the cells.

Kannan, R. M.; Kolhe, Parag; Gurdag, Sezen; Khandare, Jayant; Lieh-Lai, Mary

2004-03-01

144

Targeted Delivery System of Nanobiomaterials in Anticancer Therapy: From Cells to Clinics  

PubMed Central

Targeted delivery systems of nanobiomaterials are necessary to be developed for the diagnosis and treatment of cancer. Nanobiomaterials can be engineered to recognize cancer-specific receptors at the cellular levels and to deliver anticancer drugs into the diseased sites. In particular, nanobiomaterial-based nanocarriers, so-called nanoplatforms, are the design of the targeted delivery systems such as liposomes, polymeric nanoparticles/micelles, nanoconjugates, norganic materials, carbon-based nanobiomaterials, and bioinspired phage system, which are based on the nanosize of 1–100?nm in diameter. In this review, the design and the application of these nanoplatforms are discussed at the cellular levels as well as in the clinics. We believe that this review can offer recent advances in the targeted delivery systems of nanobiomaterials regarding in vitro and in vivo applications and the translation of nanobiomaterials to nanomedicine in anticancer therapy. PMID:24672796

Jin, Su-Eon; Jin, Hyo-Eon; Hong, Soon-Sun

2014-01-01

145

Tuning Pharmacokinetics and Biodistribution of a Targeted Drug Delivery System Through Incorporation of a Passive Targeting Component  

PubMed Central

Major challenges in the development of drug delivery systems (DDSs) have been the short half-life, poor bioavailability, insufficient accumulation and penetration of the DDSs into the tumor tissue. Understanding the pharmacokinetic (PK) parameters of the DDS is essential to overcome these challenges. Herein we investigate how surface chemistry affects the PK profile and organ distribution of a gold nanoparticle-based DDS containing both a passive and active targeting moiety via two common routes of administration: intravenous and intraperitoneal injections. Using LC/MS/MS, ELISA and INAA we report the half-life, peak plasma concentrations, area under the curve, ability to cross the peritoneal barrier and biodistribution of the nanoconjugates. The results highlight the design criteria for fine-tuning the PK parameters of a targeted drug delivery system that exploits the benefits of both active and passive targeting. PMID:25011609

Kudgus, Rachel A.; Walden, Chad A.; McGovern, Renee M.; Reid, Joel M.; Robertson, J. David; Mukherjee, Priyabrata

2014-01-01

146

Novel Drug Delivery System Shows Early Promise for Treating Lupus in Mice  

MedlinePLUS

... System Shows Early Promise for Treating Lupus in Mice A drug delivery system using nanoparticle technology that ... administered the MPA-loaded nanogel to lupus-prone mice that had not yet developed symptoms of the ...

147

Impacts of Blood-Brain Barrier in Drug Delivery and Targeting of Brain Tumors  

PubMed Central

Introduction Entry of blood circulating agents into the brain is highly selectively con-trolled by specific transport machineries at the blood brain barrier (BBB), whose excellent barrier restrictiveness make brain drug delivery and targeting very challenging. Methods Essential information on BBB cellular microenvironment were reviewed and discussed towards impacts of BBB on brain drug delivery and targeting. Results Brain capillary endothelial cells (BCECs) form unique biological structure and architecture in association with astrocytes and pericytes, in which microenvironment the BCECs express restrictive tight junctional complexes that block the paracellular inward/outward traverse of biomolecules/compounds. These cells selectively/specifically control the transportation process through carrier and/or receptor mediated transport machineries that can also be exploited for the delivery of pharmaceuticals into the brain. Intelligent molecular therapies should be designed using such transport machineries for the efficient delivery of designated drugs into the brain. For better clinical outcomes, these smart pharmaceuticals should be engineered as seamless nanosystems to provide simultaneous imaging and therapy (multimodal theranostics). Conclusion The exceptional functional presence of BBB selectively controls inward and outward transportation mechanisms, thus advanced smart multifunctional nanomedicines are needed for the effective brain drug delivery and targeting. Fully understanding the biofunctions of BBB appears to be a central step for engineering of intelligent seamless therapeutics consisting of homing device for targeting, imaging moiety for detecting, and stimuli responsive device for on-demand liberation of therapeutic agent. PMID:23678437

Omidi, Yadollah; Barar, Jaleh

2012-01-01

148

A polyvalent aptamer system for targeted drug delivery.  

PubMed

Poor efficacy and off-target systemic toxicity are major problems associated with current chemotherapeutic approaches to treat cancer. We developed a new form of polyvalent therapeutics that is composed of multiple aptamer units synthesized by rolling circle amplification and physically intercalated chemotherapy agents (termed as "Poly-Aptamer-Drug"). Using a leukemia cell-binding aptamer and doxorubicin as a model system, we have successfully constructed Poly-Aptamer-Drug systems and demonstrated that the Poly-Aptamer-Drug is significantly more effective than its monovalent counterpart in targeting and killing leukemia cells due to enhanced binding affinity (? 40 fold greater) and cell internalization via multivalent effects. We anticipate that our Poly-Aptamer-Drug approach will yield new classes of tunable therapeutics that can be utilized to effectively target and treat cancers while minimizing the side effects of chemotherapy. PMID:24044994

Zhang, Zhiqing; Ali, M Monsur; Eckert, Mark A; Kang, Dong-Ku; Chen, Yih Yang; Sender, Leonard S; Fruman, David A; Zhao, Weian

2013-12-01

149

Nanogel surface coatings for improved single-molecule imaging substrates  

E-print Network

Nanogel surface coatings for improved single-molecule imaging substrates Lee A. Tessler1, Casey D counting revealed that nanogel-coated surfaces exhibit lower protein adsorp- tion than covalently coupled-background surface coatings have been developed that reduce protein adsorption to SM levels--levels at which

Mitra, Rob

150

Synthesis and Evaluation of Fluorescent Magnetic Composites as Targeted Drug Delivery Carriers  

NASA Astrophysics Data System (ADS)

We have developed Fe3O4@ZnS-based fluorescent magnetic composites as targeted drug delivery carriers via a facile route. The results indicated that the composites exhibited both magnetic and fluorescent properties. Fe3O4@ZnS possessed high saturation magnetization (68.25 emu/g) at room temperature. Ultraviolet light can be easily obtained by exposing the microspheres to different excitation wavelengths. The drug loading studies showed that Fe3O4@ZnS-based fluorescent magnetic composites had an excellent drug loading performance. These traits made the composites better for the application of medical imaging and magnetic targeted drug delivery.

Jiang, Wei; Chen, Xiaolong; Wu, Juan; Xu, Shanshan; Tian, Renbing

2015-01-01

151

An Efficient Targeted Drug Delivery through Apotransferrin Loaded Nanoparticles  

Microsoft Academic Search

BackgroundCancerous state is a highly stimulated environment of metabolically active cells. The cells under these conditions over express selective receptors for assimilation of factors essential for growth and transformation. Such receptors would serve as potential targets for the specific ligand mediated transport of pharmaceutically active molecules. The present study demonstrates the specificity and efficacy of protein nanoparticle of apotransferrin for

Athuluri Divakar Sai Krishna; Raj Kumar Mandraju; Golla Kishore; Anand Kumar Kondapi

2009-01-01

152

The application of carbon nanotubes in target drug delivery systems for cancer therapies  

PubMed Central

Among all cancer treatment options, chemotherapy continues to play a major role in killing free cancer cells and removing undetectable tumor micro-focuses. Although chemotherapies are successful in some cases, systemic toxicity may develop at the same time due to lack of selectivity of the drugs for cancer tissues and cells, which often leads to the failure of chemotherapies. Obviously, the therapeutic effects will be revolutionarily improved if human can deliver the anticancer drugs with high selectivity to cancer cells or cancer tissues. This selective delivery of the drugs has been called target treatment. To realize target treatment, the first step of the strategies is to build up effective target drug delivery systems. Generally speaking, such a system is often made up of the carriers and drugs, of which the carriers play the roles of target delivery. An ideal carrier for target drug delivery systems should have three pre-requisites for their functions: (1) they themselves have target effects; (2) they have sufficiently strong adsorptive effects for anticancer drugs to ensure they can transport the drugs to the effect-relevant sites; and (3) they can release the drugs from them in the effect-relevant sites, and only in this way can the treatment effects develop. The transporting capabilities of carbon nanotubes combined with appropriate surface modifications and their unique physicochemical properties show great promise to meet the three pre-requisites. Here, we review the progress in the study on the application of carbon nanotubes as target carriers in drug delivery systems for cancer therapies. PMID:21995320

2011-01-01

153

Delivery of Small Interfering RNA by Peptide-Targeted Mesoporous Silica Nanoparticle-Supported Lipid Bilayers  

PubMed Central

The therapeutic potential of small interfering RNAs (siRNAs) is severely limited by the availability of delivery platforms that protect siRNA from degradation, deliver it to the target cell with high specificity and efficiency, and promote its endosomal escape and cytosolic dispersion. Here we report that mesoporous silica nanoparticle-supported lipid bilayers (or ‘protocells’), exhibit multiple properties that overcome many of the limitations of existing delivery platforms. Protocells have a 10- to 100-fold greater capacity for siRNA than corresponding lipid nanoparticles and are markedly more stable when incubated under physiological conditions. Protocells loaded with a cocktail of siRNAs bind to cells in a manner dependent on the presence of an appropriate targeting peptide and, through an endocytic pathway followed by endosomal disruption, promote delivery of the silencing nucleotides to the cytoplasm. The expression of each of the genes targeted by the siRNAs was shown to be repressed at the protein level, resulting in a potent induction of growth arrest and apoptosis. Incubation of control cells that lack expression of the antigen recognized by the targeting peptide with siRNA-loaded protocells induced neither repression of protein expression nor apoptosis, indicating the precise specificity of cytotoxic activity. In terms of loading capacity, targeting capabilities, and potency of action, protocells provide unique attributes as a delivery platform for therapeutic oligonucleotides. PMID:22309035

Ashley, Carlee E.; Carnes, Eric C.; Epler, Katharine E.; Padilla, David P.; Phillips, Genevieve K.; Castillo, Robert E.; Wilkinson, Dan C.; Wilkinson, Brian S.; Burgard, Cameron A.; Sewell, Robin M.; Townson, Jason L.; Chackerian, Bryce; Willman, Cheryl L.; Peabody, David S.; Wharton, Walker; Brinker, C. Jeffrey

2012-01-01

154

A Nonpolycationic Fully Proteinaceous Multiagent System for Potent Targeted Delivery of siRNA.  

PubMed

Protein-based methods of targeted short-interfering RNA (siRNA) delivery have the potential to solve some of the problems faced by nanoparticle-based methods, such as poor pharmacokinetics and biodistribution, low tumor penetration, and polydispersity. However, protein-based targeted delivery has been limited to fusion proteins with polycationic peptides as siRNA carriers, whose high charge density in some cases results in undesirable biophysical and in vivo properties. Here, we present a fully proteinaceous, multiagent approach for targeted siRNA delivery to epidermal growth factor receptor (EGFR), using a nonpolycationic carrier for siRNA. Each agent contributes a fundamentally different mechanism of action that work together for potent targeted RNA interference. The first agent is an EGFR-targeted fusion protein that uses a double-stranded RNA-binding domain as a nonpolycationic siRNA carrier. This double-stranded RNA-binding domain fusion protein can deliver siRNA to the endosomes of an EGFR-expressing cell line. A second agent delivers the cholesterol-dependent cytolysin, perfringolysin O, in a targeted manner, which enhances the endosomal escape of siRNA and induces gene silencing. A third agent that clusters EGFR increases gene-silencing potency and decreases cytolysin toxicity. Altogether, this system is potent, with only 16 nmol/l siRNA required for gene silencing and a therapeutic window that spans two orders of magnitude of targeted cytolysin concentrations. PMID:24825362

Liu, David V; Yang, Nicole J; Wittrup, K Dane

2014-01-01

155

Methotrexate delivery via folate targeted dendrimer-based nanotherapeutic platform  

PubMed Central

This paper provides a synopsis of the advancements made in advancing a dendrimer-based nanomedicine towards human clinical trials by the Michigan Nanotechnology Institute for Medicine and Biological Sciences. A brief description of the synthesis and characterization of a targeted multifunctional therapeutic will demonstrate the simple yet delicate task of producing novel chemotherapeutic agents. The results obtained from in vitro and in vivo studies not only authenticate the potential of using nanoparticles to target therapeutics but also provide valuable insight towards the future directions of this technology. A fundamental, cross-disciplinary collaboration was necessary to achieve the synthesis and testing of this technology, and was the keystone to establishing this innovative invention. Throughout this paper, we will stress that the unique collaboration that facilitated the evolution of this technology is vital to the success of future developments in nanomedicine. PMID:20049813

Majoros, István J.; Williams, Christopher R.; Becker, Andrew; Baker, James R.

2010-01-01

156

Azo polymeric hydrogels for colon targeted drug delivery.  

PubMed

Azo polymeric hydrogels were developed for colon specific targeting. Methacryloyloxy azobenzene was synthesized and hydrogels were prepared by copolymerizing with hydroxyethyl methacrylate. These hydrogels were characterized by various spectral techniques such as Fourier transform infrared spectroscopy, thermogravimetric analysis and scanning electron microscopy. Equilibrium swelling measurements of the hydrogels were carried out in distilled water and also in simulated gastric and intestinal fluids. The in vitro release studies of the incorporated 5-flurouracil were carried out in simulated gastric and intestinal fluids. The in vitro release profiles of the drug were also obtained in the presence of azoreductase in the culture of intestinal flora. The release was faster and almost followed a zero order pattern. This can be attributed to the cleavage of the azo crosslinks in the hydrogel by the azoreductase and the release of the entrapped drug at the site of targeting i.e., colon. PMID:8573669

Shantha, K L; Ravichandran, P; Rao, K P

1995-11-01

157

A new acivicin prodrug designed for tumor-Targeted delivery  

Microsoft Academic Search

Acivicin is an antitumor agent known to inhibit cell growth. A new prodrug 9b of acivicin 10 was synthesized, based on a p-hydroxybenzylcarbamate self-immolative spacer capable to release acivicin under esterase activity. The prodrug includes a maleimide-containing arm for linkage with thiol-containing macromolecules such as antibodies. This molecule is intended for the conception of bioconjugates to target an inactive acivicin

Christophe Antczak; Brigitte Bauvois; Claude Monneret; Jean-Claude Florent

2001-01-01

158

Near-infrared-controlled, targeted hydrophobic drug-delivery system for synergistic cancer therapy.  

PubMed

Hydrophobicity has been an obstacle that hinders the use of many anticancer drugs. A critical challenge for cancer therapy concerns the limited availability of effective biocompatible delivery systems for most hydrophobic therapeutic anticancer drugs. In this study, we have developed a targeted near-infrared (NIR)-regulated hydrophobic drug-delivery platform based on gold nanorods incorporated within a mesoporous silica framework (AuMPs). Upon application of NIR light, the photothermal effect of the gold nanorods leads to a rapid rise in the local temperature, thus resulting in the release of the entrapped drug molecules. By integrating chemotherapy and photothermotherapy into one system, we have studied the therapeutic effects of camptothecin-loaded AuMP-polyethylene glycol-folic acid nanocarrier. Results revealed a synergistic effect in vitro and in vivo, which would make it possible to enhance the therapeutic effect of hydrophobic drugs and decrease drug side effects. Studies have shown the feasibility of using this nanocarrier as a targeted and noninvasive remote-controlled hydrophobic drug-delivery system with high spatial/temperal resolution. Owing to these advantages, we envision that this NIR-controlled, targeted drug-delivery method would promote the development of high-performance hydrophobic anticancer drug-delivery system in future clinical applications. PMID:23765904

Yang, Xinjian; Liu, Zhen; Li, Zhenhua; Pu, Fang; Ren, Jinsong; Qu, Xiaogang

2013-07-29

159

Tetanus toxin C fragment conjugated nanoparticles for targeted drug delivery to neurons  

PubMed Central

The use of nanoparticles for targeted drug delivery is often facilitated by specific conjugation of functional targeting molecules to the nanoparticle surface. We compared different biotin binding proteins (avidin, streptavidin, or neutravidin) as crosslinkers to conjugate proteins to biodegradable nanoparticles prepared from PLGA-PEG-biotin polymers. Avidin gave the highest levels of overall protein conjugation, whereas neutravidin minimized protein non-specific binding to the polymer. The tetanus toxin C fragment (TTC), which is efficiently retrogradely transported in neurons and binds to neurons with high specificity and affinity, retained the ability to bind to neuroblastoma cells following amine group modifications. TTC was conjugated to nanoparticles using neutravidin, and the resulting nanoparticles were shown to selectively target neuroblastoma cells in vitro. TTC-conjugated nanoparticles have the potential to serve as drug delivery vehicles targeted to the central nervous system. PMID:17854886

Townsend, Seth A.; Evrony, Gilad D.; Gu, Frank X.; Schulze, Martin P.; Brown, Robert H.; Langer, Robert S.

2008-01-01

160

Transferrin receptor-targeted theranostic gold nanoparticles for photosensitizer delivery in brain tumors  

NASA Astrophysics Data System (ADS)

Therapeutic drug delivery across the blood-brain barrier (BBB) is not only inefficient, but also nonspecific to brain stroma. These are major limitations in the effective treatment of brain cancer. Transferrin peptide (Tfpep) targeted gold nanoparticles (Tfpep-Au NPs) loaded with the photodynamic pro-drug, Pc 4, have been designed and compared with untargeted Au NPs for delivery of the photosensitizer to brain cancer cell lines. In vitro studies of human glioma cancer lines (LN229 and U87) overexpressing the transferrin receptor (TfR) show a significant increase in cellular uptake for targeted conjugates as compared to untargeted particles. Pc 4 delivered from Tfpep-Au NPs clusters within vesicles after targeting with the Tfpep. Pc 4 continues to accumulate over a 4 hour period. Our work suggests that TfR-targeted Au NPs may have important therapeutic implications for delivering brain tumor therapies and/or providing a platform for noninvasive imaging.

Dixit, Suraj; Novak, Thomas; Miller, Kayla; Zhu, Yun; Kenney, Malcolm E.; Broome, Ann-Marie

2015-01-01

161

Overcoming the stromal barrier for targeted delivery of HPMA copolymers to pancreatic tumors.  

PubMed

Delivery of macromolecules to pancreatic cancer is inhibited by a dense extracellular matrix composed of hyaluronic acid, smooth muscle actin and collagen fibers. Hyaluronic acid causes a high intratumoral fluidic pressure which prevents diffusion and penetration into the pancreatic tumor. This study involves the breaking down of hyaluronic acid by treating CAPAN-1 xenograft tumors in athymic nu/nu mice with targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers radiolabeled with (111)In for single photon emission computerized tomography (SPECT) imaging. Two targeting strategies were investigated including ?v?3 integrin and HER2 receptors. HPMA copolymers were targeted to these receptors by conjugating short peptide ligands cRGDfK and KCCYSL to the side chains of the copolymer. Results demonstrate that tumor targeting can be achieved in vivo after treatment with hyaluronidase. This approach shows promise for enhanced delivery of polymer-peptide conjugates to solid tumors. PMID:23933441

Buckway, Brandon; Wang, Yongjian; Ray, Abhijit; Ghandehari, Hamidreza

2013-11-01

162

Glycyrrhetinic acid-modified chitosan\\/poly(ethylene glycol) nanoparticles for liver-targeted delivery  

Microsoft Academic Search

A liver-targeted drug delivery carrier, composed of chitosan\\/poly(ethylene glycol)–glycyrrhetinic acid (CTS\\/PEG–GA) nanoparticles, was prepared by an ionic gelation process, in which glycyrrhetinic acid (GA) acted as the targeting ligand. The formation and characterization of these nanoparticles were confirmed by FT-IR, dynamic light scattering (DLS) and zeta potential measurements. The biodistribution of the nanoparticles was assessed by single-photon emission computed tomography

Qin Tian; Chuang-Nian Zhang; Xiu-Hua Wang; Wei Wang; Wei Huang; Rui-Tao Cha; Chun-Hong Wang; Zhi Yuan; Min Liu; Hai-Ying Wan; Hua Tang

2010-01-01

163

Biomolecular corona on nanoparticles: a survey of recent literature and its implications in targeted drug delivery  

PubMed Central

Achieving controlled cellular responses of nanoparticles (NP) is critical for the successful development and translation of NP-based drug delivery systems. However, precise control over the physicochemical and biological properties of NPs could become convoluted, diminished, or completely lost as a result of the adsorption of biomolecules to their surfaces. Characterization of the formation of the “biomolecular” corona has thus received increased attention due to its impact on NP and protein structure as well as its negative effect on NP-based targeted drug delivery. This review presents a concise survey of the recent literature concerning the importance of the NP-biomolecule corona and how it can be utilized to improve the in vivo efficacy of targeted delivery systems. PMID:25506050

Pearson, Ryan M.; Juettner, Vanessa V.; Hong, Seungpyo

2014-01-01

164

Chlorotoxin-conjugated graphene oxide for targeted delivery of an anticancer drug  

PubMed Central

Current chemotherapy for glioma is rarely satisfactory due to low therapeutic efficiency and systemic side effects. We have developed a glioma-targeted drug delivery system based on graphene oxide. Targeted peptide chlorotoxin-conjugated graphene oxide (CTX-GO) sheets were successfully synthesized and characterized. Doxorubicin was loaded onto CTX-GO (CTX-GO/DOX) with high efficiency (570 mg doxorubicin per gram CTX-GO) via noncovalent interactions. Doxorubicin release was pH-dependent and showed sustained-release properties. Cytotoxicity experiments demonstrated that CTX-GO/DOX mediated the highest rate of death of glioma cells compared with free doxorubicin or graphene oxide loaded with doxorubicin only. Further, conjugation with chlorotoxin enhanced accumulation of doxorubicin within glioma cells. These findings indicate that CTX-GO is a promising platform for drug delivery and provide a rationale for developing a glioma-specific drug delivery system. PMID:24672236

Wang, Hao; Gu, Wei; Xiao, Ning; Ye, Ling; Xu, Qunyuan

2014-01-01

165

Targeted delivery of Epirubicin to cancer cells by PEGylated A10 aptamer.  

PubMed

Clinical administrations of anthracyclines are limited by cardiotoxicity and myelosuppression. Targeted delivery of anticancer agents is especially important in reducing their side effects. In this work, A10 (Apt), an aptamer for prostate-specific membrane anytigen (PSMA), was applied for targeted delivery of Epirubicin (Epi) to LNCaP cells (PSMA(+)). Flow cytometry analysis showed that PEG-Apt-Epi complex was internalized effectively to LNCaP cells (PSMA(+)), but not to PC3 cells (PSMA(-)). This fact was confirmed by less cytotoxicity of PEG-Apt-Epi complex in PC3 cells in comparison with Epi alone. No significant change in viability between Epi- and complex-treated LNCaP cells was observed. In conclusion, PEG-Apt-Epi complex is an efficient and simple system for specific delivery of drug to PSMA-expressing cell lines. PMID:23815443

Taghdisi, Seyed Mohammad; Danesh, Noor Mohammad; Sarreshtehdar Emrani, Ahmad; Tabrizian, Kaveh; Zandkarimi, Majid; Ramezani, Mohammad; Abnous, Khalil

2013-09-01

166

Targeting blood–brain barrier changes during inflammatory pain: an opportunity for optimizing CNS drug delivery  

PubMed Central

The blood–brain barrier (BBB) is the most significant obstacle to effective CNS drug delivery. It possesses structural and biochemical features (i.e., tight-junction protein complexes and, influx and efflux transporters) that restrict xenobiotic permeation. Pathophysiological stressors (i.e., peripheral inflammatory pain) can alter BBB tight junctions and transporters, which leads to drug-permeation changes. This is especially critical for opioids, which require precise CNS concentrations to be safe and effective analgesics. Recent studies have identified molecular targets (i.e., endogenous transporters and intracellular signaling systems) that can be exploited for optimization of CNS drug delivery. This article summarizes current knowledge in this area and emphasizes those targets that present the greatest opportunity for controlling drug permeation and/or drug transport across the BBB in an effort to achieve optimal CNS opioid delivery. PMID:22468221

Ronaldson, Patrick T; Davis, Thomas P

2012-01-01

167

Magnetofection: enhancing and targeting gene delivery by magnetic force in vitro and in vivo  

Microsoft Academic Search

Low efficiencies of nonviral gene vectors, the receptor-dependent host tropism of adenoviral or low titers of retroviral vectors limit their utility in gene therapy. To overcome these deficiencies, we associated gene vectors with superparamagnetic nanoparticles and targeted gene delivery by application of a magnetic field. This potentiated the efficacy of any vector up to several hundred-fold, allowed reduction of the

F. Scherer; M. Anton; U. Schillinger; J. Henkel; C. Bergemann; A. Kruger; B. Gansbacher; C. Plank

2002-01-01

168

Targeted delivery of chlorotoxin-modified DNA-loaded nanoparticles to glioma via intravenous administration  

Microsoft Academic Search

Gene therapy offers great potential for brain glioma. However, therapeutic genes could not reach glioma spontaneously. A glioma-targeting gene delivery system is highly desired to transfer exogenous genes throughout the tumor focus. In this study, the nanoscopic high-branching dendrimer, polyamidoamine (PAMAM), was selected as the main vector. Chlorotoxin (CTX), which has been demonstrated to bind specifically to receptor expressed in

Rongqin Huang; Weilun Ke; Liang Han; Jianfeng Li; Shuhuan Liu; Chen Jiang

2011-01-01

169

Towards multifunctional, targeted drug delivery systems using mesoporous silica nanoparticles - opportunities & challenges  

NASA Astrophysics Data System (ADS)

One of the big challenges of medicine today is to deliver drugs specifically to defected cells. Nanoparticulate drug carriers have the potential to answer to this call, as nanoparticles can cross physiological barriers and access different tissues, and also be provided in a targetable form aimed at enhancing cell specificity of the carrier. Recent developments within material science and strong collaborative efforts crossing disciplinary borders have highlighted the potential of mesoporous silica nanoparticles (MSNs) for such targeted drug delivery. Here we outline recent advances which in this sense push MSNs to the forefront of drug delivery development. Relatively straightforward inside-out tuning of the vehicles, high flexibility, and potential for sophisticated release mechanisms make these nanostructures promising candidates for targeted drug delivery such as `smart' cancer therapies. Moreover, due to the large surface area and the controllable surface functionality of MSNs, they can be controllably loaded with large amounts of drugs and coupled to homing molecules to facilitate active targeting, simultaneously carrying traceable (fluorescent or magnetically active) modalities, also making them highly interesting as theragnostic agents. However, the increased relative surface area and small size, and flexible surface functionalization which is beneficially exploited in nanomedicine, consequently also includes potential risks in their interactions with biological systems. Therefore, we also discuss some safety issues regarding MSNs and highlight how different features of the drug delivery platform influence their behaviour in a biological setting. Addressing these burning questions will facilitate the application of MSNs in nanomedicine.

Rosenholm, Jessica M.; Sahlgren, Cecilia; Lindén, Mika

2010-10-01

170

TARGETED DELIVERY OF INHALED PHARMACEUTICALS USING AN IN SILICO DOSIMETRY MODEL  

EPA Science Inventory

We present an in silico dosimetry model which can be used for inhalation toxicology (risk assessment of inhaled air pollutants) and aerosol therapy ( targeted delivery of inhaled drugs). This work presents scientific and clinical advances beyond the development of the original in...

171

Self-assembled hybrid nanoparticles for targeted co-delivery of two drugs into cancer cells.  

PubMed

A therapeutic aptamer-lipid-poly(lactide-co-glycolic acid) hybrid nanoparticle-based drug delivery system was prepared and characterized. This system can co-deliver two different drugs with distinct solubility and different anticancer mechanisms to target cancer cells with high specificity and efficiency. PMID:24516863

Huang, Fujian; You, Mingxu; Chen, Tao; Zhu, Guizhi; Liang, Haojun; Tan, Weihong

2014-03-21

172

Cell-specific aptamers and their conjugation with nanomaterials for targeted drug delivery.  

PubMed

Introduction: Aptamers are short, single-stranded DNA or RNA sequences that can fold into complex secondary and tertiary structures and bind to various target molecules with high affinity and specificity. These properties, as well as rapid tissue penetration and ease of chemical modification, make aptamers ideal recognition elements for in vivo targeted drug delivery and attractive molecules for use in disease diagnosis and therapy. Areas covered: The general properties of aptamers as well as advantages over their counterpart antibodies are briefly discussed. Next, aptamer selection by cell- systematic evolution of ligands by exponential enrichment is described in detail. Finally, the review summarizes recent progress in the field of targeted drug delivery based on aptamers and their conjugation to liposomes, micelles and other nanomaterials. Expert opinion: Advances in nanotechnology have led to new and improved nanomaterials for biomedical applications. Conjugation of nanoparticles (NPs) with aptamers exploits both technologies, making aptamer-NP conjugates ideal agents for drug delivery with proven therapeutic effects and the reduction of toxicity to normal tissue. The use of multivalent aptamer-conjugated nanomaterials represents one of the new directions for drug development in the future; as such, continuing studies of these multivalent aptamers and bioconjugates should result in important clinical applications in targeted drug delivery. PMID:25430795

Liao, Jie; Liu, Bo; Liu, Jun; Zhang, Jiani; Chen, Ke; Liu, Huixia

2014-11-28

173

Theranostic Nanoparticles Carrying Doxorubicin Attenuate Targeting Ligand Specific Antibody Responses Following Systemic Delivery  

PubMed Central

Understanding the effects of immune responses on targeted delivery of nanoparticles is important for clinical translations of new cancer imaging and therapeutic nanoparticles. In this study, we found that repeated administrations of magnetic iron oxide nanoparticles (IONPs) conjugated with mouse or human derived targeting ligands induced high levels of ligand specific antibody responses in normal and tumor bearing mice while injections of unconjugated mouse ligands were weakly immunogenic and induced a very low level of antibody response in mice. Mice that received intravenous injections of targeted and polyethylene glycol (PEG)-coated IONPs further increased the ligand specific antibody production due to differential uptake of PEG-coated nanoparticles by macrophages and dendritic cells. However, the production of ligand specific antibodies was markedly inhibited following systemic delivery of theranostic nanoparticles carrying a chemotherapy drug, doxorubicin. Targeted imaging and histological analysis revealed that lack of the ligand specific antibodies led to an increase in intratumoral delivery of targeted nanoparticles. Results of this study support the potential of further development of targeted theranostic nanoparticles for the treatment of human cancers. PMID:25553097

Yang, Emmy; Qian, Weiping; Cao, Zehong; Wang, Liya; Bozeman, Erica N.; Ward, Christina; Yang, Bin; Selvaraj, Periasamy; Lipowska, Malgorzata; Wang, Y. Andrew; Mao, Hui; Yang, Lily

2015-01-01

174

Depth-targeted transvascular drug delivery by using annular-shaped photomechanical waves  

NASA Astrophysics Data System (ADS)

Laser-based drug delivery is attractive for the targeting capability due to high spatial controllability of laser energy. Recently, we found that photomechanical waves (PMWs) can transiently increase the permeability of blood vessels in skin, muscle and brain of rats. In this study, we examined the use of annular-shaped PMWs to increase pressure at target depths due to superposition effect of pressure waves. This can increase the permeability of blood vessels located in the specific depth regions, enabling depth-targeted transvascular drug delivery. Annular PMWs were produced by irradiating a laser-absorbing material with annular-shaped pulsed laser beams that were produced by using an axicon lens. We first examined propagation and pressure characteristics of annular PMWs in tissue phantoms and confirmed an increased pressure at a target depth, which can be controlled by changing laser parameters. We injected Evans blue (EB) into a rat tail vein, and annular PMWs (inner diameter, 3 mm; outer diameter, 5 mm) were applied from the myofascial surface of the anterior tibialis muscle. After perfusion fixation, we observed fluorescence originating from EB in the tissue. We observed intense fluorescence at a target depth region of around 5 mm. These results demonstrate the capability of annular PMWs for depth-targeted transvascular drug delivery.

Akiyama, Takuya; Sato, Shunichi; Ashida, Hiroshi; Terakawa, Mitsuhiro

2011-02-01

175

Targeted Polymersome Delivery of siRNA Induces Cell Death of Breast Cancer Cells Dependent upon Orai3 Protein Expression  

E-print Network

Targeted Polymersome Delivery of siRNA Induces Cell Death of Breast Cancer Cells Dependent upon 55455, United States ABSTRACT: Polymersomes, polymeric vesicles that self-assemble in aqueous solutions. Past work has highlighted peptide- functionalized polymersomes as a highly promising targeted delivery

Kokkoli, Efie

176

Acoustic Molecular Imaging and Targeted Drug Delivery with Perfluorocarbon Nanoparticles  

NASA Astrophysics Data System (ADS)

Advances in molecular biology and cellular biochemistry are providing new opportunities for diagnostic medical imaging to "see" beyond the anatomical manifestations of disease to the earliest biochemical signatures of disease. Liquid perfluorocarbon nanoparticles provide inherent acoustic contrast when bound to targets, e.g., fibrin deposits in a thrombus, but unbound nanoparticles are undetectable. This nanoparticle platform may be further functionalized with paramagnetic metals, such as gadolinium, or radionuclides, with homing ligands, like anti-?v?3-integrins, and therapeutic agents. Acoustic imaging of densely distributed biomarkers, e.g., fibrin epitopes, is readily accommodated with fundamental imaging, but for sparse biomarkers, e.g., integrins, we have developed and implemented novel, nonlinear imaging techniques based upon information-theoretic receivers (i.e., thermodynamic receivers). These novel receivers allow sensitive direct imaging of contrast development.

Lanza, Gregory M.; Hughes, Michael. S.; Marsh, Jon N.; Scott, Michael J.; Zhang, Huiying; Lacy, Elizabeth K.; Allen, John S.; Wickline, Samuel A.

2005-03-01

177

Targeted delivery of carbon nanotubes to cancer cells  

NASA Astrophysics Data System (ADS)

CD22 is broadly expressed on human B cell lymphomas. Monoclonal anti-CD22 antibodies (MAbs) alone, or coupled to toxins, have been used to selectively target these tumors both in severe combined immunodeficient (SCID) mice with xenografted human lymphomas and in patients. Single-walled carbon nanotubes (CNTs) attached to antibodies or peptides represent another approach to targeting cancer cells. CNTs convert absorbed near-infrared (NIR) light into heat, which can thermally ablate cells in the vicinity of the CNTs. We have made MAb-CNT constructs where the MAb was either noncovalently or covalently coupled to CNTs, and investigated their ability to bind specifically to cells and to thermally ablate them after exposure to NIR light. The specific binding of these MAb-CNT constructs to antigen-positive and antigen-negative cells was demonstrated in vitro by using CD22+CD25 - Daudi cells, CD22-CD25+ phytohemagglutinin (PHA)-activated normal human peripheral blood mononuclear cells (PBMCs) and CNTs coupled non-covalently or covalently to either anti-CD22 or anti-CD25. We then demonstrated that the MAb-CNTs could bind to tumor cells expressing the relevant antigen but not to cells lacking the antigen. Furthermore we showed that, following exposure to NIR light, the cells could be thermally ablated. We also determined the stability of the MAb-CNTs in conditions designed to mimic the in vivo environment, i.e. mouse serum at 37°C. We then use the intrinsic Raman signature of CNTs to study the circulation and tissue distribution of intravenously injected MAb-CNTs in a murine xenograft model of lymphoma in vivo over a period of 24 hrs. We demonstrated that the MAb-CNTs have a short half-life in blood and that most of them are cleared by the reticuloendothelial system (RES). In the current embodiment, these constructs would therefore be of limited effectiveness in vivo.

Chakravarty, Pavitra

178

Synthesis of Doxorubicin loaded magnetic chitosan nanoparticles for pH responsive targeted drug delivery.  

PubMed

Targeted drug delivery is a promising alternative to overcome the limitations of classical chemotherapy. In an ideal targeted drug delivery system carrier nanoparticles would be directed to the tumor tissue and selectively release therapeutic molecules. As a novel approach, chitosan coated magnetic nanoparticles (CS MNPs) maintain a pH dependent drug delivery which provides targeting of drugs to the tumor site under a magnetic field. Among various materials, chitosan has a great importance as a pH sensitive, natural, biodegradable, biocompatible and bioadhesive polymer. The aim of this study was to obtain an effective targeted delivery system for Doxorubicin, using chitosan coated MNPs. Different sized CS MNPs were produced by in situ synthesis method. The anti-cancer agent Doxorubicin was loaded onto CS MNPs which were characterized previously. Doxorubicin loading was confirmed by FTIR. Drug loading and release characteristics, and stability of the nanoparticles were investigated. Our results showed that the CS MNPs have pH responsive release characteristics. The cellular internalization of Doxorubicin loaded CS MNPs were visualized by fluorescent microscopy. Doxorubicin loaded CS MNPs are efficiently taken up by MCF-7 (MCF-7/S) and Doxorubicin resistant MCF-7 (MCF-7/1 ?M) breast cancer cells, which increases the efficacy of drug and also maintains overcoming the resistance of Doxorubicin in MCF-7/Dox cells. Consequently, CS MNPs synthesized at various sizes can be effectively used for the pH dependent release of Doxorubicin in cancer cells. Results of this study can provide new insights in the development of pH responsive targeted drug delivery systems to overcome the side effects of conventional chemotherapy. PMID:24931189

Unsoy, Gozde; Khodadust, Rouhollah; Yalcin, Serap; Mutlu, Pelin; Gunduz, Ufuk

2014-10-01

179

Iron Oxide Nanoparticles as a Drug Delivery Vehicle for MRI Monitored Magnetic Targeting of Brain Tumors  

PubMed Central

This study explored the possibility of utilizing iron oxide nanoparticles as a drug delivery vehicle for minimally invasive, MRI-monitored magnetic targeting of brain tumors. In vitro determined hydrodynamic diameter of ~100nm, saturation magnetization of 94 emu/g Fe and T2 relaxivity of 43 s?1mM?1 of the nanoparticles suggested their applicability for this purpose. In vivo effect of magnetic targeting on the extent and selectivity of nanoparticle accumulation in tumors of rats harboring orthotopic 9L-gliosarcomas was quantified with MRI. Animals were intravenously injected with nanoparticles (12 mg Fe/kg) under a magnetic field density of 0 T (control) or 0.4 T (experimental) applied for 30 minutes. MR images were acquired prior to administration of nanoparticles and immediately after magnetic targeting at 1 hour intervals for 4 hours. Image analysis revealed that magnetic targeting induced a 5-fold increase in the total glioma exposure to magnetic nanoparticles over non-targeted tumors (p=0.005) and a 3.6-fold enhancement in the target selectivity index of nanoparticle accumulation in glioma over the normal brain (p=0.025). In conclusion, accumulation of iron oxide nanoparticles in gliosarcomas can be significantly enhanced by magnetic targeting and successfully quantified by MR imaging. Hence, these nanoparticles appear to be a promising vehicle for glioma-targeted drug delivery. PMID:17964647

Chertok, Beata; Moffat, Bradford A.; David, Allan E.; Yu, Faquan; Bergemann, Christian; Ross, Brian D.; Yang, Victor C.

2009-01-01

180

Recent approaches of lipid-based delivery system for lymphatic targeting via oral route.  

PubMed

Lymphatic system is a key target in research field due to its distinctive makeup and huge contributing functions within the body. Intestinal lymphatic drug transport (chylomicron pathway) is intensely described in research field till date because it is considered to be the best for improving oral drug delivery by avoiding first pass metabolism. The lymphatic imaging techniques and potential therapeutic candidates are engaged for evaluating disease states and overcoming these conditions. The novel drug delivery systems such as self-microemulsifying drug delivery system, nanoparticles, liposomes, nano-lipid carriers, solid lipid carriers are employed for delivering drugs through lymphatic system via various routes such as subcutaneous route, intraperitoneal route, pulmonary route, gastric sub-mucosal injection, intrapleural and intradermal. Among these colloidal particles, lipid-based delivery system is considered to be the best for lymphatic delivery. From the last few decades, mesenteric lymph duct cannulation and thoracic lymph duct cannulation are followed to assess lymphatic uptake of drugs. Due to their limitations, chylomicrons inhibitors and in-vitro models are employed, i.e. lipolysis model and permeability model. Currently, research on this topic still continues and drainage system used to deliver the drugs against lymphatic disease as well as targeting other organs by modulating the chylomicron pathway. PMID:25148607

Chaudhary, Shilpa; Garg, Tarun; Murthy, R S R; Rath, Goutam; Goyal, Amit K

2014-12-01

181

Single-Antibody, Targeted Nanoparticle Delivery of Camptothecin  

PubMed Central

We have developed a new method for assembling targeted nanoparticles that utilizes the complexation between targeting agents that contain boronic acids and polymer-drug conjugates that possess diols. Here, we report the first in vivo, antitumor results of a nanoparticle formed via this new assembly methodology. A nanoparticle consisting of a mucic acid polymer conjugate of camptothecin (CPT), MAP-CPT; and containing on average one Herceptin antibody is investigated in nude mice bearing HER2 overexpressing BT-474 human breast cancer tumors. Nontargeted MAP-CPT and antibody-containing MAP-CPT nanoparticles of ca. 30–40 nm diameter and slightly negative zeta potential show prolonged in vivo circulation and similar biodistributions after intravenous tail vein injections in mice. The maximum tolerated dose (MTD) of the nontargeted and Herceptin-containing MAP-CPT nanoparticles are found to be 10 and 8 mg CPT/kg, respectively, in mice. Mice bearing BT-474 human breast tumors treated with nontargeted MAP-CPT nanoparticles at 8 mg CPT/kg show significant tumor growth inhibition (mean tumor volume of 63 mm3) when compared to Irinotecan at 80 mg/kg (mean tumor volume of 575 mm3) and CPT at 8 mg/kg (mean tumor volume of 808 mm3) at the end of the study. Herceptin antibody treatment at 5.9 mg/kg results in complete tumor regressions in 5 out of 8 mice, with a mean tumor volume of 60 mm3 at the end of the study. Mice treated with MAP-CPT nanoparticles at 1 mg CPT/kg do not show tumor inhibition. However, all mice receiving administrations of MAP-CPT nanoparticles (1 mg CPT/kg) that contain on average a single Herceptin molecule per nanoparticle (5.9 mg Herceptin equivalent/kg) show complete tumor regression by the end of the study. These results demonstrate that the antitumor efficacy of nanoparticles carrying anticancer drugs can be enhanced by incorporating on average a single antibody. PMID:23676007

Han, Han; Davis, Mark E.

2013-01-01

182

Naltrexone: a review of existing sustained drug delivery systems and emerging nano-based systems.  

PubMed

Narcotic antagonists such as naltrexone (NTX) have shown some efficiency in the treatment of both opiate addiction and alcohol dependence. A few review articles have focused on clinical findings and pharmacogenetics of NTX, advantages and limitations of sustained release systems as well as pharmacological studies of NTX depot formulations for the treatment of alcohol and opioid dependency. To date, three NTX implant systems have been developed and tested in humans. In this review, we summarize the latest clinical data on commercially available injectable and implantable NTX-sustained release systems and discuss their safety and tolerability aspects. Emphasis is also laid on recent developments in the area of nanodrug delivery such as NTX-loaded micelles and nanogels as well as related research avenues. Due to their ability to increase the therapeutic index and to improve the selectivity of drugs (targeted delivery), nanodrug delivery systems are considered as promising sustainable drug carriers for NTX in addressing opiate and alcohol dependence. PMID:24704710

Goonoo, Nowsheen; Bhaw-Luximon, Archana; Ujoodha, Reetesh; Jhugroo, Anil; Hulse, Gary K; Jhurry, Dhanjay

2014-06-10

183

A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy.  

PubMed

Targeted drug delivery vehicles with low immunogenicity and toxicity are needed for cancer therapy. Here we show that exosomes, endogenous nano-sized membrane vesicles secreted by most cell types, can deliver chemotherapeutics such as doxorubicin (Dox) to tumor tissue in BALB/c nude mice. To reduce immunogenicity and toxicity, mouse immature dendritic cells (imDCs) were used for exosome production. Tumor targeting was facilitated by engineering the imDCs to express a well-characterized exosomal membrane protein (Lamp2b) fused to ?v integrin-specific iRGD peptide (CRGDKGPDC). Purified exosomes from imDCs were loaded with Dox via electroporation, with an encapsulation efficiency of up to 20%. iRGD exosomes showed highly efficient targeting and Dox delivery to ?v integrin-positive breast cancer cells in vitro as demonstrated by confocal imaging and flow cytometry. Intravenously injected targeted exosomes delivered Dox specifically to tumor tissues, leading to inhibition of tumor growth without overt toxicity. Our results suggest that exosomes modified by targeting ligands can be used therapeutically for the delivery of Dox to tumors, thus having great potential value for clinical applications. PMID:24345736

Tian, Yanhua; Li, Suping; Song, Jian; Ji, Tianjiao; Zhu, Motao; Anderson, Gregory J; Wei, Jingyan; Nie, Guangjun

2014-02-01

184

Targeted Delivery of Doxorubicin Using a Colorectal Cancer-Specific ssDNA Aptamer.  

PubMed

Targeted drug delivery is particularly important in cancer treatment because many antitumor drugs are nonspecific and highly toxic to both cancerous and normal cells. The L33 aptamer is a single-stranded DNA (ssDNA) sequence that has the ability to recognize human colorectal cancer (CRC) cell line HCT116 specifically. In this study, we demonstrated that the L33 aptamer can selectively internalize into target HCT116 cells via receptor-mediated endocytosis. Based on this finding, we developed an aptamer-based drug delivery system using L33 as the carrier of the antitumor drug doxorubicin (Dox). The L33-Dox complex exhibited specific and high affinity (Kd ?=?14.3?±?2.2 nM) binding to HCT116 cells. The results of cytotoxicity assays revealed that the L33-Dox complex was capable of selectively delivering the drug to the target HCT116 cells and lowered the toxicity for nontarget CL187 cells. These findings indicate that the aptamer-based targeted drug delivery system has the potential to be used in clinical settings and may overcome drug resistance to a certain extent because high drug dosages can be directed toward target cells. Anat Rec, 297:2280-2288, 2014. © 2014 Wiley Periodicals, Inc. PMID:25044297

Li, Wanming; Chen, Hang; Yu, Min; Fang, Jin

2014-12-01

185

Preparation and characterisation of thermoresponsive nanogels for smart antibacterial fabrics.  

PubMed

The present investigation involves the preparation and characterisation of silver containing nanogels and their incorporation onto the surface of woven fabrics so that they can be potentially used in biomedical applications such as wound dressings. These silver nanoparticles were mixed with N-isopropylacrylamide (NIPAM) based nanogels during and at the end of polymerisation process prior to their application onto the fabrics. NIPAM based nanogels were found to have a peak of lower critical solution temperature (LCST) that is close to the human body temperature. These nanogels were applied on cotton fabrics and cured for 15 h at 30°C. Silver based nanogels were padded onto the fabrics followed by drying at 30°C overnight. Scanning electron microscopy images have shown excellent distribution of silver nanoparticles on the fabric surface. EDX analysis was also conducted to confirm the presence of silver particles on the fabric surface. The results showed that a cotton fabric treated with silver based nanogels prevented the growth of bacteria, i.e. Gram-positive (Staphylococcus epidermidis) and Gram-negative (Escherichia coli), on whereas the control cotton fabric samples exhibited considerable level of bacterial growth. Specifically, the nanogels in which the silver particles were added during the polymerisation process were observed to have higher antibacterial efficacy towards both types of bacteria. PMID:24857475

Zafar, Muhammad; Shah, Tahir; Rawal, Amit; Siores, Elias

2014-07-01

186

Nanomaterials for targeted drug delivery to cancer stem cells.  

PubMed

Recent developments in cancer biology have identified the existence of a sub-poplulation of cells - cancer stem cells (CSC) that are resistant to most traditional therapies (e.g. chemotherapy and radiotherapy) and have the ability to repair their damaged DNA. These findings have necessitated a break with traditional oncology management and encouraged new perspectives concerning cancer treatment. Understanding the functional biology of CSCs - especially the signaling pathways that are involved in their self-renewal mechanisms - is crucial for discovering new forms of treatment. In this review, we highlight current and future prospects for potential cancer therapies based on the use of nano-sized materials. Nanomaterials could revolutionize cancer management because of their distinctive features - unique surface chemistry, strong electronic, optic, and magnetic properties - that are found neither in bulk materials nor in single molecules. Based on these distinct properties, we believe that nanomaterials could be excellent candidates for use in CSC research in order to optimize cancer therapeutics. Moreover, we propose these nanomaterials for the inhibition of the self-renewal pathways of CSCs by focusing on the Hedgehog, Notch, and Wnt/?-catenin self-renewal mechanisms. By introducing these methods for the detection, targeting, and destruction of CSCs, an efficient alternative treatment for the incurable disease of cancer could be provided. PMID:24697156

Orza, Anamaria; Casciano, Daniel; Biris, Alexandru

2014-05-01

187

Recent advances in lymphatic targeted drug delivery system for tumor metastasis  

PubMed Central

The lymphatic system has an important defensive role in the human body. The metastasis of most tumors initially spreads through the surrounding lymphatic tissue and eventually forms lymphatic metastatic tumors; the tumor cells may even transfer to other organs to form other types of tumors. Clinically, lymphatic metastatic tumors develop rapidly. Given the limitations of surgical resection and the low effectiveness of radiotherapy and chemotherapy, the treatment of lymphatic metastatic tumors remains a great challenge. Lymph node metastasis may lead to the further spread of tumors and may be predictive of the endpoint event. Under these circumstances, novel and effective lymphatic targeted drug delivery systems have been explored to improve the specificity of anticancer drugs to tumor cells in lymph nodes. In this review, we summarize the principles of lymphatic targeted drug delivery and discuss recent advances in the development of lymphatic targeted carriers. PMID:25610710

Zhang, Xiao-Yu; Lu, Wei-Yue

2014-01-01

188

Bioresponsive hyaluronic acid-capped mesoporous silica nanoparticles for targeted drug delivery.  

PubMed

In this paper, we present a facile strategy to synthesize hyaluronic acid (HA) conjugated mesoporous silica nanoparticles (MSP) for targeted enzyme responsive drug delivery, in which the anchored HA polysaccharides not only act as capping agents but also as targeting ligands without the need of additional modification. The nanoconjugates possess many attractive features including chemical simplicity, high colloidal stability, good biocompatibility, cell-targeting ability, and precise cargo release, making them promising agents for biomedical applications. As a proof-of-concept demonstration, the nanoconjugates are shown to release cargoes from the interior pores of MSPs upon HA degradation in response to hyaluronidase-1 (Hyal-1). Moreover, after receptor-mediated endocytosis into cancer cells, the anchored HA was degraded into small fragments, facilitating the release of drugs to kill the cancer cells. Overall, we envision that this system might open the door to a new generation of carrier system for site-selective, controlled-release delivery of anticancer drugs. PMID:23303570

Chen, Zhaowei; Li, Zhenhua; Lin, Youhui; Yin, Meili; Ren, Jinsong; Qu, Xiaogang

2013-01-28

189

Recent advances in lymphatic targeted drug delivery system for tumor metastasis.  

PubMed

The lymphatic system has an important defensive role in the human body. The metastasis of most tumors initially spreads through the surrounding lymphatic tissue and eventually forms lymphatic metastatic tumors; the tumor cells may even transfer to other organs to form other types of tumors. Clinically, lymphatic metastatic tumors develop rapidly. Given the limitations of surgical resection and the low effectiveness of radiotherapy and chemotherapy, the treatment of lymphatic metastatic tumors remains a great challenge. Lymph node metastasis may lead to the further spread of tumors and may be predictive of the endpoint event. Under these circumstances, novel and effective lymphatic targeted drug delivery systems have been explored to improve the specificity of anticancer drugs to tumor cells in lymph nodes. In this review, we summarize the principles of lymphatic targeted drug delivery and discuss recent advances in the development of lymphatic targeted carriers. PMID:25610710

Zhang, Xiao-Yu; Lu, Wei-Yue

2014-12-01

190

Targeted delivery of EV peptide to tumor cell cytoplasm using lipid coated calcium carbonate nanoparticles.  

PubMed

Intracellular-acting peptide drugs are effective for inhibiting cytoplasmic protein targets, yet face challenges with penetrating the cancer cell membrane. We have developed a lipid nanoparticle formulation that utilizes a pH-sensitive calcium carbonate complexation mechanism to enable the targeted delivery of the intracellular-acting therapeutic peptide EEEEpYFELV (EV) into lung cancer cells. Lipid-calcium-carbonate (LCC) nanoparticles were conjugated with anisamide, a targeting ligand for the sigma receptor which is expressed on lung cancer cells. LCC EV nanoparticle treatment provoked severe apoptotic effects in H460 non-small cell lung cancer cells in vitro. LCC NPs also mediated the specific delivery of Alexa-488-EV peptide to tumor tissue in vivo, provoking a high tumor growth retardation effect with minimal uptake by external organs and no toxic effects. PMID:22796364

Kim, Sang Kyoon; Foote, Michael B; Huang, Leaf

2013-07-01

191

Targeted in vivo delivery of siRNA and an endosome-releasing agent to hepatocytes.  

PubMed

The discoveries of RNA interference (RNAi) and short interfering RNAs (siRNAs) have provided the opportunity to treat diseases in a fundamentally new way: by co-opting a natural process to inhibit gene expression at the mRNA level. Given that siRNAs must interact with the cells' natural RNAi machinery in order to exert their silencing effect, one of the most fundamental requirements for their use is efficient delivery to the desired cell type and, specifically, into the cytoplasm of those cells. Numerous research efforts involving the testing of a large number of delivery approaches using various carrier molecules and inventing several distinct formulation technologies during the past decade illustrate the difficulty and complexity of this task. We have developed synthetic polymer formulations for in vivo siRNA delivery named Dynamic PolyConjugates™ (DPCs) that are designed to mimic the features viruses possess for efficient delivery of their nucleic acids. These include small size, long half-life in circulation, capability of displaying distinct host cell tropism, efficient receptor binding and cell entry, disassembly in the endosome and subsequent release of the nucleic acid cargo to the cytoplasm. Here we present an example of this delivery platform composed of a hepatocyte-targeted endosome-releasing agent and a cholesterol-conjugated siRNA (chol-siRNA). This delivery platform forms the basis of ARC-520, an siRNA-based therapeutic for the treatment of chronic hepatitis B virus (HBV) infection. In this chapter, we provide a general overview of the steps in developing ARC-520 and detailed protocols for two critical stages of the discovery process: (1) verifying targeted in vivo delivery to hepatocytes and (2) evaluating in vivo drug efficacy using a mouse model of chronic HBV infection. PMID:25319651

Sebestyén, Magdolna G; Wong, So C; Trubetskoy, Vladimir; Lewis, David L; Wooddell, Christine I

2015-01-01

192

Tumor cell-targeted delivery of nanoconjugated oligonucleotides in composite spheroids.  

PubMed

Standard tissue culture has often been a poor model for predicting the efficacy of anti-cancer agents including oligonucleotides. In contrast to the simplicity of monolayer tissue cultures, a tumor mass includes tightly packed tumor cells, tortuous blood vessels, high levels of extracellular matrix, and stromal cells that support the tumor. These complexities pose a challenge for delivering therapeutic agents throughout the tumor, with many drugs limited to cells proximal to the vasculature. Multicellular tumor spheroids are superior to traditional monolayer cell culture for the assessment of cancer drug delivery, since they possess many of the characteristics of metastatic tumor foci. However, homogeneous spheroids comprised solely of tumor cells do not account for some of the key aspects of metastatic tumors, particularly the interaction with host cells such as fibroblasts. Further, homogeneous culture does not allow for the assessment of targeted delivery to tumor versus host cells. Here we have evaluated delivery of targeted and untargeted oligonucleotide nanoconjugates and of oligonucleotide polyplexes in both homogeneous and composite tumor spheroids. We find that inclusion of fibroblasts in the spheroids reduces delivery efficacy of the polyplexes. In contrast, targeted multivalent RGD-oligonucleotide nanoconjugates were able to effectively discriminate between melanoma cells and fibroblasts, thus providing tumor-selective uptake and pharmacological effects. PMID:25238564

Carver, Kyle; Ming, Xin; Juliano, Rudy L

2014-12-01

193

Targeted drug-delivery approaches by nanoparticulate carriers in the therapy of inflammatory diseases  

PubMed Central

Limitations in therapy induced by adverse effects due to unselective drug availability and therefore the use of potentially too high doses are a common problem. One prominent example for this dilemma are inflammatory diseases. Colloidal carriers allow one to improve delivery of drugs to the site of action and appear promising to overcome this general therapeutic drawback. Specific uptake of nanoparticles by immune-related cells in inflamed barriers offers selective drug targeting to the inflamed tissue. Here we focus on nanocarrier-based drug delivery strategies for the treatment of common inflammatory disorders like rheumatoid arthritis, multiple sclerosis, uveitis or inflammatory bowel disease. PMID:19940000

Ulbrich, Wiebke; Lamprecht, Alf

2010-01-01

194

Surface proteomic analysis of osteosarcoma identifies EPHA2 as receptor for targeted drug delivery  

PubMed Central

Background: Osteosarcoma (OS) is the most common bone tumour in children and adolescents. Despite aggressive therapy regimens, treatment outcomes are unsatisfactory. Targeted delivery of drugs can provide higher effective doses at the site of the tumour, ultimately improving the efficacy of existing therapy. Identification of suitable receptors for drug targeting is an essential step in the design of targeted therapy for OS. Methods: We conducted a comparative analysis of the surface proteome of human OS cells and osteoblasts using cell surface biotinylation combined with nano-liquid chromatography – tandem mass spectrometry-based proteomics to identify surface proteins specifically upregulated on OS cells. This approach generated an extensive data set from which we selected a candidate to study for its suitability as receptor for targeted treatment delivery to OS. First, surface expression of the ephrin type-A receptor 2 (EPHA2) receptor was confirmed using FACS analysis. Ephrin type-A receptor 2 expression in human tumour tissue was tested using immunohistochemistry. Receptor targeting and internalisation studies were conducted to assess intracellular uptake of targeted modalities via EPHA2. Finally, tissue micro arrays containing cores of human OS tissue were stained using immunohistochemistry and EPHA2 staining was correlated to clinical outcome measures. Results: Using mass spectrometry, a total of 2841 proteins were identified of which 156 were surface proteins significantly upregulated on OS cells compared with human primary osteoblasts. Ephrin type-A receptor 2 was highly upregulated and the most abundant surface protein on OS cells. In addition, EPHA2 was expressed in a vast majority of human OS samples. Ephrin type-A receptor 2 effectively mediates internalisation of targeted adenoviral vectors into OS cells. Patients with EPHA2-positive tumours showed a trend toward inferior overall survival. Conclusion: The results presented here suggest that the EPHA2 receptor can be considered an attractive candidate receptor for targeted delivery of therapeutics to OS. PMID:24064975

PosthumaDeBoer, J; Piersma, S R; Pham, T V; van Egmond, P W; Knol, J C; Cleton-Jansen, A M; van Geer, M A; van Beusechem, V W; Kaspers, G J L; van Royen, B J; Jiménez, C R; Helder, M N

2013-01-01

195

Molecular design and nanoparticle-mediated intracellular delivery of functional proteins to target cellular pathways  

NASA Astrophysics Data System (ADS)

Intracellular delivery of specific proteins and peptides represents a novel method to influence stem cells for gain-of-function and loss-of-function. Signaling control is vital in stem cells, wherein intricate control of and interplay among critical pathways directs the fate of these cells into either self-renewal or differentiation. The most common route to manipulate cellular function involves the introduction of genetic material such as full-length genes and shRNA into the cell to generate (or prevent formation of) the target protein, and thereby ultimately alter cell function. However, viral-mediated gene delivery may result in relatively slow expression of proteins and prevalence of oncogene insertion into the cell, which can alter cell function in an unpredictable fashion, and non-viral delivery may lead to low efficiency of genetic delivery. For example, the latter case plagues the generation of induced pluripotent stem cells (iPSCs) and hinders their use for in vivo applications. Alternatively, introducing proteins into cells that specifically recognize and influence target proteins, can result in immediate deactivation or activation of key signaling pathways within the cell. In this work, we demonstrate the cellular delivery of functional proteins attached to hydrophobically modified silica (SiNP) nanoparticles to manipulate specifically targeted cell signaling proteins. In the Wnt signaling pathway, we have targeted the phosphorylation activity of glycogen synthase kinase-3beta (GSK-3beta) by designing a chimeric protein and delivering it in neural stem cells. Confocal imaging indicates that the SiNP-chimeric protein conjugates were efficiently delivered to the cytosol of human embryonic kidney cells and rat neural stem cells, presumably via endocytosis. This uptake impacted the Wnt signaling cascade, indicated by the elevation of beta-catenin levels, and increased transcription of Wnt target genes, such as c-MYC. The results presented here suggest that functional proteins can be delivered intracellularly in vitro using nanoparticles and used to target key signaling proteins and regulate cell signaling pathways. The same concept of naturally occurring protein-protein interactions can also be implemented to selectively bring intracellular protein targets in close proximity to proteasomal degradation machinery in cells and effect their depletion from the cellular compartments. This approach will be able to not only target entire pool of proteins to ubiquitination-mediated degradation, but also to specific sub-pools of posttranslationally modified proteins in the cell, provided peptides having distinct binding affinities are identified for posttranslational modifications. This system can then be tested for intracellular protein delivery using nanoparticle carriers to identify roles of different posttranslational modifications on the protein's activity. In future work, we propose to develop a cellular detection system, based on GFP complementation, which can be used to evaluate the efficiency of different protein delivery carriers to internalize proteins into the cell cytosol. We envision the application of nanoscale materials as intracellular protein delivery vehicles to target diverse cell signaling pathways at the posttranslational level, and subsequent metabolic manipulation, which may have interesting therapeutic properties and can potentially target stem cell fate.

Shah, Dhiral Ashwin

196

Targeted drug delivery into reversibly injured myocardium with silica nanoparticles: surface functionalization, natural biodistribution, and acute toxicity  

PubMed Central

The clinical outcome of patients with ischemic heart disease can be significantly improved with the implementation of targeted drug delivery into the ischemic myocardium. In this paper, we present our original findings relevant to the problem of therapeutic heart targeting with use of nanoparticles. Experimental approaches included fabrication of carbon and silica nanoparticles, their characterization and surface modification. The acute hemodynamic effects of nanoparticle formulation as well as nanoparticle biodistribution were studied in male Wistar rats. Carbon and silica nanoparticles are nontoxic materials that can be used as carriers for heart-targeted drug delivery. Concepts of passive and active targeting can be applied to the development of targeted drug delivery to the ischemic myocardial cells. Provided that ischemic heart-targeted drug delivery can be proved to be safe and efficient, the results of this research may contribute to the development of new technologies in the pharmaceutical industry. PMID:20463939

Galagudza, Michael M; Korolev, Dmitry V; Sonin, Dmitry L; Postnov, Viktor N; Papayan, Garry V; Uskov, Ivan S; Belozertseva, Anastasia V; Shlyakhto, Eugene V

2010-01-01

197

Glycoprotein CD98 as a receptor for colitis-targeted delivery of nanoparticle.  

PubMed

Treatment strategies for inflammatory bowel disease have been constrained by limited therapeutic efficacy and serious adverse effects owing to a lack of receptor for targeted drug delivery to the inflamed colon. Upon inflammation, CD98 expression is highly elevated in colonic epithelial cells and infiltrating immune cells. To investigate whether CD98 can be used as a colitis-targeted delivery receptor, we constructed CD98 Fab'-bearing quantum dots (QDs)-loaded nanoparticles (Fab'-NPs). The resultant Fab'-NPs had desired particle size (~458 nm) with a narrow size distribution and zeta-potential (approximately +19 mV), low cytotoxicity, and excellent fluorescence properties. Electron microscopy images provided direct evidence for the well-dispersed distribution of QDs within spherical Fab'-NPs. Cellular uptake experiments demonstrated that Fab'-NPs were efficiently internalized into Colon-26 and RAW 264.7 cells through the CD98-mediated endocytosis pathway, and showed that the targeting effect of CD98 Fab' markedly increased their cellular uptake efficiency compared with control pegylated QDs-loaded NPs (PEG-NPs). Furthermore, ex vivo studies showed much more effective accumulation of Fab'-NPs in colitis tissue than that of PEG-NPs. These findings suggest that because of inflammation-dependent over-expression of CD98, active colitis-targeted delivery can be accomplished using NPs decorated with CD98 antibody. PMID:24729869

Xiao, Bo; Yang, Yang; Viennois, Emilie; Zhang, Yuchen; Ayyadurai, Saravanan; Baker, Mark; Laroui, Hamed; Merlin, Didier

2014-03-21

198

LIPOSOMAL MODULAR COMPLEXES FOR SIMULTANEOUS TARGETED DELIVERY OF BIOACTIVE GASES AND THERAPEUTICS  

PubMed Central

Intrinsically echogenic liposomes (ELIP) can be adapted to encapsulate nitric oxide to facilitate ultrasound-enhanced delivery of therapeutic agents to atherosclerotic plaques. However, the NO loading of targeted ELIP caused a 93% decrease of antibody (Ab) immunoreactivity. The following hypothesis was tested: biotin/avidin-mediated coupling of NO-ELIP and Ab-conjugated ELIP will enable co-delivery of bioactive gases and ELIP that can encapsulate other agents without loss of targeting efficiency. Complex formation was initiated by addition of excess streptavidin to equal proportions of biotinylated Ab-ELIP and NO-ELIP. Fluorescence deconvolution microscopy, Coulter Multisizer 3 analysis and flow cytometry demonstrated that the ELIP coupling procedure formed mixed aggregates of ?10 liposomes within 1 minute. Intravascular ultrasound imaging and ELISA showed that echogenicity and targeting efficiency were completely and 69–99% retained, respectively. When complexed to NO-ELIP, ELIP bifunctionally targeted to both CD34 and ICAM-1 (BF-ELIP) increased human mononuclear cell migration through human coronary artery endothelial cell monolayers in transwell plates 4-fold relative to a nonspecific IgG-ELIP control and 2-fold relative to BF-ELIP alone. It was concluded that this novel multi-functional conjugation methodology provides a platform technology for site-specific co-delivery of bioactive gases and other agents. PMID:19903503

Klegerman, Melvin E.; Wassler, Michael; Huang, Shao-Ling; Zou, Yuejiao; Kim, Hyunggun; Shelat, Harnath S.; Holland, Christy K.; Geng, Yong-Jian; McPherson, David D.

2010-01-01

199

Targeted drug delivery for cancer therapy: the other side of antibodies  

PubMed Central

Therapeutic monoclonal antibody (TMA) based therapies for cancer have advanced significantly over the past two decades both in their molecular sophistication and clinical efficacy. Initial development efforts focused mainly on humanizing the antibody protein to overcome problems of immunogenicity and on expanding of the target antigen repertoire. In parallel to naked TMAs, antibody-drug conjugates (ADCs) have been developed for targeted delivery of potent anti-cancer drugs with the aim of bypassing the morbidity common to conventional chemotherapy. This paper first presents a review of TMAs and ADCs approved for clinical use by the FDA and those in development, focusing on hematological malignancies. Despite advances in these areas, both TMAs and ADCs still carry limitations and we highlight the more important ones including cancer cell specificity, conjugation chemistry, tumor penetration, product heterogeneity and manufacturing issues. In view of the recognized importance of targeted drug delivery strategies for cancer therapy, we discuss the advantages of alternative drug carriers and where these should be applied, focusing on peptide-drug conjugates (PDCs), particularly those discovered through combinatorial peptide libraries. By defining the advantages and disadvantages of naked TMAs, ADCs and PDCs it should be possible to develop a more rational approach to the application of targeted drug delivery strategies in different situations and ultimately, to a broader basket of more effective therapies for cancer patients. PMID:23140144

2012-01-01

200

Folate-polyethylene glycol conjugated carboxymethyl chitosan for tumor-targeted delivery of 5-fluorouracil.  

PubMed

Targeted drug delivery has been evolving at an increasing rate due to its potential to reduce the minimum effective dose of a drug and its accompanying side effects. It has shown improved therapeutic efficacy at equivalent plasma concentrations; however, the development of effective targeted delivery systems has remained a major task. In this study, a drug carrier was designed and synthesized by conjugation of folate acid (FA) to carboxymethyl chitosan (CMCS) through a polyethylene glycol (PEG) spacer. The resulting conjugates were confirmed by 1H nuclear magnetic resonance and infrared spectroscopy. The cytotoxicity of CMCS and CMCS?5?fluorouracil (5?FU) was determined by a crystal violet stain assay. The potential of CMCS?PEG?FA for use in the targeted delivery of 5?FU was investigated using 3?(4,5?dimethylthiazol?2?yl)?2,5?diphenyltetrazolium bromide analysis in two cell lines, HeLa and A549, which contain different numbers of folate receptors on their surfaces. The MTT results revealed that in HeLa cells, the cytotoxicity of (CMCS?5?FU)?PEG?FU cells is greater compared with CMCS?5?FU, suggesting that folate receptor?mediated endocytosis may affect the cellular uptake efficiency of 5?FU?loaded CMCS?PEG?FA. The CMCS?PEG?FA conjugates presented in this study show promise as carriers for chemotherapeutic agents due to their solubility at physiological pH, efficiency in carrying chemotherapeutic agents, low cytotoxicity and targeting ability. PMID:24469407

Li, Hai-Lang; He, Ya-Xing; Gao, Qian-Hong; Wu, Guo-Zhong

2014-03-01

201

Cell-mediated Delivery and Targeted Erosion of Vascular Endothelial Growth Factor-Crosslinked Hydrogelsa  

PubMed Central

We have previously reported a novel polymeric delivery vehicle that is assembled via interaction between heparin and the vascular endothelial growth factor (VEGF). Here, the cell-responsiveness of this hydrogel — including the delivery of VEGF in response to VEGFR-2 overexpressing PAE/KDR cells (porcine aortic endothelial cells (PAE) equipped with the transcript for the kinase insert domain receptor (KDR)), consequent erosion of the hydrogel matrix, and cellular response — are highlighted. The release of VEGF and hydrogel erosion reached 100% only in the presence of PAE/KDR. The [PEG-LMWH/VEGF] hydrogel (PEG = poly(ethylene glycol), LMWH = low molecular weight heparin) correspondingly prompted increases in VEGFR-2 phosphorylation and proliferation of PAE/KDR cells. This study proves that growth factor-crosslinked hydrogels can liberate VEGF in response to specific receptors, causing gel erosion and desired cell responses. The promise of these approaches in therapeutic applications, including targeted delivery, is suggested. PMID:21567519

Kim, Sung Hye; Kiick, Kristi L.

2011-01-01

202

Targeted electro-delivery of oligonucleotides for RNA interference: siRNA and antimiR.  

PubMed

For more than a decade, the understanding of RNA interference (RNAi) has been a growing field of interest. Micro-RNAs (miRNAs) are small regulatory RNAs that play an important role in disease development and progression and therefore represent a potential new class of therapeutic targets. However, delivery of RNAi-based oligonucleotides is one of the most challenging hurdles to RNAi-based drug development. Electropermeabilization (EP) is recognized as a successful non-viral method to transfer nucleic acids into living cells both in vitro and in vivo. EP is the direct application of electric pulses to cells or tissues that transiently permeabilize plasma membranes, allowing the efficient delivery of exogenous molecules. The present review focused on the mechanism of RNAi-based oligonucleotides electrotransfer, from cellular uptake to intracellular distribution. Biophysical theories on oligonucleotide electrotransfer will be also presented. The advantages and few drawbacks of EP-mediated delivery will also be discussed. PMID:24819217

Chabot, Sophie; Teissié, Justin; Golzio, Muriel

2015-01-01

203

Targeted magnetic delivery and tracking of cells using a magnetic resonance imaging system.  

PubMed

The success of cell therapies depends on the ability to deliver the cells to the site of injury. Targeted magnetic cell delivery is an emergent technique for localised cell transplantation therapy. The use of permanent magnets limits such a treatment to organs close to the body surface or an implanted magnetic source. A possible alternative method for magnetic cell delivery is magnetic resonance targeting (MRT), which uses magnetic field gradients inherent to all magnetic resonance imaging system, to steer ferromagnetic particles to their target region. In this study we have assessed the feasibility of such an approach for cell targeting, using a range of flow rates and different super paramagnetic iron oxide particles in a vascular bifurcation phantom. Using MRT we have demonstrated that 75% of labelled cells could be guided within the vascular bifurcation. Furthermore we have demonstrated the ability to image the labelled cells before and after magnetic targeting, which may enable interactive manipulation and assessment of the distribution of cellular therapy. This is the first demonstration of cellular MRT and these initial findings support the potential value of MRT for improved targeting of intravascular cell therapies. PMID:20382425

Riegler, Johannes; Wells, Jack A; Kyrtatos, Panagiotis G; Price, Anthony N; Pankhurst, Quentin A; Lythgoe, Mark F

2010-07-01

204

Surface-Engineered Targeted PPI Dendrimer for Efficient Intracellular and Intratumoral siRNA Delivery  

PubMed Central

Low penetration ability of Small Interfering RNA (siRNA) through the cellular plasma membrane combined with its limited stability in blood, limits the effectiveness of the systemic delivery of siRNA. In order to overcome such difficulties, we constructed a nanocarrier-based delivery system by taking advantage of the lessons learned from the problems in the delivery of DNA. In the present study, siRNA nanoparticles were first formulated with Poly(Propyleneimine) (PPI) dendrimers. To provide lateral and steric stability to withstand the aggressive environment in the blood stream, the formed siRNA nanoparticles were caged with a dithiol containing cross-linker molecules followed by coating them with Poly(Ethylene Glycol) (PEG) polymer. A synthetic analog of Luteinizing Hormone-Releasing Hormone (LHRH) peptide was conjugated to the distal end of PEG polymer to direct the siRNA nanoparticles specifically to the cancer cells. Our results demonstrated that this layer-by-layer modification and targeting approach confers the siRNA nanoparticles stability in plasma and intracellular bioavailability, provides for their specific uptake by tumor cells, accumulation of siRNA in the cytoplasm of cancer cells, and efficient gene silencing. In addition, in vivo body distribution data confirmed high specificity of the proposed targeting delivery approach which created the basis for the prevention of adverse side effects of the treatment on healthy organs. PMID:19567257

Taratula, Oleh; Garbuzenko, Olga B.; Kirkpatrick, Paul; Pandya, Ipsit; Savla, Ronak; Pozharov, Vitaly P.; He, Huixin; Minko, Tamara

2009-01-01

205

Integrated hollow mesoporous silica nanoparticles for target drug/siRNA co-delivery.  

PubMed

A hollow mesoporous silica nanoparticle (HMSNP) based drug/siRNA co-delivery system was designed and fabricated, aiming at overcoming multidrug resistance (MDR) in cancer cells for targeted cancer therapy. The as-prepared HMSNPs have perpendicular nanochannels connecting to the internal hollow cores, thereby facilitating drug loading and release. The extra volume of the hollow core enhances the drug loading capacity by two folds as compared with conventional mesoporous silica nanoparticles (MSNPs). Folic acid conjugated polyethyleneimine (PEI-FA) was coated on the HMSNP surfaces under neutral conditions through electrostatic interactions between the partially charged amino groups of PEI-FA and the phosphate groups on the HMSNP surfaces, blocking the mesopores and preventing the loaded drugs from leakage. Folic acid acts as the targeting ligand that enables the co-delivery system to selectively bind with and enter into the target cancer cells. PEI-FA-coated HMSNPs show enhanced siRNA binding capability on account of electrostatic interactions between the amino groups of PEI-FA and siRNA, as compared with that of MSNPs. The electrostatic interactions provide the feasibility of pH-controlled release. In vitro pH-responsive drug/siRNA co-delivery experiments were conducted on HeLa cell lines with high folic acid receptor expression and MCF-7 cell lines with low folic acid receptor expression for comparison, showing effective target delivery to the HeLa cells through folic acid receptor meditated cellular endocytosis. The pH-responsive intracellular drug/siRNA release greatly minimizes the prerelease and possible side effects of the delivery system. By simultaneously delivering both doxorubicin (Dox) and siRNA against the Bcl-2 protein into the HeLa cells, the expression of the anti-apoptotic protein Bcl-2 was successfully suppressed, leading to an enhanced therapeutic efficacy. Thus, the present multifunctional nanoparticles show promising potentials for controlled and targeted drug and gene co-delivery in cancer treatment. PMID:24123533

Ma, Xing; Zhao, Yun; Ng, Kee Woei; Zhao, Yanli

2013-11-11

206

Enhanced Delivery of Gold Nanoparticles with Therapeutic Potential for Targeting Human Brain Tumors  

NASA Astrophysics Data System (ADS)

The blood brain barrier (BBB) remains a major challenge to the advancement and application of systemic anti-cancer therapeutics into the central nervous system. The structural and physiological delivery constraints of the BBB significantly limit the effectiveness of conventional chemotherapy, thereby making systemic administration a non-viable option for the vast majority of chemotherapy agents. Furthermore, the lack of specificity of conventional systemic chemotherapy when applied towards malignant brain tumors remains a major shortcoming. Hence novel therapeutic strategies that focus both on targeted and enhanced delivery across the BBB are warranted. In recent years nanoparticles (NPs) have emerged as attractive vehicles for efficient delivery of targeted anti-cancer therapeutics. In particular, gold nanoparticles (AuNPs) have gained prominence in several targeting applications involving systemic cancers. Their enhanced permeation and retention within permissive tumor microvasculature provide a selective advantage for targeting. Malignant brain tumors also exhibit transport-permissive microvasculature secondary to blood brain barrier disruption. Hence AuNPs may have potential relevance for brain tumor targeting. However, the permeation of AuNPs across the BBB has not been well characterized, and hence is a potential limitation for successful application of AuNP-based therapeutics within the central nervous system (CNS). In this dissertation, we designed and characterized AuNPs and assessed the role of polyethylene glycol (PEG) on the physical and biological properties of AuNPs. We established a size-dependent permeation profile with respect to core size as well as PEG length when AuNPs were assessed through a transport-permissive in-vitro BBB. This study was the first of its kind to systematically examine the influence of design on permeation of AuNPs through transport-permissive BBB. Given the significant delivery limitations through the non-transport permissive and intact BBB, we also assessed the role of magnetic resonance imaging (MRI) guided focused ultrasound (MRgFUS) disruption of the BBB in enhancing permeation of AuNPs across the intact BBB and tumor BBB in vivo. MRgFUS is a novel technique that can transiently increase BBB permeability thereby allowing delivery of therapeutics into the CNS. We demonstrated enhanced delivery of AuNPs with therapeutic potential into the CNS via MRgFUS. Our study was the first to establish a definitive role for MRgFUS in delivering AuNPs into the CNS. In summary, this thesis describes results from a series of research projects that have contributed to our understanding of the influence of design features on AuNP permeation through the BBB and also the potential role of MRgFUS in AuNP permeation across the BBB.

Etame, Arnold B.

207

Development of multiple-layer polymeric particles for targeted and controlled drug delivery  

PubMed Central

The purpose of this work was to develop multilayered particles consisting of a magnetic core and two encompassing shells made up of poly (N-isopropylacrylamide) (PNIPAAm) and poly(d,l-lactide-co-glycolide) (PLGA) for targeted and controlled drug delivery. Transmission electron microscopy confirmed that multilayered particles were obtained with PNIPAAm magnetic nanoparticles embedded within the PLGA shell. Factorial analysis studies also showed that the particle size was inversely proportional to the surfactant concentration and sonication power and directly proportional to the PLGA concentration. Drug-release results demonstrated that these multilayer particles produced an initial burst release and a subsequent sustained release of both bovine serum albumin (BSA) and curcumin loaded into the core and shell of the particle, respectively. BSA release was also affected by changes in temperature. In conclusion, our results indicate that the multilayered magnetic particles could be synthesized and used for targeted and controlled delivery of multiple drugs with different release mechanisms. PMID:19699325

Koppolu, Bhanuprasanth; Rahimi, Maham; Nattama, Sivaniarvindpriya; Wadajkar, Aniket; Nguyen, Kytai Truong

2010-01-01

208

Poly(2-oxazoline)-Based Nanogels as Biocompatible Pseudopolypeptide Nanoparticles.  

PubMed

Hydrophilic nanogels based on partially hydrolyzed poly(2-ethyl-2-oxazoline) were synthesized in dilute aqueous media in the presence of 1,6-hexanediol diglycidyl ether as a cross-linker. Nanogel formation was monitored by DLS and HSQC NMR spectroscopy, and the final nano-objects were characterized by DLS, TEM, AFM, and NanoSight analyses. Nanogels with a hydrodynamic radius of 78 nm exhibiting a slight positive surface charge were obtained. MTS assays (cell metabolic activity test) evidenced that nanogels were nontoxic in the investigated concentration range (i.e., 0.1 to 400 ?g/mL) and that no specific interaction with bovine serum albumin was observed. PMID:25409266

Legros, Camille; Wirotius, Anne-Laure; De Pauw-Gillet, Marie-Claire; Tam, Kam Chiu; Taton, Daniel; Lecommandoux, Sébastien

2015-01-12

209

Metal Chelating Crosslinkers Form Nanogels with High Chelation Stability  

PubMed Central

We present a series of hydrogel nanoparticles (nanogels) incorporating either acyclic or cyclic metal chelates as crosslinkers. These crosslinkers are used to formulate polyacrylamide-based nanogels (diameter 50 to 85 nm) yielding contrast agents with enhanced relaxivities (up to 6-fold greater than Dotarem®), because this nanogel structure slows the chelator's tumbling frequency and allows fast water exchange. Importantly, these nanogels also stabilize Gd3+ within the chelator thermodynamically and kinetically against metal displacement through transmetallation, which should reduce toxicity associated with release of free Gd3+. This chelation stability suggests that the chelate crosslinker strategy may prove useful for other applications of metal-chelating nanoparticles in medicine, including other imaging modalities and radiotherapy. PMID:24505553

Elst, Luce Vander; Schopf, Eric; Mahmoud, Enas; Laurent, Sophie; Almutairi, Adah

2013-01-01

210

Transferrin receptors and the targeted delivery of therapeutic agents against cancer  

PubMed Central

Background Traditional cancer therapy can be successful in destroying tumors, but can also cause dangerous side effects. Therefore, many targeted therapies are in development. The transferrin receptor (TfR) functions in cellular iron uptake through its interaction with transferrin. This receptor is an attractive molecule for the targeted therapy of cancer since it is upregulated on the surface of many cancer types and is efficiently internalized. This receptor can be targeted in two ways: 1) for the delivery of therapeutic molecules into malignant cells or 2) to block the natural function of the receptor leading directly to cancer cell death. Scope of review In the present article we discuss the strategies used to target the TfR for the delivery of therapeutic agents into cancer cells. We provide a summary of the vast types of anti-cancer drugs that have been delivered into cancer cells employing a variety of receptor binding molecules including Tf, anti-TfR antibodies, or TfR-binding peptides alone or in combination with carrier molecules including nanoparticles and viruses. Major conclusions Targeting the TfR has been shown to be effective in delivering many different therapeutic agents and causing cytotoxic effects in cancer cells in vitro and in vivo. General significance The extensive use of TfR for targeted therapy attests to the versatility of targeting this receptor for therapeutic purposes against malignant cells. More advances in this area are expected to further improve the therapeutic potential of targeting the TfR for cancer therapy leading to an increase in the number of clinical trials of molecules targeting this receptor. PMID:21851850

Daniels, Tracy R.; Bernabeu, Ezequiel; Rodríguez, José A.; Patel, Shabnum; Kozman, Maggie; Chiappetta, Diego A.; Holler, Eggehard; Ljubimova, Julia Y.; Helguera, Gustavo; Penichet, Manuel L.

2012-01-01

211

Targeted Delivery of siRNA to Macrophages for Anti-inflammatory Treatment  

Microsoft Academic Search

Inflammation mediated by tumor necrosis factor-? (TNF-?) and the associated neuronal apoptosis characterizes a number of neurologic disorders. Macrophages and microglial cells are believed to be the major source of TNF-? in the central nervous system (CNS). Here, we show that suppression of TNF-? by targeted delivery of small interfering RNA (siRNA) to macrophage\\/microglial cells dramatically reduces lipopolysaccharide (LPS)-induced neuroinflammation

Sang-Soo Kim; Chunting Ye; Priti Kumar; Isaac Chiu; Sandesh Subramanya; Haoquan Wu; Premlata Shankar; N Manjunath

2010-01-01

212

Self-assembling chitosan\\/poly-?-glutamic acid nanoparticles for targeted drug delivery  

Microsoft Academic Search

For the purpose of targeted drug delivery, composite biodegradable nanoparticles were prepared from chitosan and the poly-?-glutamic\\u000a acid via an ionotropic gelation process. These stable self-assembled nanoparticles were characterized by dynamic light scattering,\\u000a transmission electron microscopy, and atomic force microscopy, which demonstrated that the nanosystem consists of spherical\\u000a particles with a smooth surface both in aqueous environment and in dried

Zsolt Keresztessy; Magdolna Bodnár; Elizabeth Ber; István Hajdu; Min Zhang; John F. Hartmann; Tamara Minko; János Borbély

2009-01-01

213

Nucleolin targeting AS1411 modified protein nanoparticle for antitumor drugs delivery.  

PubMed

Over recent years, cell surface nucleolin as an anticancer target has attracted many researchers' attentions. To improve the antitumor efficacy, we developed a nucleolin targeted protein nanoparticle (NTPN) delivery system in which human serum albumin (HSA) was used as drug carrier and a DNA aptamer named AS1411, which had high affinity to nucleolin, was used as a bullet. The HSA nanoparticles (NPs-PTX) were fabricated by a novel self-assembly method and then modified with AS1411 (Apt-NPs-PTX). The resulted Apt-NPs-PTX were spherical. Compared with NPs-PTX, the uptake of Apt-NPs-PTX displayed a significant increase in MCF-7 cells while there was a decrease in nontumor cell lines such as MCF-10A and 3T3 cells. In a cytotoxic study, Apt-NPs-PTX displayed an enhanced cytotoxicity in MCF-7 tumor cells while there was almost no cytotoxicity in MCF-10A cells. Endostatin, a nucleolin inhibitor, could significantly decrease the internalization of Apt-NPs-PTX, suggesting nucleolin mediates the transmembrane process of Apt-NPs-PTX. Therefore, the AS1411 modified NTPN delivery system might be a promising targeted drug delivery system. PMID:23679916

Wu, Jinhui; Song, Chenchen; Jiang, Chenxiao; Shen, Xin; Qiao, Qian; Hu, Yiqiao

2013-10-01

214

Formulation design for target delivery of iron nanoparticles to TCE zones  

NASA Astrophysics Data System (ADS)

Nanoparticles of zero-valent iron (NZVI) are effective reducing agents for some dense non-aqueous phase liquid (DNAPL) contaminants such as trichloroethylene (TCE). However, target delivery of iron nanoparticles to DNAPL zones in the aquifer remains an elusive feature for NZVI technologies. This work discusses three strategies to deliver iron nanoparticles to DNAPL zones. To this end, iron oxide nanoparticles coated with oleate (OL) ions were used as stable analogs for NZVI. The OL-coated iron oxide nanoparticles are rendered lipophilic via (a) the addition of CaCl2, (b) acidification, or (c) the addition of a cationic surfactant, benzethonium chloride (BC). Mixtures of OL and BC show promise as a target delivery strategy due to the high stability of the nanoparticles in water, and their preferential partition into TCE in batch experiments. Column tests show that while the OL-BC coated iron oxide nanoparticles remain largely mobile in TCE-free columns, a large fraction of these particles are retained in TCE-contaminated columns, confirming the effectiveness of this target delivery strategy.

Wang, Ziheng; Acosta, Edgar

2013-12-01

215

Targeted Polymeric Micelle System for Delivery of Combretastatin A4 to Tumor Vasculature In Vitro  

Microsoft Academic Search

Purpose  To develop an efficient tumor vasculature-targeted polymeric micelle delivery system for combretastatin A4 (CA4), a novel\\u000a antivascular agent.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  CA4-loaded micelles were prepared from poly (ethylene glycol)-b-poly (d, l-lactide) copolymers. RGD peptides that target integrins ?v?3 and ?v?5, markers of angiogenic endothelial cells,\\u000a were coupled to the surface of micelles. The micelles were characterized in terms of particle size, morphology, drug

Yiguang Wang; Tingyuan Yang; Xun Wang; Jiancheng Wang; Xuan Zhang; Qiang Zhang

2010-01-01

216

Facile Preparation of Nanogels Using Activated Ester Containing Polymers  

PubMed Central

A facile methodology to prepare water-dispersible nanogels based on pentafluorophenyl acrylate and polyethylene glycol methacrylate random copolymer and diamine cross-linkers has been developed. Cross-linking reaction was characterized by FTIR and 19F NMR. We show that those nanogels : (i) are water-dispersible; (ii) can conveniently encapsulate lipophilic guest molecules; (iii) can be prepared with different nanosizes; (iv) are engineered to allow for surface decoration with additional functional groups.

Zhuang, Jiaming; Jiwpanich, Siriporn; Deepak, V. D.; Thayumanavan, S.

2014-01-01

217

Self-assembled nanoplatform for targeted delivery of chemotherapy agents via affinity-regulated molecular interactions  

PubMed Central

Site-specific delivery of drugs while minimizing unwanted distribution has been one of the pursued goals in cancer therapy. In this endeavor, we have developed targeted polymeric nanoparticles called amphiphilic urethane acrylate nonionomer (UAN) for encapsulation of diverse water-insoluble drugs and diagnostic agents, as well as for simple and reproducible surface conjugation of targeting ligands. Using monoclonal antibodies or lymphocyte function-associated antigen-1 (LFA-1) I domain engineered for varying affinities to intercellular adhesion molecule (ICAM)-1, we were able to deliver UAN nanoparticles to human cancer cells with the efficiency dependent on the strength of the molecular interactions and the degree of ICAM-1 expression on cell surface. Compared to non-specific uptake of free drugs, targeted delivery of UAN nanoparticles carrying equal amount of drugs produced more potent cytotoxicity. Notably, without the targeting ligands attached, UAN nanoparticles were largely precluded from non-specific uptake by the cells, resulting in much lower toxicity. The versatility of our UAN nanoparticles in both payload encapsulation and presentation of targeting ligands may facilitate developing a robust platform for evaluating various combinations of cancer drugs and molecular interactions toward developing effective cancer therapy formulations. PMID:20667589

Park, Spencer; Kang, Sungkwon; Veach, Alexander J.; Vedvyas, Yogindra; Zarnegar, Rasa; Kim, Ju-Young; Jin, Moonsoo M.

2010-01-01

218

Magnetic chitosan nanoparticles as a drug delivery system for targeting photodynamic therapy  

NASA Astrophysics Data System (ADS)

Photodynamic therapy (PDT) has become an increasingly recognized alternative to cancer treatment in clinic. However, PDT therapy agents, namely photosensitizer (PS), are limited in application as a result of prolonged cutaneous photosensitivity, poor water solubility and inadequate selectivity, which are encountered by numerous chemical therapies. Magnetic chitosan nanoparticles provide excellent biocompatibility, biodegradability, non-toxicity and water solubility without compromising their magnetic targeting. Nevertheless, no previous attempt has been reported to develop an in vivo magnetic drug delivery system with chitosan nanoparticles for magnetic resonance imaging (MRI) monitored targeting photodynamic therapy. In this study, magnetic targeting chitosan nanoparticles (MTCNPs) were prepared and tailored as a drug delivery system and imaging agents for PS, designated as PHPP. Results showed that PHPP-MTCNPs could be used in MRI monitored targeting PDT with excellent targeting and imaging ability. Non-toxicity and high photodynamic efficacy on SW480 carcinoma cells both in vitro and in vivo were achieved with this method at the level of 0-100 µM. Notably, localization of nanoparticles in skin and hepatic tissue was significantly less than in tumor tissue, therefore photosensitivity and hepatotoxicity can be attenuated.

Sun, Yun; Chen, Zhi-long; Yang, Xiao-xia; Huang, Peng; Zhou, Xin-ping; Du, Xiao-xia

2009-04-01

219

Bifunctional Coupling Agents for Radiolabeling of Biomolecules and Target-Specific Delivery of Metallic Radionuclides  

PubMed Central

Receptor-based radiopharmaceuticals are of great current interest in early molecular imaging and radiotherapy of cancers, and provide a unique tool for target-specific delivery of radionuclides to the diseased tissues. In general, a target-specific radiopharmaceutical can be divided into four parts: targeting biomolecule (BM), pharmacokinetic modifying (PKM) linker, bifunctional coupling or chelating agent (BFC), and radionuclide. The targeting biomolecule serves as a “carrier” for specific delivery of the radionuclide. PKM linkers are used to modify radiotracer excretion kinetics. BFC is needed for radiolabeling of biomolecules with a metallic radionuclide. Different radiometals have significant difference in their coordination chemistry, and require BFCs with different donor atoms and chelator frameworks. Since the radiometal chelate can have a significant impact on physical and biological properties of the target-specific radiopharmaceutical, its excretion kinetics can be altered by modifying the coordination environment with various chelators or coligand, if needed. This review will focus on the design of BFCs and their coordination chemistry with technetium, copper, gallium, indium, yttrium and lanthanide radiometals. PMID:18538888

Liu, Shuang

2008-01-01

220

Nucleic Acid aptamer-mediated drug delivery for targeted cancer therapy.  

PubMed

Aptamers are emerging as promising therapeutic agents and recognition elements. In particular, cell-SELEX (systematic evolution of ligands by exponential enrichment) allows in vitro selection of aptamers selective to whole cells without prior knowledge of the molecular signatures on the cell surface. The advantage of aptamers is their high affinitiy and binding specificity towards the target. This Minireview focuses on single-stranded (ss) oligonucleotide (DNA or RNA)-based aptamers as cancer therapeutics/theranostics. Specifically, aptamer-nanomaterial conjugates, aptamer-drug conjugates, targeted phototherapy and targeted biotherapy are covered in detail. In reviewing the literature, the potential of aptamers as delivery systems for therapeutic and imaging applications in cancer is clear, however, major challenges remain to be resolved, such as the poorly understood pharmacokinetics, toxicity and off-target effects, before they can be fully exploited in a clinical setting. PMID:25277749

Zhu, Huijie; Li, Jin; Zhang, Xiao-Bing; Ye, Mao; Tan, Weihong

2015-01-01

221

Hybrid micro-/nanogels for optical sensing and intracellular imaging  

PubMed Central

Hybrid micro-/nanogels are playing an increasing important part in a diverse range of applications, due to their tunable dimensions, large surface area, stable interior network structure, and a very short response time. We review recent advances and challenges in the developments of hybrid micro-/nanogels toward applications for optical sensing of pH, temperature, glucose, ions, and other species as well as for intracellular imaging. Due to their unique advantages, hybrid micro-/nanogels as optical probes are attracting substantial interests for continuous monitoring of chemical parameters in complex samples such as blood and bioreactor fluids, in chemical research and industry, and in food quality control. In particular, their intracellular probing ability enables the monitoring of the biochemistry and biophysics of live cells over time and space, thus contributing to the explanation of intricate biological processes and the development of novel diagnoses. Unlike most other probes, hybrid micro-/nanogels could also combine other multiple functions into a single probe. The rational design of hybrid micro-/nanogels will not only improve the probing applications as desirable, but also implement their applications in new arenas. With ongoing rapid advances in bionanotechnology, the well-designed hybrid micro-/nanogel probes will be able to provide simultaneous sensing, imaging diagnosis, and therapy toward clinical applications. PMID:22110866

Wu, Weitai; Zhou, Shuiqin

2010-01-01

222

Targeting stents with local delivery of paclitaxel-loaded magnetic nanoparticles using uniform fields  

PubMed Central

The use of stents for vascular disease has resulted in a paradigm shift with significant improvement in therapeutic outcomes. Polymer-coated drug-eluting stents (DES) have also significantly reduced the incidence of reobstruction post stenting, a disorder termed in-stent restenosis. However, the current DESs lack the capacity for adjustment of the drug dose and release kinetics to the disease status of the treated vessel. We hypothesized that these limitations can be addressed by a strategy combining magnetic targeting via a uniform field-induced magnetization effect and a biocompatible magnetic nanoparticle (MNP) formulation designed for efficient entrapment and delivery of paclitaxel (PTX). Magnetic treatment of cultured arterial smooth muscle cells with PTX-loaded MNPs caused significant cell growth inhibition, which was not observed under nonmagnetic conditions. In agreement with the results of mathematical modeling, significantly higher localization rates of locally delivered MNPs to stented arteries were achieved with uniform-field–controlled targeting compared to nonmagnetic controls in the rat carotid stenting model. The arterial tissue levels of stent-targeted MNPs remained 4- to 10-fold higher in magnetically treated animals vs. control over 5 days post delivery. The enhanced retention of MNPs at target sites due to the uniform field-induced magnetization effect resulted in a significant inhibition of in-stent restenosis with a relatively low dose of MNP-encapsulated PTX (7.5 ?g PTX/stent). Thus, this study demonstrates the feasibility of site-specific drug delivery to implanted magnetizable stents by uniform field-controlled targeting of MNPs with efficacy for in-stent restenosis. PMID:20404175

Chorny, Michael; Fishbein, Ilia; Yellen, Benjamin B.; Alferiev, Ivan S.; Bakay, Marina; Ganta, Srinivas; Adamo, Richard; Amiji, Mansoor; Friedman, Gary; Levy, Robert J.

2010-01-01

223

Enhanced Affinity Bifunctional Bisphosphonates for Targeted Delivery of Therapeutic Agents to Bone  

PubMed Central

Skeletal diseases have a major impact on the worldwide population and economy. Although several therapeutic agents and treatments are available for addressing bone diseases, they are not being fully utilized because of their uptake in non-targeted sites and related side effects. Active targeting with controlled delivery is an ideal approach for treatment of such diseases. Because bisphosphonates are known to have high affinity to bone and are being widely used in treatment of osteoporosis, they are well-suited for drug targeting to bone. In this study, a targeted delivery of therapeutic agent to resorption sites and wound healing sites of bone was explored. Towards this goal, bifunctional hydrazine-bisphosphonates (HBPs), with spacers of various lengths, were synthesized and studied for their enhanced affinity to bone. Crystal growth inhibition studies showed that these HBPs have high affinity to hydroxyapatite, and HBPs with shorter spacers bind stronger than alendronate to hydroxyapatite. The HBPs did not affect proliferation of MC3T3-E1 pre-osteoblasts, did not induce apoptosis, and were not cytotoxic at the concentration range tested (10?6 - 10?4 M). Furthermore, drugs can be linked to the HBPs through a hydrazone linkage that is cleavable at the low pH of bone resorption and wound healing sites, leading to release of the drug. This was demonstrated using hydroxyapatite as a model material of bone and 4-nitrobenzaldehyde as a model drug. This study suggests that these HBPs could be used for targeted delivery of therapeutic agents to bone. PMID:22073906

Yewle, Jivan N.; Puleo, David A.; Bachas, Leonidas G.

2011-01-01

224

Gene delivery with active targeting to ovarian cancer cells mediated by folate receptor alpha.  

PubMed

Folate receptor alpha (FRalpha) is overexpressed on ovarian cancer cells and is a promising molecular target for ovarian cancer gene therapy, but there was still no related report. In this study, folate modified cationic liposomes (F-PEG-CLPs) for ovarian cancer gene delivery were developed for the first time. Folate-poly(ethylene glycol)-succinate-cholesterol (F-PEG-suc-Chol) was firstly synthesized and then used to prepare folate-targeted cationic liposomes/plasmid DNA complexes (F-targeted lipoplexes). F-targeted lipoplexes were prepared by post-insertion method, and displayed membrane structure by transmission electron microscopy observation with the diameter of 193 nm-200 nm and the zeta potential of 35 mV-38 mV. DNase degradation experiments showed that plasmid DNA could be effectively shielded by F-targeted lipoplexes in vitro. F-targeted lipoplexes could transfer gene into human ovarian carcinoma cell line SKOV-3, and 0.1% F-PEG-CLPs composed by DOTAP/Chol/mPEG-Chol/F-PEG-suc-Chol (50:45:5:0.1, molar ratio) had the highest transfection efficiency. The transfection activity of F-targeted lipoplexes could be competitively inhibited by free folic acid, demonstrating that folate-FRalpha interaction caused high transfection efficiency of F-targeted lipoplexes. The uptake mechanism of F-targeted lipoplexes was further validated on human oral carcinoma cell line KB and human liver carcinoma cell line HepG2. The concentration-dependent and time-dependent cytotoxicity of targeted material F-PEG-suc-Chol was observed by MTT assay on SKOV-3 cell and its application would not increase the cytotoxicity of F-targeted lipoplexes in SKOV-3 cells. All the data indicated that F-PEG-CLPs would be a promising gene vector targeting for ovarian cancer therapy. PMID:23802413

He, Zhiyao; Yu, Yiyi; Zhang, Ying; Yan, Yongdong; Zheng, Yu; He, Jun; Xie, Yongmei; He, Gu; Wei, Yuquan; Song, Xiangrong

2013-05-01

225

Nanoparticle-mediated delivery of siRNA targeting Parp1 extends survival of mice bearing tumors  

E-print Network

Nanoparticle-mediated delivery of siRNA targeting Parp1 extends survival of mice bearing tumors the survival of mice bearing tumors derived from Brca1-deficient ovarian cancer cells but not from Brca1 wild

Bhatia, Sangeeta

226

Cancer Nanotheranostics: Improving Imaging and Therapy by Targeted Delivery across Biological Barriers  

PubMed Central

Cancer nanotheranostics aims to combine imaging and therapy of cancer through use of nanotechnology. The ability to engineer nanomaterials to interact with cancer cells at the molecular level can significantly improve the effectiveness and specificity of therapy to cancers that are currently difficult to treat. In particular, metastatic cancers, drug-resistant cancers, and cancer stem cells impose the greatest therapeutic challenge that requires targeted therapy to treat effectively. Targeted therapy can be achieved with appropriate designed drug delivery vehicles such as nanoparticles, adult stem cells, or T cells in immunotherapy. In this article, we first review the different types of materials commonly used to synthesize nanotheranostic particles and their use in imaging. We then discuss biological barriers that these nanoparticles encounter and must bypass to reach the target cancer cells, including the blood, liver, kidneys, spleen, and particularly the blood-brain barrier. We then review how nanotheranostics can be used to improve targeted delivery and treatment of cancer cells using nanoparticles, adult stem cells, and T cells in immunotherapy. Finally, we discuss development of nanoparticles to overcome current limitations in cancer therapy. PMID:21842473

Kievit, Forrest M.; Zhang, Miqin

2012-01-01

227

Carrier-free, functionalized pure drug nanorods as a novel cancer-targeted drug delivery platform  

NASA Astrophysics Data System (ADS)

A one-dimensional drug delivery system (1D DDS) is highly attractive since it has distinct advantages such as enhanced drug efficiency and better pharmacokinetics. However, drugs in 1D DDSs are all encapsulated in inert carriers, and problems such as low drug loading content and possible undesirable side effects caused by the carriers remain a serious challenge. In this paper, a novel, carrier-free, pure drug nanorod-based, tumor-targeted 1D DDS has been developed. Drugs are first prepared as nanorods and then surface functionalized to achieve excellent water dispersity and stability. The resulting drug nanorods show enhanced internalization rates mainly through energy-dependent endocytosis, with the shape-mediated nanorod (NR) diffusion process as a secondary pathway. The multiple endocytotic mechanisms lead to significantly improved drug efficiency of functionalized NRs with nearly ten times higher cytotoxicity than those of free molecules and unfunctionalized NRs. A targeted drug delivery system can be readily achieved through surface functionalization with targeting group linked amphipathic surfactant, which exhibits significantly enhanced drug efficacy and discriminates between cell lines with high selectivity. These results clearly show that this tumor-targeting DDS demonstrates high potential toward specific cancer cell lines.

Li, Yanan; Yang, Yinlong; An, Feifei; Liu, Zhuang; Zhang, Xiujuan; Zhang, Xiaohong

2013-01-01

228

Molecularly self-assembled nucleic acid nanoparticles for targeted in vivo siRNA delivery  

NASA Astrophysics Data System (ADS)

Nanoparticles are used for delivering therapeutics into cells. However, size, shape, surface chemistry and the presentation of targeting ligands on the surface of nanoparticles can affect circulation half-life and biodistribution, cell-specific internalization, excretion, toxicity and efficacy. A variety of materials have been explored for delivering small interfering RNAs (siRNAs)--a therapeutic agent that suppresses the expression of targeted genes. However, conventional delivery nanoparticles such as liposomes and polymeric systems are heterogeneous in size, composition and surface chemistry, and this can lead to suboptimal performance, a lack of tissue specificity and potential toxicity. Here, we show that self-assembled DNA tetrahedral nanoparticles with a well-defined size can deliver siRNAs into cells and silence target genes in tumours. Monodisperse nanoparticles are prepared through the self-assembly of complementary DNA strands. Because the DNA strands are easily programmable, the size of the nanoparticles and the spatial orientation and density of cancer-targeting ligands (such as peptides and folate) on the nanoparticle surface can be controlled precisely. We show that at least three folate molecules per nanoparticle are required for optimal delivery of the siRNAs into cells and, gene silencing occurs only when the ligands are in the appropriate spatial orientation. In vivo, these nanoparticles showed a longer blood circulation time (t1/2 ~ 24.2 min) than the parent siRNA (t1/2 ~ 6 min).

Lee, Hyukjin; Lytton-Jean, Abigail K. R.; Chen, Yi; Love, Kevin T.; Park, Angela I.; Karagiannis, Emmanouil D.; Sehgal, Alfica; Querbes, William; Zurenko, Christopher S.; Jayaraman, Muthusamy; Peng, Chang G.; Charisse, Klaus; Borodovsky, Anna; Manoharan, Muthiah; Donahoe, Jessica S.; Truelove, Jessica; Nahrendorf, Matthias; Langer, Robert; Anderson, Daniel G.

2012-06-01

229

Formulation of Functionalized PLGA-PEG Nanoparticles for In Vivo Targeted Drug Delivery  

PubMed Central

Nanoparticle (NP) size has been shown to significantly effect the biodistribution of targeted and non-targeted NPs in an organ specific manner. Herein we have developed NPs from carboxy-terminated poly (d,l-lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-b-PEG-COOH) polymer and studied the effects of altering the following formulation parameters on the size of NPs, including: 1) polymer concentration, 2) drug loading, 3) water miscibility of solvent, and 4) the ratio of water to solvent. We found that NP mean volumetric size correlates linearly with polymer concentration for NPs between 70 and 250 nm in diameter (linear coefficient = 0.99 for NPs formulated with solvents studied). NPs with desirable size, drug loading, and polydispersity were conjugated to the A10 RNA aptamer (Apt) that binds to the Prostate Specific Membrane Antigen (PSMA), and NP and NP-Apt biodistribution was evaluated in a LNCaP (PSMA+) xenograft mouse model of PCa. The surface functionalization of NPs with the A10 PSMA aptamer significantly enhanced delivery of NPs to tumors vs. equivalent NPs lacking the A10 PSMA aptamer (a 3.77-fold increase at 24 hrs; NP-Apt 0.83% ± 0.21% vs. NP 0.22% ± 0.07% of injected dose per gram of tissue; mean ± s.d., n = 4, p = 0.002). The ability to control NP size together with targeted delivery may result in favorable biodistribution and development of clinically relevant targeted therapies. PMID:17055572

Cheng, Jianjun; Teply, Benjamin A.; Sherifi, Ines; Sung, Josephine; Luther, Gaurav; Gu, Frank X.; Levy-Nissenbaum, Etgar; Radovic-Moreno, Aleksandar F.; Langer, Robert; Farokhzad, Omid C.

2009-01-01

230

Cardiological Biopharmaceuticals in the Conception of Drug Targeting Delivery: Practical Results and Research Perspectives  

PubMed Central

The results of the clinical use of thrombolytic and antithrombotic preparations developed on the basis of protein conjugates obtained within the framework of the conception of drug targeting delivery in the organism are considered. A decrease has been noted in the number of biomedical projects focused on these derivatives as a result of various factors: the significant depletion of financial and organizational funds, the saturation of the pharmaceutical market with preparations of this kind, and the appearance of original means for interventional procedures. Factors that actively facilitate the conspicuous potentiation of the efficacy of bioconjugates were revealed: the biomedical testing of protein domains and their selected combinations, the optimization of molecular sizes for the bioconjugates obtained, the density of target localization, the application of cell adhesion molecules as targets, and the application of connected enzyme activities. Enzyme antioxidants and the opportunity for further elaboration of the drug delivery conception via the elucidation and formation of therapeutic targets for effective drug reactions by means of pharmacological pre- and postconditioning of myocardium arouse significant interest. PMID:23150805

Maksimenko, A.V.

2012-01-01

231

Targeted Delivery of Antibiotics to Intracellular Chlamydial Infections using PLGA Nanoparticles  

PubMed Central

Chlamydia trachomatis and C pneumoniae are intracellular bacterial pathogens that have been shown to cause, or are strongly associated with, diverse chronic diseases. Persistent infections by both organisms are refractory to antibiotic therapy. The lack of therapeutic efficacy results from the attenuated metabolic rate of persistently infecting chlamydiae in combination with the modest intracellular drug concentrations achievable by normal delivery of antibiotics to the inclusions within which chlamydiae reside in the host cell cytoplasm. In this research, we evaluated whether nanoparticles formulated using the biodegradable poly(d-L-lactide-co-glycolide) (PLGA) polymer can enhance the delivery of antibiotics to the chlamydial inclusion complexes. We initially studied the trafficking of PLGA nanoparticles in Chlamydia-infected cells. We then evaluated nanoparticles for the delivery of antibiotics to the inclusions. Intracellular trafficking studies show that PLGA nanoparticles efficiently concentrate in inclusions in both acutely and persistently infected cells. Further, encapsulation of rifampin and azithromycin antibiotics in PLGA nanoparticles enhanced the effectiveness of the antibiotics in reducing microbial burden. Combination of rifampin and azithromycin was more effective than the individual drugs. Overall, our studies show that PLGA nanoparticles can be effective carriers for targeted delivery of antibiotics to intracellular chlamydial infections. PMID:21652065

Toti, Udaya S.; Guru, Bharath R.; Hali, Mirabela; McPharlin, Christopher; Wykes, Susan M.; Panyam, Jayanth; Whittum-Hudson, Judith A.

2011-01-01

232

A comprehensive overview of exosomes as drug delivery vehicles - endogenous nanocarriers for targeted cancer therapy.  

PubMed

Exosomes denote a class of secreted nanoparticles defined by size, surface protein and lipid composition, and the ability to carry RNA and proteins. They are important mediators of intercellular communication and regulators of the cellular niche, and their altered characteristics in many diseases, such as cancer, suggest them to be important both for diagnostic and therapeutic purposes, prompting the idea of using exosomes as drug delivery vehicles, especially for gene therapy. This review covers the current status of evidence presented in the field of exosome-based drug delivery systems. Components for successful exosome-based drug delivery, such as choice of donor cell, therapeutic cargo, use of targeting peptide, loading method and administration route are highlighted and discussed with a general focus pertaining to the results obtained in models of different cancer types. In addition, completed and on-going clinical trials are described, evaluating exosome-based therapies for the treatment of different cancer types. Due to their endogenous origin, exosome-based drug delivery systems may have advantages in the treatment of cancer, but their design needs further refinement to justify their usage on the clinical scale. PMID:24747178

Johnsen, Kasper Bendix; Gudbergsson, Johann Mar; Skov, Martin Najbjerg; Pilgaard, Linda; Moos, Torben; Duroux, Meg

2014-08-01

233

Non-Condensing Polymeric Nanoparticles for Targeted Gene and siRNA Delivery  

PubMed Central

Gene therapy has shown a tremendous potential to benefit patients in a variety of disease conditions. However, finding a safe and effective systemic delivery system is the major obstacle in this area. Although viral vectors showed promise for high transfection rate, the immunogenicity associated with these systems has hindered further development. As an alternative to viral gene delivery, this review focuses on application of novel safe and effective non-condensing polymeric systems that have shown high transgene expression when administered systemically or by the oral route. Type B gelatin-based engineered nanocarriers were evaluated for passive and active tumor-targeted delivery and transfection using both reporter and therapeutic plasmid DNA. Additionally, we have shown that nanoparticles-in-microsphere oral system (NiMOS) can efficiently deliver reporter and therapeutic gene constructs in the gastrointestinal tract. Additionally, there has been a significant recent interest in the use small interfering RNA (siRNA) as a therapeutic system for gene silencing. Both gelatin nanoparticles and NiMOS have shown activity in systemic and oral delivery of siRNA, respectively. PMID:21621597

Xu, Jing; Ganesh, Shanthi; Amiji, Mansoor

2011-01-01

234

NIR-to-visible upconversion nanoparticles for fluorescent labeling and targeted delivery of siRNA  

NASA Astrophysics Data System (ADS)

Near-infrared (NIR)-to-visible upconversion fluorescent nanoparticles were synthesized and used for imaging and targeted delivery of small interfering RNA (siRNA) to cancer cells. Silica-coated NaYF4 upconversion nanoparticles (UCNs) co-doped with lanthanide ions (Yb/Er) were synthesized. Folic acid and anti-Her2 antibody conjugated UCNs were used to fluorescently label the folate receptors of HT-29 cells and Her2 receptors of SK-BR-3 cells, respectively. The intracellular uptake of the folic acid and antibody conjugated UCNs was visualized using a confocal fluorescence microscope equipped with an NIR laser. siRNA was attached to anti-Her2 antibody conjugated UCNs and the delivery of these nanoparticles to SK-BR-3 cells was studied. Meanwhile, a luciferase assay was established to confirm the gene silencing effect of siRNA. Upconversion nanoparticles can serve as a fluorescent probe and delivery system for simultaneous imaging and delivery of biological molecules.

Jiang, Shan; Zhang, Yong; Lim, Kian Meng; Sim, Eugene K. W.; Ye, Lei

2009-04-01

235

Safety Assessment of Liver-Targeted Hydrodynamic Gene Delivery in Dogs  

PubMed Central

Evidence in support of safety of a gene delivery procedure is essential toward gene therapy. Previous studies using the hydrodynamics-based procedure primarily focus on gene delivery efficiency or gene function analysis in mice. The current study focuses on an assessment of the safety of computer-controlled and liver-targeted hydrodynamic gene delivery in dogs as the first step toward hydrodynamic gene therapy in clinic. We demonstrate that the impacts of the hydrodynamic procedure were limited in the injected region and the influences were transient. Histological examination and the hepatic microcirculation measurement using reflectance spectrophotometry reveal that the liver-specific impact of the procedure involves a transient expansion of the liver sinusoids. No systemic damage or toxicity was observed. Physiological parameters, including electrocardiogram, heart rate, blood pressure, oxygen saturation, and body temperature, remained in normal ranges during and after hydrodynamic injection. Body weight was also examined to assess the long-term effects of the procedure in animals who underwent 3 hydrodynamic injections in 6 weeks with 2-week time interval in between. Serum biochemistry analysis showed a transient increase in liver enzymes and a few cytokines upon injection. These results demonstrate that image-guided, liver-specific hydrodynamic gene delivery is safe. PMID:25251246

Kamimura, Kenya; Kanefuji, Tsutomu; Yokoo, Takeshi; Abe, Hiroyuki; Suda, Takeshi; Kobayashi, Yuji; Zhang, Guisheng; Aoyagi, Yutaka; Liu, Dexi

2014-01-01

236

Cargo-towing fuel-free magnetic nanoswimmers for targeted drug delivery.  

PubMed

Fuel-free nanomotors are essential for future in-vivo biomedical transport and drug-delivery applications. Herein, the first example of directed delivery of drug-loaded magnetic polymeric particles using magnetically driven flexible nanoswimmers is described. It is demonstrated that flexible magnetic nickel-silver nanoswimmers (5-6 ?m in length and 200 nm in diameter) are able to transport micrometer particles at high speeds of more than 10 ?m s(-1) (more than 0.2 body lengths per revolution in dimensionless speed). The fundamental mechanism of the cargo-towing ability of these magnetic (fuel-free) nanowire motors is modelled, and the hydrodynamic features of these cargo-loaded motors discussed. The effect of the cargo size on swimming performance is evaluated experimentally and compared to a theoretical model, emphasizing the interplay between hydrodynamic drag forces and boundary actuation. The latter leads to an unusual increase of the propulsion speed at an intermediate particle size. Potential applications of these cargo-towing nanoswimmers are demonstrated by using the directed delivery of drug-loaded microparticles to HeLa cancer cells in biological media. Transport of the drug carriers through a microchannel from the pick-up zone to the release microwell is further illustrated. It is expected that magnetically driven nanoswimmers will provide a new approach for the rapid delivery of target-specific drug carriers to predetermined destinations. PMID:22174121

Gao, Wei; Kagan, Daniel; Pak, On Shun; Clawson, Corbin; Campuzano, Susana; Chuluun-Erdene, Erdembileg; Shipton, Erik; Fullerton, Eric E; Zhang, Liangfang; Lauga, Eric; Wang, Joseph

2012-02-01

237

Hyaluronic acid modified mesoporous silica nanoparticles for targeted drug delivery to CD44-overexpressing cancer cells  

NASA Astrophysics Data System (ADS)

In this paper, a targeted drug delivery system has been developed based on hyaluronic acid (HA) modified mesoporous silica nanoparticles (MSNs). HA-MSNs possess a specific affinity to CD44 over-expressed on the surface of a specific cancer cell line, HCT-116 (human colon cancer cells). The cellular uptake performance of fluorescently labelled MSNs with and without HA modification has been evaluated by confocal microscopy and fluorescence-activated cell sorter (FACS) analysis. Compared to bare MSNs, HA-MSNs exhibit a higher cellular uptake via HA receptor mediated endocytosis. An anticancer drug, doxorubicin hydrochloride (Dox), has been loaded into MSNs and HA-MSNs as drug delivery vehicles. Dox loaded HA-MSNs show greater cytotoxicity to HCT-116 cells than free Dox and Dox-MSNs due to the enhanced cell internalization behavior of HA-MSNs. It is expected that HA-MSNs have a great potential in targeted delivery of anticancer drugs to CD44 over-expressing tumors.

Yu, Meihua; Jambhrunkar, Siddharth; Thorn, Peter; Chen, Jiezhong; Gu, Wenyi; Yu, Chengzhong

2012-12-01

238

A novel liposomal formulation of FTY720 (Fingolimod) for promising enhanced targeted delivery  

PubMed Central

We describe here the development and characterization of the physicochemical and pharmacokinetic properties of a novel liposomal formulation for FTY720 delivery, LP-FTY720. The mean diameter of LP-FTY720 was ~157 nm, and the FTY720 entrapment efficiency was ~85%. The liposomal formulation protected FTY720 from degradation in aqueous buffer and showed toxicity in CLL patient B cells comparable to that of free FTY720. Following intravenous injection in ICR mice, LP-FTY720 had an increased elimination phase half-life (~28 vs. ~19 hr) and decreased clearance (235 vs. 778 mL/h/kg) compared to the free drug. Antibodies against CD19, CD20 and CD37 were incorporated into LP-FTY720, which provided targeted delivery to CLL patient B cells and thus achieved higher killing efficacy. The novel liposomal carrier of FTY720 demonstrated improved pharmacokinetic properties, comparable activity, and a potential platform for targeted delivery to CLL by overcoming the limited application of free FTY720 to B malignancy treatment. PMID:23969101

Mao, Yicheng; Wang, Jiang; Zhao, Yuan; Wu, Yun; Kwak, Kwang Joo; Chen, Ching-Shih; Byrd, John C.; Lee, Robert J.; Phelps, Mitch A.; Lee, L. James; Muthusamy, Natarajan

2014-01-01

239

Synthesis and Characterization of Polymer Nanocarriers for the Targeted Delivery of Therapeutic Enzymes  

PubMed Central

Protein drugs, such as recombinant enzymes useful for detoxification and replacement therapies, have extraordinary specificity and potency. However, inherently inadequate delivery to target sites and rapid inactivation limit their medical utility. Using chaperone polymeric particles designed within an injectible size range (sub-micron) may help solve these shortcomings. Such nanocarriers would (i) prevent premature inactivation of encapsulated therapeutic protein cargoes, (ii) provide a carrier that can be surface decorated by targeting ligands, and (iii) optimize sub-cellular localization of the drug. This chapter describes the techniques successfully employed for the preparation of polymer nanocarriers (PNC) loaded with the antioxidant enzyme, catalase, and targeted to endothelial cells. Methods of PNC synthesis, loading with catalase, characterization, coupling of a targeting moiety, and in vitro testing of the enzymatic and targeting activities are provided here. Advantages and disadvantages of specific designs are discussed. Due to the modular nature of the targeting methodology employed, it is believed that these protocols will provide a solid foundation for the formulation of a wide variety of enzymatic drug targeting strategies. PMID:20013177

Simone, Eric; Dziubla, Thomas; Shuvaev, Vladimir; Muzykantov, Vladimir R.

2011-01-01

240

Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging  

PubMed Central

Magnetic nanoparticles (MNPs) represent a class of non-invasive imaging agents that have been developed for magnetic resonance (MR) imaging. These MNPs have traditionally been used for disease imaging via passive targeting, but recent advances have opened the door to cellular-specific targeting, drug delivery, and multi-modal imaging by these nanoparticles. As more elaborate MNPs are envisioned, adherence to proper design criteria (e.g. size, coating, molecular functionalization) becomes even more essential. This review summarizes the design parameters that affect MNP performance in vivo, including the physicochemical properties and nanoparticle surface modifications, such as MNP coating and targeting ligand functionalizations that can enhance MNP management of biological barriers. A careful review of the chemistries used to modify the surfaces of MNPs is also given, with attention paid to optimizing the activity of bound ligands while maintaining favorable physicochemical properties. PMID:19909778

Veiseh, Omid; Gunn, Jonathan; Zhang, Miqin

2009-01-01

241

Investigation of strategies for drug delivery by combination targeting of nanocarriers to multiple epitopes or receptors  

NASA Astrophysics Data System (ADS)

Development of drug delivery systems (ie. nanocarriers) with controllable composition, architecture, and functionalities is heavily investigated in the field of drug delivery in order to improve clinical interventions. Designing drug nanocarriers which possess targeting properties is critical to enable them to reach the intended site of intervention in the body. To achieve this goal, the surface of drug nanocarriers can be modified with targeting moieties (antibodies, peptides, etc.) addressed to cell surface molecules expressed on the diseased tissues and cells. If these molecules are receptors capable of internalizing bound ligands via endocytosis, targeting can then enable drug transport into cells or across cellular barriers in the body. Yet, addressing nanocarriers to single targets presents limited control over cellular interactions and biodistribution. Since most cell-surface markers are not exclusively expressed in a precise site in vivo, high affinity of targeted nanocarriers may lead to non-desired accumulation in regions of the body associated with low expression. Modification of nanocarriers to achieve combined-targeting (binding to more than one cell-surface receptor) may help modulate binding to cells and also endocytosis, since cell receptors possess distinct functions and features affecting these parameters, such as their expression, location on the plasmalemma, activation in disease, mechanism of endocytosis, etc. Further, targeting nanocarriers to multiple epitopes of the same receptor, a strategy which has never been tested, may also modulate these parameters since they are highly epitope specific. In this dissertation, we investigate the effect of targeting model polymer nanocarriers to: (1) multiple receptors of similar function (intercellular-, platelet-endothelial-, and/or vascular-cell adhesion molecules), (2) multiple receptors of different function (intercellular adhesion molecule 1 and transferrin receptor), or (3) multiple epitopes of the same receptor (transferrin receptor epitopes 8D3 and R17). Binding to cells, endocytosis within cells, and biodistribution in mice were tested. Results indicate that combination targeting enhanced performance of nanocarriers with regard to these three parameters as compared to non-targeted nanocarriers and modulated their outcome relative to single-targeted nanocarriers. This modulation was observed as enhanced, intermediate, or diminished interaction with cells, accumulation in particular organs, and specificity for diseased sites relative to single-targeted nanocarriers. These results were general to strategies 1--3 and were difficult to foresee a priori due to the complex nature of said interactions. Importantly, outcomes depended on the multiplicity (dual- vs. triple-targeting) and/or combination of affinity moieties displayed on the nanocarrier surface, as well as the physiological/pathological state of cells and tissues. Modulation of the delivery of a model therapeutic cargo in mice relative to single-targeted nanocarriers demonstrated the potential of these strategies to control the biodistribution of therapeutic agents. Therefore, these findings illustrate that combination-targeting enables modulation over cellular interactions and biodistribution of nanocarriers, which may aid the development of nanocarriers tailored for particular therapeutic needs.

Papademetriou, Iason Titos

242

Tumor-targeted liposomal drug delivery mediated by a diseleno bond-stabilized cyclic peptide  

PubMed Central

Peptide ligands have played an important role in tumor-targeted drug delivery as targeting moieties. The in vivo fate of peptide-mediated drug delivery systems and the following antitumor effects may greatly depend on the stability of the peptide ligand. In the current study, a tumor-targeting cyclic peptide screened by phage display, Lyp-1 (a peptide that specifically binds to tumor and endothelial cells of tumor lymphatics in certain tumors), was structurally modified by replacement of the original intramolecular disulfide bond with a diseleno bond. The produced analog Syp-1 (seleno derivative of Lyp-1) maintained specific binding ability to the target protein p32 (Kd = 18.54 nM), which is similar to that of Lyp-1 (Kd = 10.59 nM), indicated by surface plasmon resonance assay. Compared with Lyp-1, Syp-1 showed significantly improved stability against serum. After the peptide attached onto the surface of fluorophore-encapsulating liposomes, the more efficient tumor uptake of liposomal fluorophore mediated by Syp-1 was observed. Furthermore, Syp-1 modified liposomal doxorubicin presented the most potent tumor growth inhibitory ability among all the therapeutic groups, with a low half maximal inhibitory concentration of 588 nM against MDA-MB-435 cells in vitro and a high tumor inhibition rate of 73.5% in vivo. These findings clearly indicated that Syp-1 was a stable and effective tumor targeting ligand and suggest that the sulfur-to-selenium replacement strategy may help stabilize the phage-displayed cyclic peptide containing disulfide-bond under physiological conditions and strongly support the validity of peptide-mediated drug targeting. PMID:23515368

Li, Chong; Wang, Yixin; Zhang, Xiaolin; Deng, Li; Zhang, Yan; Chen, Zhangbao

2013-01-01

243

Plasmid DNA nanogels as photoresponsive materials for multifunctional bio-applications.  

PubMed

This study provides a detailed description on the synthesis and characterization of novel polyamine plasmid DNA nanogels. Ethylene glycol diglycidyl ether was used as cross-linker, in conjugation with polyamines to promote pDNA condensation. The biocompatible nanovectors exhibit a unique swelling behaviour in water and salt solutions. These systems are light photodegradable allowing their use in a broad range of biotechnological applications. Different plasmids, pVAX1-LacZ and pcDNA3-FLAG-p53, and anticancer drugs were, thus, efficiently loaded in the nanogels and their controlled release was demonstrated. Furthermore, the dual delivery of pcDNA3-FLAG-p53 gene and anticancer drugs illustrates the possibility of the combination of chemical and gene therapies. This new versatile and easy method of nanohydrogels preparation provides a potential synthetic approach for the design of tunable systems which can display multiple functions, sensitivity to different stimuli and exhibit programmed responses as well. PMID:25449013

Costa, Diana; Valente, Artur J M; Queiroz, João

2014-11-20

244

Single molecular mechanics of a cholesterol-bearing pullulan nanogel at the hydrophobic interfaces.  

PubMed

The study of nanogel (hydrogel nanoparticle) has intensified in the last decade due to the enormous potential applications in biomimetics, biosensors, artificial muscles and drug delivery (or release) systems. Cholesterol-bearing pullulan (CHP) is composed of hydrophilic pullulan backbone and partly substituted hydrophobic cholesterol, and is capable of forming a stable hydrogel nanoparticle in aqueous solution due to the self-assembly of hydrophobic cholesterol moieties. The conformation of CHP changes dramatically at the hydrophobic interfaces. In order to understand the interfacial responses of CHP, the interaction forces of CHP nanogels to the hydrophobic HOPG (highly orientated pyrolytic graphite) or carbon-coated surfaces were measured using atomic force microscope. The freely jointed china model for CHP molecular elasticity was applied to the force-extension curves and debonding force-pull-off distance in order to estimate the contour lengths and the segment lengths of the CHP molecules. The segment length of CHP chains in aqueous solution was estimated 0.32+/-0.19 nm showing a very flexible chain. From our analysis of the dynamic force measurements, the debonding forces were shown to depend on the applied loading forces. The zero kinetic off-rate K(off)(0) and the transition state x(b) were estimated to be 1.1 x 10(-3)s(-1) and 2.9A, respectively. PMID:14967522

Lee, ImShik; Akiyoshi, K

2004-07-01

245

Multifunctional disulfide-based cationic dextran conjugates for intravenous gene delivery targeting ovarian cancer cells.  

PubMed

A folate-decorated, disulfide-based cationic dextran conjugate having dextran as the main chain and disulfide-linked 1,4-bis(3-aminopropyl)piperazine (BAP) residues as the grafts was designed and successfully prepared as a multifunctional gene delivery vector for targeted gene delivery to ovarian cancer SKOV-3 cells in vitro and in vivo. Initially, a new bioreducible cationic polyamide (denoted as pSSBAP) was prepared by polycondensation reaction of bis(p-nitrophenyl)-3,3'-dithiodipropanoate, a disulfide-containing monomer, and BAP. It was found that the pSSBAP was highly efficient for in vitro gene delivery against MCF-7 and SKOV-3 cell lines. Subsequently, two cationic dextran conjugates with different amounts of BAP residues (denoted as Dex-SSBAP6 and Dex-SSBAP30, respectively) were synthesized by coupling BAP to disulfide-linked carboxylated dextran or coupling pSSBAP-oligomer to p-nitrophenyl carbonated dextran. Both two conjugates were able to bind DNA to form nanosized polyplexes with an improved colloidal stability in physiological conditions. The polyplexes, however, were rapidly dissociated to liberate DNA in a reducing environment. In vitro transfection experiments revealed that the polyplexes of Dex-SSBAP30 efficiently transfected SKOV-3 cells, yielding transfection efficiency that is comparable to that of linear polyethylenimine or lipofectamine 2000. AlamarBlue assay showed that the conjugates had low cytotoxicity in vitro at a high concentration of 100 mg/L. Further, Dex-SSBAP30 has primary amine side groups and thus allows for folate (FA) conjugation, yielding FA-coupled Dex-SSBAP30 (Dex-SSBAP30-FA). It was found that Dex-SSBAP30-FA was efficient for targeted gene delivery to SKOV-3 tumor xenografted in a nude mouse model by intravenous injection, inducing a higher level of gene expression in the tumor as compared to Dex-SSBAP30 lacking FA and comparable gene expression to linear polyethylenimine as one of the most efficient polymeric vectors for intravenous gene delivery in vivo. Disulfide-based cationic dextran system thus has a high potential for intravenous gene delivery toward cancer gene therapy. PMID:24892216

Song, Yanyan; Lou, Bo; Zhao, Peng; Lin, Chao

2014-07-01

246

Preparation of chitin nanogels containing nickel nanoparticles.  

PubMed

In this work, we developed 120-150 nm sized nickel nanoparticles loaded chitin nanogels (Ni-Chitin NGs) by regeneration chemistry approach to investigate and determine its cytocompatibility and antibacterial activity against Staphylococcus aureus. The nickel nanoparticles were prepared by hydrothermal method. The prepared Ni-Chitin NGs were well characterized by SEM, FTIR, TG/DTA/DTG and XRD and the in vitro cytocompatibility was tested on A549 and L929 cells which showed that they are completely non-toxic. Ni-Chitin NGs showed better toxicity to the bacterial strains when compared to previous study with other nanoparticles using serial dilution method. The rhodamine labeled-Ni-Chitin NGs showed cellular localization on both L929 and A549 cells without perturbing their cellular constituents. These studies showed that the Ni-Chitin NGs could be used for various applications in biomedical filed. PMID:23911472

Kumar, N Ashwin; Rejinold, N Sanoj; Anjali, P; Balakrishnan, Avinash; Biswas, Raja; Jayakumar, R

2013-09-12

247

Simultaneous nuclear imaging and intranuclear drug delivery by nuclear-targeted multifunctional upconversion nanoprobes.  

PubMed

Nuclear-targeted therapy by delivering anticancer drug directly into cancer cell nuclei can elicit synergistic therapeutic effects and kill these cancer cells with much enhanced efficiencies. Besides nuclear targeting, another difficulty in nuclear-targeted therapy is how to achieve real-time monitoring of the therapy process simultaneously. In this article we report on the development of multifunctional upconversion nanoparticles (UCNPs) which were able to target cancer cell nuclei, and thus deliver the anticancer drug directly to the nuclear region and simultaneously image cell nucleus by magnetic resonance (MR)/upconversion fluorescent for real-time guidance of their therapeutic action simultaneously. The Er/Yb-doped NaYF(4) core and NaGdF(4) shell endow the core/shell structured UCNPs with enhanced upconversion fluorescent imaging and more sensitive T(1)-MR imaging performances, and the surface conjugation of TAT peptide served as a key role in the nuclear targeting and nuclear transport process. This multifunctional UCNPs-based nano-theranostic was used to improve the efficacy of DOX in Hela humor tumor models, by direct DOX delivery to the nucleus under the synchronous monitoring of the nano-theranostics. Further development of this technology may provide more exciting opportunities in treating cancer disease by nuclear-targeted therapy. PMID:22796158

Liu, Jia-nan; Bu, Wenbo; Pan, Li-min; Zhang, Shengjian; Chen, Feng; Zhou, Liangping; Zhao, Kuai-le; Peng, Weijun; Shi, Jianlin

2012-10-01

248

Membrane domain formation—a key factor for targeted intracellular drug delivery  

PubMed Central

Protein molecules, toxins and viruses internalize into the cell via receptor-mediated endocytosis (RME) using specific proteins and lipids in the plasma membrane. The plasma membrane is a barrier for many pharmaceutical agents to enter into the cytoplasm of target cells. In the case of cancer cells, tissue-specific biomarkers in the plasma membrane, like cancer-specific growth factor receptors, could be excellent candidates for RME-dependent drug delivery. Recent data suggest that agent binding to these receptors at the cell surface, resulting in membrane domain formation by receptor clustering, can be used for the initiation of RME. As a result, these pharmaceutical agents are internalized into the cells and follow different routes until they reach their final intracellular targets like lysosomes or Golgi. We propose that clustering induced formation of plasma membrane microdomains enriched in receptors, sphingolipids, and inositol lipids, leads to membrane bending which functions as the onset of RME. In this review we will focus on the role of domain formation in RME and discuss potential applications for targeted intracellular drug delivery. PMID:25520666

Popov-?eleketi?, Dušan; van Bergen en Henegouwen, Paul M. P.

2014-01-01

249

Functionalized Single-Walled Carbon Nanotubes as Rationally Designed Vehicles for Tumor-Targeted Drug Delivery  

SciTech Connect

A novel single-walled carbon nanotube (SWNT)-based tumor-targeted drug delivery system (DDS) has been developed, which consists of a functionalized SWNT linked to tumor-targeting modules as well as prodrug modules. There are three key features of this nanoscale DDS: (a) use of functionalized SWNTs as a biocompatible platform for the delivery of therapeutic drugs or diagnostics, (b) conjugation of prodrug modules of an anticancer agent (taxoid with a cleavable linker) that is activated to its cytotoxic form inside the tumor cells upon internalization and in situ drug release, and (c) attachment of tumor-recognition modules (biotin and a spacer) to the nanotube surface. To prove the efficacy of this DDS, three fluorescent and fluorogenic molecular probes were designed, synthesized, characterized, and subjected to the analysis of the receptor-mediated endocytosis and drug release inside the cancer cells (L1210FR leukemia cell line) by means of confocal fluorescence microscopy. The specificity and cytotoxicity of the conjugate have also been assessed and compared with L1210 and human noncancerous cell lines. Then, it has unambiguously been proven that this tumor-targeting DDS works exactly as designed and shows high potency toward specific cancer cell lines, thereby forming a solid foundation for further development.

Chen,J.; Wong,S.; Chen, S.; Zhao, X.; Kuznetsova, L.V.; and Ojima, I.

2008-11-14

250

A dual-functionally modified chitosan derivative for efficient liver-targeted gene delivery.  

PubMed

Galactosylated chitosan-hydroxypropyltrimethylammonium (gal-HTCC) was synthesized by galactosylating and quaternizing chitosan to endue chitosan with targeting specificity for potential applications as gene vectors. The composition and physicochemical properties of gal-HTCC were characterized by FT-IR, (1) H NMR, elemental analysis, X-ray diffraction, and turbidity measurement. It was found that water-soluble gal-HTCC showed a more amorphous structure than chitosan, and it also had a much better plasmid condensation capability than galactosylated chitosan. Cytotoxicity measurements revealed that gal-HTCC showed significantly lower cytotoxicity in HepG2 and HeLa cell lines compared to branched polyethylenimine (bPEI, 25 kDa) which was used as a positive control. The nanoparticles (NPs) consisted of gal-HTCC and plasmid DNA had desirable particle size (around 250 nm) with a narrow size distribution. Confocal laser scanning microscopy confirmed that NPs could be internalized and transported to the nucleus efficiently within 6 h. In vitro gene transfection results indicated that gal-HTCC had significantly higher transfection efficiency (7- to 32-fold) compared to chitosan and gal-chitosan for targetable delivery of pGL3 luciferase plasmid to HepG2, and its transfection efficiency was highly inhibited in the presence of galactose (20 mM). All these results suggest that gal-HTCC can function as a promising nonviral gene vector for efficient liver-targeted gene delivery. PMID:23203540

Xiao, Bo; Wang, Xiaoyu; Qiu, Zhiye; Ma, Jun; Zhou, Lei; Wan, Ying; Zhang, Shengmin

2013-07-01

251

Hyaluronic acid oligosaccharide modified redox-responsive mesoporous silica nanoparticles for targeted drug delivery.  

PubMed

A redox-responsive delivery system based on colloidal mesoporous silica (CMS) has been developed, in which 6-mercaptopurine (6-MP) was conjugated to vehicles by cleavable disulfide bonds. The oligosaccharide of hyaluronic acid (oHA) was modified on the surface of CMS by disulfide bonds as a targeting ligand and was able to increase the stability and biocompatibility of CMS under physiological conditions. In vitro release studies indicated that the cumulative release of 6-MP was less than 3% in the absence of glutathione (GSH), and reached nearly 80% within 2 h in the presence of 3 mM GSH. Confocal microscopy and fluorescence-activated cell sorter (FACS) methods were used to evaluate the cellular uptake performance of fluorescein isothiocyanate (FITC) labeled CMS, with and without oHA modification. The CMS-SS-oHA exhibited a higher cellular uptake performance via CD44 receptor-mediated endocytosis in HCT-116 (CD44 receptor-positive) cells than in NIH-3T3 (CD44 receptor-negative) cells. 6-MP loaded CMS-SS-oHA exhibited greater cytotoxicity against HCT-116 cells than NIH-3T3 cells due to the enhanced cell uptake behavior of CMS-SS-oHA. This study provides a novel strategy to covalently link bioactive drug and targeting ligand to the interiors and exteriors of mesoporous silica to construct a stimulus-responsive targeted drug delivery system. PMID:25311422

Zhao, Qinfu; Geng, Hongjian; Wang, Ying; Gao, Yikun; Huang, Jiahao; Wang, Yan; Zhang, Jinghai; Wang, Siling

2014-11-26

252

Urokinase Plasminogen Activator System Targeted Delivery of Nanobins as a Novel Ovarian Cancer Therapeutics  

PubMed Central

The urokinase system is overexpressed in epithelial ovarian cancer (OvCa) cells and is expressed at low levels in normal cells. To develop a platform for intracellular and targeted delivery of therapeutics in OvCa, we conjugated urokinase plasminogen activator (uPA) antibodies to liposomal nanobins. The arsenic trioxide loaded nanobins had favorable physicochemical properties and the ability to bind specifically to uPA. Confocal microscopy showed that the uPA targeted nanobins were internalized by OvCa cells, while both ICP-MS and FACS analyses confirmed >4-fold higher uptake of targeted nanobins when compared to untargeted nanobins. In a co-culture assay, the targeted nanobins showed efficient uptake in OvCa cells but not in the normal primary omental mesothelial cells. Moreover, this uptake could be blocked by either down-regulating uPA receptor expression in the OvCa cells using shRNA or by competition with free uPA or uPA antibody. In proof-of-concept experiments, mice bearing orthotopic ovarian tumors showed a greater reduction in tumor burden when treated with targeted nanobins than with untargeted nanobins (47% versus 27%; p<0.001). The targeted nanobins more effectively inhibited tumor cell growth both in vitro and in vivo compared to untargeted nanobins, inducing caspase-mediated apoptosis and impairing stem cell marker, ALDH1A1, expression. Ex vivo fluorescence imaging of tumors and organs corroborated these results, showing preferential localization of the targeted nanobins to the tumor. These findings suggest that uPA targeted nanobins capable of specifically and efficiently delivering payloads to cancer cells could serve as the foundation for a new targeted cancer therapy utilizing protease receptors. PMID:24061648

Zhang, Yilin; Kenny, Hilary A.; Swindell, Elden P.; Mitra, Anirban K.; Hankins, Patrick L.; Ahn, Richard W.; Gwin, Katja; Mazar, Andrew P.; O’Halloran, Thomas V.; Lengyel, Ernst

2013-01-01

253

Targeted Delivery of Paclitaxel to EphA2-Expressing Cancer Cells  

PubMed Central

Purpose YSA is an EphA2-targeting peptide that effectively delivers anti-cancer agents to prostate cancer tumors (1). Here, we report on how we increased the drug-like properties of this delivery system. Experimental Design By introducing non-natural amino acids, we have designed two new EphA2 targeting peptides: YNH, where norleucine and homoserine replace the two methionine residues of YSA, and dYNH, where a D-tyrosine replaces the L-tyrosine at the first position of the YNH peptide. We describe the details of the synthesis of YNH and dYNH paclitaxel conjugates (YNH-PTX and dYNH-PTX) and their characterization in cells and in vivo. Results dYNH-PTX showed improved stability in mouse serum and significantly reduced tumor size in a prostate cancer xenograft model and also reduced tumor vasculature in a syngeneic orthotopic allograft mouse model of renal cancer compared to vehicle or paclitaxel treatments. Conclusion This study reveals that targeting EphA2 with dYNH drug conjugates could represent an effective way to deliver anti-cancer agents to a variety of tumor types. Translational Relevance Overexpression of the EphA2 positively correlates with tumor malignancy and poor prognosis. For this reason, EphA2 is an attractive target for cancer cell specific drug delivery. In this study, we report on the development of dYNH, an EphA2 targeting peptide that when coupled to paclitaxel (PTX) has favorable pharmacological properties and possesses powerful anti-tumor activity in vivo. dYNH-PTX may allow for an expanded therapeutic index of paclitaxel as well as precluding the need for complex formulations and long infusion times. PMID:23155185

Wang, Si; Noberini, Roberta; Stebbins, John L.; Das, Swadesh; Zhang, Ziming; Wu, Bainan; Mitra, Sayantan; Billet, Sandrine; Fernandez, Ana; Bhowmick, Neil A.; Kitada, Shinichi; Pasquale, Elena B.; Fisher, Paul B.; Pellecchia, Maurizio

2012-01-01

254

Odorranalectin Is a Small Peptide Lectin with Potential for Drug Delivery and Targeting  

PubMed Central

Background Lectins are sugar-binding proteins that specifically recognize sugar complexes. Based on the specificity of protein–sugar interactions, different lectins could be used as carrier molecules to target drugs specifically to different cells which express different glycan arrays. In spite of lectin's interesting biological potential for drug targeting and delivery, a potential disadvantage of natural lectins may be large size molecules that results in immunogenicity and toxicity. Smaller peptides which can mimic the function of lectins are promising candidates for drug targeting. Principal Findings Small peptide with lectin-like behavior was screened from amphibian skin secretions and its structure and function were studied by NMR, NMR-titration, SPR and mutant analysis. A lectin-like peptide named odorranalectin was identified from skin secretions of Odorrana grahami. It was composed of 17 aa with a sequence of YASPKCFRYPNGVLACT. L-fucose could specifically inhibit the haemagglutination induced by odorranalectin. 125I-odorranalectin was stable in mice plasma. In experimental mouse models, odorranalectin was proved to mainly conjugate to liver, spleen and lung after i.v. administration. Odorranalectin showed extremely low toxicity and immunogenicity in mice. The small size and single disulfide bridge of odorranalectin make it easy to manipulate for developing as a drug targeting system. The cyclic peptide of odorranalectin disclosed by solution NMR study adopts a ?-turn conformation stabilized by one intramolecular disulfide bond between Cys6-Cys16 and three hydrogen bonds between Phe7-Ala15, Tyr9-Val13, Tyr9-Gly12. Residues K5, C6, F7, C16 and T17 consist of the binding site of L-fucose on odorranalectin determined by NMR titration and mutant analysis. The structure of odorranalectin in bound form is more stable than in free form. Conclusion These findings identify the smallest lectin so far, and show the application potential of odorranalectin for drug delivery and targeting. It also disclosed a new strategy of amphibian anti-infection. PMID:18584053

Xu, Xueqing; Yang, Hailong; Wu, Bingxian; Wang, Yipeng; Zhu, Jianhua; Lai, Ren; Jiang, Xinguo; Lin, Donghai; Prescott, Mark C.; Rees, Huw H.

2008-01-01

255

Design of an integrated hardware interface for AOSLO image capture and cone-targeted stimulus delivery  

PubMed Central

We demonstrate an integrated FPGA solution to project highly stabilized, aberration-corrected stimuli directly onto the retina by means of real-time retinal image motion signals in combination with high speed modulation of a scanning laser. By reducing the latency between target location prediction and stimulus delivery, the stimulus location accuracy, in a subject with good fixation, is improved to 0.15 arcminutes from 0.26 arcminutes in our earlier solution. We also demonstrate the new FPGA solution is capable of delivering stabilized large stimulus pattern (up to 256x256 pixels) to the retina. PMID:20721171

Yang, Qiang; Arathorn, David W.; Tiruveedhula, Pavan; Vogel, Curtis R.; Roorda, Austin

2010-01-01

256

Synthetic Nano-Low Density Lipoprotein as Targeted Drug DeliveryVehicle for Glioblastoma Multiforme  

SciTech Connect

This paper discribes a synthetic low density lipoprotein(LDL) made by complexing a 29 amino acid that consists of a lipid bindingdomain and the LDL receptor binding domain with a lipid microemulsion.The nano-LDL particles were intermdiate in size between LDL and HDL andbound to LDL receptors on GBM brain tumor cells. Synthetic nano-LDLuptake by GBM cells was LDL receptor specific and dependent on cellreceptor number. It is suggested that these synthetic particles can serveas a delivery vehicle for hydophobic anti-tumor drugs by targeting theLDL receptor.

Nikanjam, Mina; Blakely, Eleanor A.; Bjornstad, Kathleen A.; Shu,Xiao; Budinger, Thomas F.; Forte, Trudy M.

2006-06-14

257

Control of polymerization shrinkage and stress in nanogel-modified monomer and composite materials  

PubMed Central

Objectives This study demonstrates the effects of nano-scale prepolymer particles as additives to model dental monomer and composite formulations. Methods Discrete nanogel particles were prepared by solution photopolymerization of isobornyl methacrylate and urethane dimethacrylate in the presence of a chain transfer agent, which also provided a means to attach reactive groups to the prepolymer. Nanogel was added to triethylene glycol dimethacrylate (TEGDMA) in increments between 5 and 40 wt% with resin viscosity, reaction kinetics, shrinkage, mechanical properties, stress and optical properties evaluated. Maximum loading of barium glass filler was determined as a function of nanogel content and composites with varied nanogel content but uniform filler loading were compared in terms of consistency, conversion, shrinkage and mechanical properties. Results High conversion, high molecular weight internally crosslinked and cyclized nanogel prepolymer was efficiently prepared and redispersed into TEGDMA with an exponential rise in viscosity accompanying nanogel content. Nanogel addition at any level produced no deleterious effects on reaction kinetics, conversion or mechanical properties, as long as reactive nanogels were used. A reduction in polymerization shrinkage and stress was achieved in proportion to nanogel content. Even at high nanogel concentrations, the maximum loading of glass filler was only marginally reduced relative to the control and high strength composite materials with low shrinkage were obtained. Significance The use of reactive nanogels offers a versatile platform from which resin and composite handling properties can be adjusted while the polymerization shrinkage and stress development that challenge the adhesive bonding of dental restoratives are controllably reduced. PMID:21388669

Moraes, Rafael R.; Garcia, Jeffrey W.; Barros, Matthew D.; Lewis, Steven H.; Pfeifer, Carmem S.; Liu, JianCheng; Stansbury, Jeffrey W.

2011-01-01

258

Photo-Reactive Nanogel as a Means to Tune Properties during Polymer Network Formation  

PubMed Central

Photo-reactive nanogels with an integrated photoinitiator-based functionality were synthesized via a Reversible Addition-Fragmentation Chain Transfer (RAFT) process. Without additional free initiators, this nanogel is capable of radical generation and initiating polymerization of a secondary monomer (i.e. dimethacrylate) that infiltrates and disperses the nanogel particles. Due to the presence of RAFT functionality and the fact that all initiating sites are initially located within the nanogel structure, gelation can be delayed by sequencing the polymerization from the nanogel to the bulk matrix. During polymerization of a nanogel-filled resin system, a progressive delay of gelation conversion from about 2 % for conventional chain growth polymerization to 18 % for the same monomer containing 20 wt% nanogel additive was achieved. A significant delay of stress development was also observed with much lower final stress achieved with the nanogel-modified systems due to the change of network formation mechanics. Compared with the nanogel-free dimethacrylate control, which contained uniformly distributed free initiator, the flexural modulus and mechanical strength results were maintained for the photopolymers with nanogel contents greater than 10 wt%. There appears to be a critical interparticle spacing of the photo-reactive nanogel that provides effective photopolymerization while providing delayed gelation and substantial stress reduction. PMID:24348753

Liu, JianCheng; Rad, Ima Y.; Sun, Fang; Stansbury, Jeffrey W.

2013-01-01

259

AAV-Mediated Delivery of Zinc Finger Nucleases Targeting Hepatitis B Virus Inhibits Active Replication  

PubMed Central

Despite an existing effective vaccine, hepatitis B virus (HBV) remains a major public health concern. There are effective suppressive therapies for HBV, but they remain expensive and inaccessible to many, and not all patients respond well. Furthermore, HBV can persist as genomic covalently closed circular DNA (cccDNA) that remains in hepatocytes even during otherwise effective therapy and facilitates rebound in patients after treatment has stopped. Therefore, the need for an effective treatment that targets active and persistent HBV infections remains. As a novel approach to treat HBV, we have targeted the HBV genome for disruption to prevent viral reactivation and replication. We generated 3 zinc finger nucleases (ZFNs) that target sequences within the HBV polymerase, core and X genes. Upon the formation of ZFN-induced DNA double strand breaks (DSB), imprecise repair by non-homologous end joining leads to mutations that inactivate HBV genes. We delivered HBV-specific ZFNs using self-complementary adeno-associated virus (scAAV) vectors and tested their anti-HBV activity in HepAD38 cells. HBV-ZFNs efficiently disrupted HBV target sites by inducing site-specific mutations. Cytotoxicity was seen with one of the ZFNs. scAAV-mediated delivery of a ZFN targeting HBV polymerase resulted in complete inhibition of HBV DNA replication and production of infectious HBV virions in HepAD38 cells. This effect was sustained for at least 2 weeks following only a single treatment. Furthermore, high specificity was observed for all ZFNs, as negligible off-target cleavage was seen via high-throughput sequencing of 7 closely matched potential off-target sites. These results show that HBV-targeted ZFNs can efficiently inhibit active HBV replication and suppress the cellular template for HBV persistence, making them promising candidates for eradication therapy. PMID:24827459

Weber, Nicholas D.; Stone, Daniel; Sedlak, Ruth Hall; De Silva Feelixge, Harshana S.; Roychoudhury, Pavitra; Schiffer, Joshua T.; Aubert, Martine; Jerome, Keith R.

2014-01-01

260

Engineering RNA for Targeted siRNA Delivery and Medical Application  

PubMed Central

RNA engineering for nanotechnology and medical applications is an exciting emerging research field. RNA has intrinsically defined features on the nanometer scale and is a particularly interesting candidate for such applications due to its amazing diversity, flexibility and versatility in structure and function. Specifically, the current use of siRNA to silence target genes involved in disease has generated much excitement in the scientific community. The intrinsic ability to sequence-specifically down-regulate gene expression in a temporally- and spatially-controlled fashion has led to heightened interest and rapid development of siRNA-based therapeutics. Though methods for gene silencing with high efficacy and specificity have been achieved in vitro, the effective delivery of nucleic acids to specific cells in vivo has been a hurdle for RNA therapeutics. This review covers different RNA-based approaches for diagnosis, prevention and treatment of human disease, with a focus on the latest developments of nonviral carriers of siRNA for delivery in vivo. The applications and challenges of siRNA therapy, as well as potential solutions to these problems, the approaches for using phi29 pRNA-based vectors as polyvalent vehicles for specific delivery of siRNA, ribozymes, drugs or other therapeutic agents to specific cells for therapy will also be addressed. PMID:20230868

Guo, Peixuan; Coban, Oana; Snead, Nick; Trebley, Joe; Hoeprich, Steve; Guo, Songchuan; Shu, Yi

2010-01-01

261

PEI-derivatized fullerene drug delivery using folate as a homing device targeting to tumor.  

PubMed

Fullerene (C60) has shown great potential in drug delivery. In this study, firstly, amine-functionalized C60 (C60-NH(2)) was achieved by introducing ethylenediamine onto the surface of C60, and then PEI-derivatized C60 (C60-PEI) was performed via a cationic polymerization of aziridine on the surface of C60-NH(2); FT-IR and TGA results verified the structure of water-soluble C60-PEI. C60-PEI was encapsulated with folic acid (FA) through an amide linker, and then docetaxel (DTX) was conjugated to C60-PEI-FA and obtained a drug delivery system, C60-PEI-FA/DTX. Compared with free DTX, the tumor targeting drug delivery could efficiently cross cell membranes, lead to more apoptosis and afford higher antitumor efficacy in a cultured PC3 cells in vitro. Furthermore, compared with free DTX in an in vivo murine tumor model, C60-PEI-FA/DTX afforded higher antitumor efficacy without obvious toxic effects to normal organs owing to its prolonged blood circulation and 7.5-fold higher DTX uptake of tumor, demonstrating that C60-PEI-FA/DTX may be promising for high treatment efficacy with minimal side effects in future therapy. PMID:23069706

Shi, Jinjin; Zhang, Hongling; Wang, Lei; Li, Lulu; Wang, Honghong; Wang, Zhenzhen; Li, Zhi; Chen, Chengqun; Hou, Lin; Zhang, Chaofeng; Zhang, Zhenzhong

2013-01-01

262

A novel in situ gel for sustained drug delivery and targeting.  

PubMed

The objective of this study was to develop a novel chitosan-glyceryl monooleate (GMO) in situ gel system for sustained drug delivery and targeting. The delivery system consisted of 3% (w/v) chitosan and 3% (w/v) GMO in 0.33M citric acid. In situ gel was formed at a biological pH. In vitro release studies were conducted in Sorensen's phosphate buffer (pH 7.4) and drugs were analyzed either by HPLC or spectrophotometry. Characterization of the gel included the effect of cross-linker, determination of diffusion coefficient and water uptake by thermogravimetric analysis (TGA). Mucoadhesive property of the gel was evaluated in vitro using an EZ-Tester. Incorporation of a cross-linker (glutaraldehyde) retarded the rate and extent of drug release. The in vitro release can further be sustained by replacing the free drug with drug-encapsulated microspheres. Drug release from the gel followed a matrix diffusion controlled mechanism. Inclusion of GMO enhanced the mucoadhesive property of chitosan by three- to sevenfold. This novel in situ gel system can be useful in the sustained delivery of drugs via oral as well as parenteral routes. PMID:15113617

Ganguly, Sudipta; Dash, Alekha K

2004-05-19

263

Biomaterials-based nanofiber scaffold: targeted and controlled carrier for cell and drug delivery.  

PubMed

Abstract Nanofiber scaffold formulations (diameter less than 1000?nm) were successfully used to deliver the drug/cell/gene into the body organs through different routes for an effective treatment of various diseases. Various fabrication methods like drawing, template synthesis, fiber-mesh, phase separation, fiber-bonding, self-assembly, melt-blown, and electrospinning are successfully used for fabrication of nanofibers. These formulations are widely used in various fields such as tissue engineering, drug delivery, cosmetics, as filter media, protective clothing, wound dressing, homeostatic, sensor devices, etc. The present review gives a detailed account on the need of the nanofiber scaffold formulation development along with the biomaterials and techniques implemented for fabrication of the same against innumerable diseases. At present, there is a huge extent of research being performed worldwide on all aspects of biomolecules delivery. The unique characteristics of nanofibers such as higher loading efficiency, superior mechanical performance (stiffness and tensile strength), controlled release behavior, and excellent stability helps in the delivery of plasmid DNA, large protein drugs, genetic materials, and autologous stem-cell to the target site in the future. PMID:25539071

Garg, Tarun; Rath, Goutam; Goyal, Amit K

2015-04-01

264

Synthesis of Bisethylnorspermine Lipid Prodrug as Gene Delivery Vector Targeting Polyamine Metabolism in Breast Cancer  

PubMed Central

Progress in the development of nonviral gene delivery vectors continues to be hampered by low transfection activity and toxicity. Here we proposed to develop a lipid prodrug based on a polyamine analogue bisethylnorspermine (BSP) that can function dually as gene delivery vector and, after intracellular degradation, as active anticancer agent targeting dysregulated polyamine metabolism. We synthesized a prodrug of BSP (LS-BSP) capable of intracellular release of BSP using thiolytically sensitive dithiobenzyl carbamate linker. Biodegradability of LS-BSP contributed to decreased toxicity compared with nondegradable control L-BSP. BSP showed a strong synergistic enhancement of cytotoxic activity of TNF-related apoptosis-inducing ligand (TRAIL) in human breast cancer cells. Decreased enhancement of TRAIL activity was observed for LS-BSP when compared with BSP. LS-BSP formed complexes with plasmid DNA and mediated transfection activity comparable to DOTAP and L-BSP. Our results show that BSP-based vectors are promising candidates for combination drug/gene delivery. PMID:22545813

Dong, Yanmei; Zhu, Yu; Li, Jing; Zhou, Qing-Hui; Wu, Chao; Oupický, David

2013-01-01

265

Mito-DCA: a mitochondria targeted molecular scaffold for efficacious delivery of metabolic modulator dichloroacetate.  

PubMed

Tumor growth is fueled by the use of glycolysis, which normal cells use only in the scarcity of oxygen. Glycolysis makes tumor cells resistant to normal death processes. Targeting this unique tumor metabolism can provide an alternative strategy to selectively destroy the tumor, leaving normal tissue unharmed. The orphan drug dichloroacetate (DCA) is a mitochondrial kinase inhibitor that has the ability to show such characteristics. However, its molecular form shows poor uptake and bioavailability and limited ability to reach its target mitochondria. Here, we describe a targeted molecular scaffold for construction of a multiple DCA loaded compound, Mito-DCA, with three orders of magnitude enhanced potency and cancer cell specificity compared to DCA. Incorporation of a lipophilic triphenylphosphonium cation through a biodegradable linker in Mito-DCA allowed for mitochondria targeting. Mito-DCA did not show any significant metabolic effects toward normal cells but tumor cells with dysfunctional mitochondria were affected by Mito-DCA, which caused a switch from glycolysis to glucose oxidation and subsequent cell death via apoptosis. Effective delivery of DCA to the mitochondria resulted in significant reduction in lactate levels and played important roles in modulating dendritic cell (DC) phenotype evidenced by secretion of interleukin-12 from DCs upon activation with tumor antigens from Mito-DCA treated cancer cells. Targeting mitochondrial metabolic inhibitors to the mitochondria could lead to induction of an efficient antitumor immune response, thus introducing the concept of combining glycolysis inhibition with immune system to destroy tumor. PMID:24617941

Pathak, Rakesh K; Marrache, Sean; Harn, Donald A; Dhar, Shanta

2014-05-16

266

A novel hydrolysis-resistant lipophilic folate derivative enables stable delivery of targeted liposomes in vivo  

PubMed Central

Instability of targeting ligand is a roadblock towards successful development of folate targeted liposomes. Folate ligands have been linked to polyethylene glycol (PEG) and cholesterol by an amide bond to form folate-CONH-PEG-CONH-Cholesterol (F-CONH-PEG-CONH-Chol), which is subject to hydrolysis. To increase the stability of folate ligands and promote the long circulation and targeting effects, we synthesized a chemically stable lipophilic folate derivative, folate-CONH-PEG-NH-Cholesterol (F-CONH-PEG-NH-Chol), where the amide bond was replaced by a C-N bond, to deliver liposomal doxorubicin (Dox). Its physical stability, cellular uptake, cellular toxicity, pharmacokinetics, distribution, anti-tumor efficacy, and cardiac toxicity were investigated. Our results indicate that F-CONH-PEG-NH-Chol conjugated liposomes are taken up selectively by folate receptor-positive HeLa and KB cells. Compared with F-CONH-PEG-CONH-Chol with two carbonate linkages, F-CONH-PEG-NH-Chol better retained its drug entrapment efficiency and folate receptor-targeting activity during prolonged circulation. F-CONH-PEG-NH-Chol thus represents a physically stable and effective ligand for delivering folate receptor-targeted liposomes, with prolonged circulation time and efficient tissue distribution, as well as higher efficacy and less cardiac toxicity. Collectively, these results suggest that this novel conjugate can serve as a promising derivative for the delivery of anti-tumor therapeutic agents. PMID:25302024

Huang, Yifei; Yang, Tan; Zhang, Wendian; Lu, Yao; Ye, Peng; Yang, Guang; Li, Bin; Qi, Shibo; Liu, Yong; He, Xingxing; Lee, Robert J; Xu, Chuanrui; Xiang, Guangya

2014-01-01

267

Novel tumor-targeting, self-assembling peptide nanofiber as a carrier for effective curcumin delivery  

PubMed Central

The poor aqueous solubility and low bioavailability of curcumin restrict its clinical application for cancer treatment. In this study, a novel tumor-targeting nanofiber carrier was developed to improve the solubility and tumor-targeting ability of curcumin using a self-assembled Nap-GFFYG-RGD peptide. The morphologies of the peptide nanofiber and the curcumin-encapsulated nanofiber were visualized by transmission electron microscopy. The tumor-targeting activity of the curcumin-encapsulated Nap-GFFYG-RGD peptide nanofiber (f-RGD-Cur) was studied in vitro and in vivo, using Nap-GFFYG-RGE peptide nanofiber (f-RGE-Cur) as the control. Curcumin was encapsulated into the peptide nanofiber, which had a diameter of approximately 10–20 nm. Curcumin showed sustained-release behavior from the nanofibers in vitro. f-RGD-Cur showed much higher cellular uptake in ?v?3 integrin-positive HepG2 liver carcinoma cells than did non-targeted f-RGE-Cur, thereby leading to significantly higher cytotoxicity. Ex vivo studies further demonstrated that curcumin could accumulate markedly in mouse tumors after administration of f-RGD-Cur via the tail vein. These results indicate that Nap-GFFYG-RGD peptide self-assembled nanofibers are a promising hydrophobic drug delivery system for targeted treatment of cancer. PMID:24399876

Liu, Jianfeng; Liu, Jinjian; Xu, Hongyan; Zhang, Yumin; Chu, Liping; Liu, Qingfen; Song, Naling; Yang, Cuihong

2014-01-01

268

Insights into EPR effect versus lectin-mediated targeted delivery: biodegradable polycarbonate micellar nanoparticles with and without galactose surface decoration.  

PubMed

Polymeric micelles with and without galactose are synthesized to study liver targeting ability in an orthotopic HCC rat model. Micelles with galactose accumulate more in the healthy liver tissue instead of HCC, while micelles without galactose amass in HCC by the EPR effect. These micelles show great potential as drug delivery carriers to target either the liver or HCC. PMID:25091699

Ebrahim Attia, Amalina Binte; Oh, Pamela; Yang, Chuan; Tan, Jeremy Pang Kern; Rao, Nithya; Hedrick, James L; Yang, Yi Yan; Ge, Ruowen

2014-11-12

269

Targeted Drug Delivery to the Peripheral Nervous System using Gene Therapy  

PubMed Central

Gene transfer to target delivery of neurotrophic factors to the primary sensory afferent for treatment of polyneuropathy, or of inhibitory neurotransmitters for relief of chronic pain, offers the possibility of a highly selective targeted release of bioactive molecules within the nervous system. Preclinical studies with non-replicating herpes simplex virus (HSV)-based vectors injected into the skin to transduce neurons in the dorsal root ganglion have demonstrated efficacy in reducing-pain related behaviors in animal models of inflammatory pain, neuropathic pain, and pain caused by cancer, and in preventing progression of sensory neuropathy caused by toxins, chemotherapeutic drugs or resulting from diabetes. Successful completion of the first phase 1 clinical trial of HSV-mediated gene transfer in patients with intractable pain from cancer has set the stage for further clinical trials of this approach. PMID:22565023

Wolfe, Darren; Mata, Marina; Fink, David J.

2012-01-01

270

Receptor-targeted liposome-peptide nanocomplexes for siRNA delivery.  

PubMed

RNA interference induced by double-stranded, small interfering RNA (siRNA) molecules has attracted great attention as a genetic therapeutic approach. Despite major advances in this field, new nanoparticle formulations are required for in vivo delivery of siRNA, particularly for tissue-specific delivery of siRNA reagents. We have developed and optimized LYR nanocomplex formulations for siRNA delivery that consist of a liposome (DOTMA/DOPE; L) and a targeting peptide (K??GACYGLPHKFCG; Y) which self-assemble on mixing at optimal ratios with siRNA (R). Biophysical measurements indicated that LYR nanocomplexes were strongly cationic, mainly spherical particles of less than 100 nm. These formulations packaged and protected siRNA on incubation with RNAseA with >90% intact siRNA recovery. In addition, intact siRNA was recovered from LYRs upon heparin treatment. A critical synergy was observed between the lipid and peptide components for LYR particle stability and transfection efficiency. To evaluate targeting, transfections were compared with non-targeted formulations containing K?? with no targeting ligand. Gene knockdown efficiencies with targeted formulations were more than two-fold better in all cell lines tested (p < 0.01). LYR formulations with liposomes containing DOTMA, which has an 18-carbon (C18) alkyl tail, were significantly better in silencing than formulations containing cationic lipids with shorter alkyl tails. LYRs with siRNA against endogenous luciferase and GAPDH were successful in silencing these genes in 3 cell lines (1HAEo- human airway epithelial, B104 rat neuroblastoma, Neuro2A-Luc mouse neuroblastoma) in vitro with 80% efficiency, similar in efficiency to Lipofectamine 2000. Confocal microscopy analysis with LYRs containing fluorescently labelled siRNA (Cy3) showed that the siRNA was located in the perinuclear region of the cytoplasm, where the RNA-induced silencing complex (RISC) is likely to be found. The LYR formulations may have applications for the further development of siRNA-based therapeutics. PMID:21624650

Tagalakis, Aristides D; He, Lin; Saraiva, Luisa; Gustafsson, Kenth T; Hart, Stephen L

2011-09-01

271

Targeted delivery of peptide-conjugated biocompatible gold nanoparticles into cancer cell nucleus  

NASA Astrophysics Data System (ADS)

Nucleus remains a significant target for nanoparticles with diagnostic and therapeutic applications because both genetic information of the cell and transcription machinery reside there. Novel therapeutic strategies (for example, gene therapy), enabled by safe and efficient delivery of nanoparticles and drug molecules into the nucleus, are heralded by many as the ultimate treatment for severe and intractable diseases. However, most nanomaterials and macromolecules are incapable of reaching the cell nucleus on their own, because of biological barriers carefully honed by evolution including cellular membrane and nuclear envelope. In this paper, we have demonstrated an approach of fabrication of biocompatible gold nanoparticle (Au NP)-based vehicles which can entering into cancer cell nucleus by modifying Au NPs with both PEG 5000 and two different peptides (RGD and nuclear localization signal (NLS) peptide). The Au NPs used were fabricated via femtosecond laser ablation of Au bulk target in deionized water. The Au NPs produced by this method provide chemical free, virgin surface, which allows us to carry out "Sequential Conjugation" to modify their surface with PEG 5000, RGD, and NLS. "Sequential Conjugation" described in this presentation is very critical for the fabrication of Au NP-based vehicles capable of entering into cancer cell nucleus as it enables the engineering and tuning surface chemistries of Au NPs by independently adjusting amounts of PEG and peptides bound onto surface of Au NPs so as to maximize their nuclear targeting performance and biocompatibility regarding the cell line of interest. Both optical microscopy and transmission electron microscopy (TEM) are used to confirm the in vitro targeted nuclear delivery of peptide-conjugated biocompatible Au NPs by showing their presence in the cancer cell nucleus.

Qian, Wei; Curry, Taeyjuana; Che, Yong; Kopelman, Raoul

2013-02-01

272

MRI-Visible Micellar Nanomedicine for Targeted Drug Delivery to Lung Cancer Cells  

PubMed Central

Polymeric micelles are emerging as a highly integrated nanoplatform for cancer targeting, drug delivery and tumor imaging applications. In this study, we describe a multifunctional micelle (MFM) system that is encoded with a lung cancer-targeting peptide (LCP), and encapsulated with superparamagnetic iron oxide (SPIO) and doxorubicin (Doxo) for MR imaging and therapeutic delivery, respectively. The LCP-encoded MFM showed significantly increased ?v?6-dependent cell targeting in H2009 lung cancer cells over a scrambled peptide (SP)-encoded MFM control as well as in an ?v?6-negative H460 cell control. 3H-Labeled MFM nanoparticles were used to quantify the time- and dose-dependent cell uptake of MFM nanoparticles with different peptide encoding (LCP vs SP) and surface densities (20% and 40%) in H2009 cells. LCP functionalization of the micelle surface increased uptake of the MFM by more than 3-fold compared to the SP control. These results were confirmed by confocal laser scanning microscopy, which further demonstrated the successful Doxo release from MFM and accumulation in the nucleus. SPIO clustering inside the micelle core resulted in high T2 relaxivity (>400 Fe mM?1 s?1) of the resulting MFM nanoparticles. T2-weighted MRI images showed clear contrast differences between H2009 cells incubated with LCP-encoded MFM over the SP-encoded MFM control. An ATP activity assay showed increased cytotoxicity of LCP-encoded MFM over SP-encoded MFM in H2009 cells (IC50 values were 28.3 ± 6.4 nM and 73.6 ± 6.3 nM, respectively; p < 0.005). The integrated diagnostic and therapeutic design of MFM nanomedicine potentially allows for image-guided, target-specific treatment of lung cancer. PMID:19708690

Guthi, Jagadeesh Setti; Yang, Su-Geun; Huang, Gang; Li, Shunzi; Khemtong, Chalermchai; Kessinger, Chase W.; Peyton, Michael; Minna, John D.; Brown, Kathlynn C.; Gao, Jinming

2010-01-01

273

Water-soluble polymers for targeted drug delivery to human squamous carcinoma of head and neck.  

PubMed

Human squamous cell carcinoma of the head and neck (SCCHN) is characterized by over expression of a tumor cell surface-specific receptor namely Hsp47/CBP2 that makes it a favorable candidate for targeted delivery of anticancer drugs. Several synthetic peptides have been identified as effective ligands for binding to CBP2. The purpose of this study is to investigate the potential of water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (Dox) conjugates containing a Hsp47/CBP2 binding peptide sequence, namely WHYPWFQNWAMA for targeted delivery to SCCHN. An HPMA copolymer containing Dox and CBP2 targeting peptide conjugated via lysosomally degradable glycylphenylalanylleucylglycine (GFLG) spacer was synthesized by free radical precipitation copolymerization. A control polymer without targeting moiety was also synthesized. The conjugates were characterized for drug content, peptide content, molecular weight and molecular weight distribution. The uptake of polymeric conjugates by both drug resistant and drug sensitive SCCHN cells were determined in vitro by flow cytometry using FACS scan analysis. Cytotoxicity of the conjugates towards drug sensitive as well as multidrug resistant SCCHN cells were evaluated by a clonal survival assay and compared to free Dox. The cytotoxicity of the free peptide was similarly evaluated. The internalization and subcellular fate of the conjugates in drug sensitive SCCHN cells was monitored using confocal microscopy. The new targetable copolymer contained 0.16 mmole peptide/g polymer. Studies on drug sensitive SCCHN cells demonstrated lesser uptake of both targeted and non-targeted conjugates compared to free Dox suggesting a slower endocytic mechanism of uptake for the conjugates as opposed to rapid diffusion of free Dox. At higher Dox equivalent concentrations (>20 microM) the targeted conjugate showed significantly higher uptake (p < or = 0.028) than the non-targeted conjugate. The uptake of the targeted conjugate was inhibited in the presence of an anti Hsp47 antibody suggesting the involvement of active receptor mediated endocytosis in cell entry of the conjugate. Compared to free Dox, the targeted and non-targeted conjugates caused marginally lower inhibition (p < or = 0.01) of the drug sensitive SCCHN cells. In contrast, the same conjugates showed significantly higher uptake (p < or = 0.004) by drug resistant SCCHN cells and caused significantly higher inhibition (p < or = 0.02) of drug resistant SCCHN cells when compared to free Dox. Results suggest that the polymeric conjugates were able to overcome drug resistance. Confocal microscopy studies demonstrated the uptake of the polymeric conjugates, followed by internalization, intralysosomal localization and subsequent release of Dox. HPMA copolymer-Dox-peptide conjugates targeted to SCCHN cells were able to overcome drug resistance and increase efficacy in vitro. The results suggest that targetable polymeric conjugates have potential to improve systemic head and neck cancer chemotherapy by increasing tumor localization and reducing dose-limiting toxicity. PMID:16036307

Nan, Anjan; Ghandehari, Hamidreza; Hebert, Carla; Siavash, Hessam; Nikitakis, Nikolaos; Reynolds, Mark; Sauk, John J

2005-04-01

274

Immuno-LipoTRAIL: Targeted delivery of TRAIL-functionalized liposomal nanoparticles.  

PubMed

The TNF-related apoptosis-inducing ligand (TRAIL) is a powerful inducer of apoptosis in tumor cells; however, clinical studies with recombinant soluble TRAIL were rather disappointing. Here, we developed TRAIL-functionalized liposomes (LipoTRAIL, LT) to mimic membrane-displayed TRAIL for efficient activation of death receptors DR4 and DR5 and enhanced induction of apoptosis, which were combined with an anti-EGFR single-chain Fv fragment (scFv) for targeted delivery to EGFR-positive tumor cells. These immuno-LipoTRAILs (ILTs) bound specifically to EGFR-expressing cells (Colo205) and exhibited increased cytotoxicity compared with that of nontargeted LTs. Compared to that of the soluble TRAIL, the plasma half-life of the functionalized liposomes was strongly extended, and increased antitumor activity of LT and ILT was demonstrated in a xenograft tumor model. Thus, we established a multifunctional liposomal TRAIL formulation (ILT) with improved pharmacokinetic and pharmacodynamic behavior, characterized by targeted delivery and increased induction of apoptosis due to multivalent TRAIL presentation. PMID:24766622

Seifert, Oliver; Pollak, Nadine; Nusser, Anja; Steiniger, Frank; Rüger, Ronny; Pfizenmaier, Klaus; Kontermann, Roland E

2014-05-21

275

Maximizing gene delivery efficiencies of cationic helical polypeptides via balanced membrane penetration and cellular targeting.  

PubMed

The application of non-viral gene delivery vectors is often accompanied with the poor correlation between transfection efficiency and the safety profiles of vectors. Vectors with high transfection efficiencies often suffer from high toxicities, making it unlikely to improve their efficiencies by increasing the DNA dosage. In the current study, we developed a ternary complex system which consisted of a highly membrane-active cationic helical polypeptide (PVBLG-8), a low-toxic, membrane-inactive cationic helical polypeptide (PVBLG-7) capable of mediating mannose receptor targeting, and DNA. The PVBLG-7 moiety notably enhanced the cellular uptake and transfection efficiency of PVBLG-8 in a variety of mannose receptor-expressing cell types (HeLa, COS-7, and Raw 264.7), while it did not compromise the membrane permeability of PVBLG-8 or bring additional cytotoxicities. Because of the simplicity and adjustability of the self-assembly approach, optimal formulations of the ternary complexes with a proper balance between membrane activity and targeting capability were easily identified in each specific cell type. The optimal ternary complexes displayed desired cell tolerability and markedly outperformed the PVBLG-8/DNA binary complexes as well as commercial reagent Lipofectamine™ 2000 in terms of transfection efficiency. This study therefore provides an effective and facile strategy to overcome the efficiency-toxicity poor correlation of non-viral vectors, which contributes insights into the design strategy of effective and safe non-viral gene delivery vectors. PMID:24211080

Zheng, Nan; Yin, Lichen; Song, Ziyuan; Ma, Liang; Tang, Haoyu; Gabrielson, Nathan P; Lu, Hua; Cheng, Jianjun

2014-01-01

276

Formulation, Evaluation and Optimization of Pectin- Bora Rice Beads for Colon Targeted Drug Delivery System  

PubMed Central

Purpose: The purpose of this research was to established new polysaccharide for the colon targeted drug delivery system, its formulation and in vitro and in vivo evaluation. Methods: Microspheres containing pectin and bora rice were prepared by ionotropic gelation technique using zinc acetate as cross linking agent and model drug used was glipizide. A 32 full factorial design was employed to study the effect of independent variables, polymer to drug ratio (A), and concentration of cross linking agent (B) on dependent variables, particle size, swelling index, drug entrapment efficiency and percentage drug release. Results: Results of trial batches indicated that polymer to drug ratio and concentration of cross linking agent affects characteristics of beads. Beads were discrete, spherical and free flowing. Beads exhibited small particle size and showed higher percentage of drug entrapment efficiency. The optimized batch P2 exhibited satisfactory drug entrapment efficiency 68% and drug release was also controlled for more than 24 hours. The polymer to drug ratio had a more significant effect on the dependent variables. In vivo gamma scintigraphy study of optimized pectin-bora rice beads demonstrated degradation of beads whenever they reached to the colon. Conclusion: Bora rice is potential polysaccharide for colon targeted drug delivery system. PMID:24511481

Ramteke, Kuldeep Hemraj; Nath, Lilakant

2014-01-01

277

Green synthesis of pullulan stabilized gold nanoparticles for cancer targeted drug delivery  

NASA Astrophysics Data System (ADS)

The aim of this study was to synthesize green chemistry based gold nanoparticles using liver specific biopolymer and to develop a liver cancer targeted drug delivery system with enhanced efficacy and minimal side effects. Pullulan stabilized gold nanoparticles (PAuNPs) were coupled with 5-Fluorouracil (5-Fu) and folic acid (Fa) which could be used as a tool for targeted drug delivery and imaging of cancer. The toxicity of 5-Fu, 5-Fu adsorbed gold nanoparticles (5-Fu@AuNPs), Fa-coupled 5-Fu adsorbed gold nanoparticles (5-Fu@AuNPs-Fa), was studied using zebrafish embryo as an in vivo model. The in vitro cytotoxicity of free 5-Fu, 5-Fu@AuNPs, 5-Fu@AuNPs-Fa against HepG2 cells was studied and found that the amount of 5-Fu required to achieve 50% of growth of inhibition (Ic50) was much lower in 5-Fu@AuNP-Fa than in free 5-Fu, 5-Fu@AuNPs. The in vivo biodistribution of PAuNPs showed that higher amount of gold had been accumulated in liver (54.42 ± 5.96 ?g) than in other organs.

Ganeshkumar, Moorthy; Ponrasu, Thangavel; Raja, Modhugoor Devendiran; Subamekala, Muthaiya Kannappan; Suguna, Lonchin

2014-09-01

278

Nanotechnology in the targeted drug delivery for bone diseases and bone regeneration  

PubMed Central

Nanotechnology is a vigorous research area and one of its important applications is in biomedical sciences. Among biomedical applications, targeted drug delivery is one of the most extensively studied subjects. Nanostructured particles and scaffolds have been widely studied for increasing treatment efficacy and specificity of present treatment approaches. Similarly, this technique has been used for treating bone diseases including bone regeneration. In this review, we have summarized and highlighted the recent advancement of nanostructured particles and scaffolds for the treatment of cancer bone metastasis, osteosarcoma, bone infections and inflammatory diseases, osteoarthritis, as well as for bone regeneration. Nanoparticles used to deliver deoxyribonucleic acid and ribonucleic acid molecules to specific bone sites for gene therapies are also included. The investigation of the implications of nanoparticles in bone diseases have just begun, and has already shown some promising potential. Further studies have to be conducted, aimed specifically at assessing targeted delivery and bioactive scaffolds to further improve their efficacy before they can be used clinically. PMID:23836972

Gu, Wenyi; Wu, Chengtie; Chen, Jiezhong; Xiao, Yin

2013-01-01

279

Glucose-conjugated chitosan nanoparticles for targeted drug delivery and their specific interaction with tumor cells  

NASA Astrophysics Data System (ADS)

A novel targeted drug delivery system, glucose-conjugated chitosan nanoparticles (GCNPs), was developed for specific recognition and interaction with glucose transporters (Gluts) over-expressed by tumor cells. GC was synthesized by using succinic acid as a linker between glucosamine and chitosan (CS), and successful synthesis was confirmed by NMR and elemental analysis. GCNPs were prepared by ionic crosslinking method, and characterized in terms of morphology, size, and zeta potential. The optimally prepared nanoparticles showed spherical shapes with an average particle size of (187.9 ± 3.8) nm and a zeta potential of (- 15.43 ± 0.31) mV. The GCNPs showed negligible cytotoxicity to mouse embryo fibroblast and 4T1 cells. Doxorubicin (DOX) could be efficiently entrapped into GCNPs, with a loading capacity and encapsulation efficiency of 20.11% and 64.81%, respectively. DOX-loaded nanoparticles exhibited sustained-release behavior in phosphate buffered saline (pH 7.4). In vitro cellular uptake studies showed that the GCNPs had better endocytosis ability than CSNPs, and the antitumor activity of DOX/GCNPs was 4-5 times effectiveness in 4T1 cell killing than that of DOX/CSNPs. All the results demonstrate that nanoparticles decorated with glucose have specific interactions with cancer cells via the recognition between glucose and Gluts. Therefore, Gluts-targeted GCNPs may be promising delivery agents in cancer therapies.

Li, Jing; Ma, Fang-Kui; Dang, Qi-Feng; Liang, Xing-Guo; Chen, Xi-Guang

2014-12-01

280

P-glycoprotein trafficking as a therapeutic target to optimize CNS drug delivery  

PubMed Central

The primary function of the blood-brain barrier (BBB) /neurovascular unit is to protect the CNS from potentially harmful xenobiotic substances and maintain CNS homeostasis. Restricted access to the CNS is maintained via a combination of tight junction proteins as well as a variety of efflux and influx transporters that limits the transcellular and paracellular movement of solutes. Of the transporters identified at the BBB, P-glycoprotein (P-gp) has emerged as the transporter that is the greatest obstacle to effective CNS drug delivery. In this chapter we provide data to support intracellular protein trafficking of P-gp within cerebral capillary microvessels as a potential target for improved drug delivery. We show that pain induced changes in P-gp trafficking are associated with changes in P-gp’s association with caveolin-1, a key scaffolding/trafficking protein that co-localizes with P-gp at the luminal membrane of brain microvessels. Changes in co-localization with the phosphorylated and non-phosphorylated forms of caveolin-1, by pain, are accompanied by dynamic changes in the distribution, relocalization and activation of P-gp “pools” between microvascular endothelial cell subcellular compartments. Since redox sensitive processes may be involved in signaling disassembly of higher order structures of P-gp, we feel that manipulating redox signaling, via specific protein targeting at the BBB, may protect disulfide bond integrity of P-gp reservoirs and control trafficking to the membrane surface providing improved CNS drug delivery. The advantage of therapeutic drug “relocalization” of a protein is that the physiological impact can be modified, temporarily or long term, despite pathology-induced changes in gene transcription. PMID:25307213

Davis, Thomas P.; Sanchez-Covarubias, Lucy; Tome, Margaret E.

2014-01-01

281

Delivery of CdiA nuclease toxins into target cells during contact-dependent growth inhibition.  

PubMed

Bacterial contact-dependent growth inhibition (CDI) is mediated by the CdiB/CdiA family of two-partner secretion proteins. CDI systems deploy a variety of distinct toxins, which are contained within the polymorphic C-terminal region (CdiA-CT) of CdiA proteins. Several CdiA-CTs are nucleases, suggesting that the toxins are transported into the target cell cytoplasm to interact with their substrates. To analyze CdiA transfer to target bacteria, we used the CDI system of uropathogenic Escherichia coli 536 (UPEC536) as a model. Antibodies recognizing the amino- and carboxyl-termini of CdiA(UPEC536) were used to visualize transfer of CdiA from CDI(UPEC536+) inhibitor cells to target cells using fluorescence microscopy. The results indicate that the entire CdiA(UPEC536) protein is deposited onto the surface of target bacteria. CdiA(UPEC536) transfer to bamA101 mutants is reduced, consistent with low expression of the CDI receptor BamA on these cells. Notably, our results indicate that the C-terminal CdiA-CT toxin region of CdiA(UPEC536) is translocated into target cells, but the N-terminal region remains at the cell surface based on protease sensitivity. These results suggest that the CdiA-CT toxin domain is cleaved from CdiA(UPEC536) prior to translocation. Delivery of a heterologous Dickeya dadantii CdiA-CT toxin, which has DNase activity, was also visualized. Following incubation with CDI(+) inhibitor cells targets became anucleate, showing that the D.dadantii CdiA-CT was delivered intracellularly. Together, these results demonstrate that diverse CDI toxins are efficiently translocated across target cell envelopes. PMID:23469034

Webb, Julia S; Nikolakakis, Kiel C; Willett, Julia L E; Aoki, Stephanie K; Hayes, Christopher S; Low, David A

2013-01-01

282

Synthesis and characterization of biomimetic nanogels for immunorecognition.  

PubMed

Biomimetic nanoparticles are promising materials for biomedical and biotechnological applications. Cationic poly(N-isopropylacrylamide) (PNIPAM) nanogels containing charged amine groups brought by addition of 2-aminoethylmethacrylate hydrochloride (AEMH) or N-(3-aminopropyl) methacrylamide hydrochloride (APMH) as co-monomers were prepared by surfactant-free precipitation polymerization. The influence of the relative amount and mode of addition of the co-monomer on both the size and the amine group density of the nanogel particles was studied. Two nanogels, one prepared using APMH (1%mol/mol NIPAM, in batch) and another with AEMH (2%mol/mol NIPAM, by shot addition) as co-monomers, were selected for the covalent coupling of a Protein L-mimic ligand to free amine groups on the particles. The ability of the synthesized biomimetic nanoparticles for recognizing and binding human IgG (hIgG) molecules was assessed and the selectivity toward immunoglobulin molecules evaluated. PMID:23994750

Silva, Claudia S O; Lansalot, Muriel; Garcia, Jaqueline Q; Taipa, M Ângela; Martinho, José M G

2013-12-01

283

Herbal and polymeric approaches for liver-targeting drug delivery: novel strategies and their significance.  

PubMed

Abstract The liver is a vital organ present in vertebrates, which performs many functions including detoxification, protein synthesis and production of various bio-chemicals which are very important for digestion. A large number of serious liver disorders affect millions of people worldwide which are very difficult to treat properly despite many efforts. There are several factors which are responsible for liver injuries, include plants (Crotalaria Senecio Heliotropium Symphytum officinale), drugs (analgesic and antibiotics), industrial toxins (mercury and lead), water, alcohol and so on. Herbal medicinal preparations can be used for the treatment of a large number of human liver disorders like cirrhosis, hepatitis, carcinomas, etc. Indian Medicinal Practitioner's Co-operative pharmacy and Stores (IMPCPS) approved herbal-based systems (Unani, Siddha and Ayurveda) for the treatment of various chronic liver disorders. Different types of the receptors are found on the surface of hepatocytes, Kupffer cell, hepatic stellate cell and sinusoidal endothelial cells, etc., which can be used for achieving liver targeting. These receptors bind to different types of ligands (galactosylated, lactobionic acid, asialofetuin, etc.) which can be used in the formulation to achieve targeted delivery of the drug. Various novel particulate approaches (liposomes, niosomes, nanoparticles, micelles, nanosuspensions, etc.) can be used to enhance the targeting efficiency of systems to receptors found on the surface of different cells present in the liver. In this review, we focused on the status of liver targeting via herbal and nanotechnology inspired formulation approaches. PMID:25101832

Rohilla, Raman; Garg, Tarun; Goyal, Amit K; Rath, Goutam

2014-08-01

284

Targeted drug delivery to tumor vasculature by a carbohydrate mimetic peptide  

PubMed Central

Although numerous carbohydrates play significant roles in mammalian cells, carbohydrate-based drug discovery has not been explored due to the technical difficulty of chemically synthesizing complex carbohydrate structures. Previously, we identified a series of carbohydrate mimetic peptides and found that a 7-mer peptide, designated I-peptide, inhibits hematogenous carbohydrate-dependent cancer cell colonization. During analysis of the endothelial surface receptor for I-peptide, we found that I-peptide bound to annexin 1 (Anxa1). Because Anxa1 is a highly specific tumor vasculature surface marker, we hypothesized that an I-peptide-like peptide could target anticancer drugs to the tumor vasculature. This study identifies IFLLWQR peptide, designated IF7, as homing to tumors. When synthetic IF7 peptide was conjugated to fluorescent Alexa 488 (A488) and injected intravenously into tumor-bearing mice, IF7-A488 targeted tumors within minutes. IF7 conjugated to the potent anticancer drug SN-38 and injected intravenously into nude mice carrying human colon HCT116 tumors efficiently suppressed tumor growth at low dosages with no apparent side effects. These results suggest that IF7 serves as an efficient drug delivery vehicle by targeting Anxa1 expressed on the surface of tumor vasculature. Given its extremely specific tumor-targeting activity, IF7 may represent a clinically relevant vehicle for anticancer drugs. PMID:22114188

Hatakeyama, Shingo; Sugihara, Kazuhiro; Shibata, Toshiaki K.; Nakayama, Jun; Akama, Tomoya O.; Tamura, Naoaki; Wong, Shuk-Man; Bobkov, Andrey A.; Takano, Yutaka; Ohyama, Chikara; Fukuda, Minoru; Fukuda, Michiko N.

2011-01-01

285

Preparation of Quantum Dot/Drug Nanoparticle Formulations for Traceable Targeted Delivery and Therapy  

PubMed Central

Quantum dots (QDs) are luminescent nanocrystals with rich surface chemistry and unique optical properties that make them useful as probes or carriers for traceable targeted delivery and therapy applications. QDs can be functionalized to target specific cells or tissues by conjugating them with targeting ligands. Recent advancement in making biocompatible QD formulations has made these nanocrystals suitable for in vivo applications. This review provides an overview of the preparation of QDs and their use as probes or carriers for traceable, targeted therapy of diseases in vitro and in vivo. More specifically, recent advances in the integration of QDs with drug formulations for therapy and their potential toxicity in vitro and in vivo are highlighted. The current findings and challenges for optimizing QD/drug formulations with respect to optimal size and stability, short-term and long-term toxicity, and in vivo applications are described. Lastly, we attempt to predict key trends in QD/drug formulation development over the next few years and highlight areas of therapy where their use may provide breakthrough results in the near future. PMID:22896770

Yong, Ken-Tye; Wang, Yucheng; Roy, Indrajit; Rui, Hu; Swihart, Mark T.; Law, Wing-Cheung; Kwak, Sang Kyu; Ye, Ling; Liu, Jianwei; Mahajan, Supriya D.; Reynolds, Jessica L.

2012-01-01

286

The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers  

NASA Astrophysics Data System (ADS)

Encapsulation of drugs within nanocarriers that selectively target malignant cells promises to mitigate side effects of conventional chemotherapy and to enable delivery of the unique drug combinations needed for personalized medicine. To realize this potential, however, targeted nanocarriers must simultaneously overcome multiple challenges, including specificity, stability and a high capacity for disparate cargos. Here we report porous nanoparticle-supported lipid bilayers (protocells) that synergistically combine properties of liposomes and nanoporous particles. Protocells modified with a targeting peptide that binds to human hepatocellular carcinoma exhibit a 10,000-fold greater affinity for human hepatocellular carcinoma than for hepatocytes, endothelial cells or immune cells. Furthermore, protocells can be loaded with combinations of therapeutic (drugs, small interfering RNA and toxins) and diagnostic (quantum dots) agents and modified to promote endosomal escape and nuclear accumulation of selected cargos. The enormous capacity of the high-surface-area nanoporous core combined with the enhanced targeting efficacy enabled by the fluid supported lipid bilayer enable a single protocell loaded with a drug cocktail to kill a drug-resistant human hepatocellular carcinoma cell, representing a 106-fold improvement over comparable liposomes.

Ashley, Carlee E.; Carnes, Eric C.; Phillips, Genevieve K.; Padilla, David; Durfee, Paul N.; Brown, Page A.; Hanna, Tracey N.; Liu, Juewen; Phillips, Brandy; Carter, Mark B.; Carroll, Nick J.; Jiang, Xingmao; Dunphy, Darren R.; Willman, Cheryl L.; Petsev, Dimiter N.; Evans, Deborah G.; Parikh, Atul N.; Chackerian, Bryce; Wharton, Walker; Peabody, David S.; Brinker, C. Jeffrey

2011-05-01

287

In Vivo Tumor Targeting and Image-Guided Drug Delivery with Antibody-Conjugated, Radiolabeled Mesoporous Silica Nanoparticles  

PubMed Central

Since the first use of biocompatible mesoporous silica (mSiO2) nanoparticles as drug delivery vehicles, in vivo tumor targeted imaging and enhanced anti-cancer drug delivery has remained a major challenge. In this work, we describe the development of functionalized mSiO2 nanoparticles for actively targeted positron emission tomography (PET) imaging and drug delivery in 4T1 murine breast tumor-bearing mice. Our structural design involves the synthesis, surface functionalization with thiol groups, PEGylation, TRC105 antibody (specific for CD105/endoglin) conjugation, and 64Cu-labeling of uniform 80 nm sized mSiO2 nanoparticles. Systematic in vivo tumor targeting studies clearly demonstrated that 64Cu-NOTA-mSiO2-PEG-TRC105 could accumulate prominently at the 4T1 tumor site via both the enhanced permeability and retention effect and TRC105-mediated binding to tumor vasculature CD105. As a proof-of-concept, we also demonstrated successful enhanced tumor targeted delivery of doxorubicin (DOX) in 4T1 tumor-bearing mice after intravenous injection of DOX-loaded NOTA-mSiO2-PEG-TRC105, which holds great potential for future image-guided drug delivery and targeted cancer therapy. PMID:24083623

Chen, Feng; Hong, Hao; Zhang, Yin; Valdovinos, Hector F.; Shi, Sixiang; Kwon, Glen S.; Theuer, Charles P.; Barnhart, Todd E.; Cai, Weibo

2013-01-01

288

Targeted delivery of antibody-based therapeutic and imaging agents to CNS tumors: Crossing the blood-brain-barrier divide  

PubMed Central

Introduction Brain tumors are inherently difficult to treat in large part due to the cellular blood-brain barriers (BBB) that limit the delivery of therapeutics to the tumor tissue from the systemic circulation. Virtually no large-molecules, including antibody-based proteins, can penetrate the BBB. With antibodies fast becoming attractive ligands for highly specific molecular targeting to tumor antigens, a variety of methods are being investigated to enhance the access of these agents to intracranial tumors for imaging or therapeutic applications. Areas covered This review describes the characteristics of the BBB and the vasculature in brain tumors, described as the blood-brain tumor barrier (BBTB). Antibodies targeted to molecular markers of CNS tumors will be highlighted, and current strategies for enhancing the delivery of antibodies across these cellular barriers into the brain parenchyma to the tumor will be discussed. Non-invasive imaging approaches to assess BBB/BBTB permeability and/or antibody targeting will be presented as a means of guiding the optimal delivery of targeted agents to brain tumors. Expert Opinion Pre-clinical and clinical studies highlight the potential of several approaches in increasing brain tumor delivery across the blood-brain barrier divide. However, each carries its own risks and challenges. There is tremendous potential in using neuroimaging strategies to assist in understanding and defining the challenges to translating and optimizing molecularly-targeted antibody delivery to CNS tumors to improve clinical outcomes. PMID:23751126

Chacko, Ann-Marie; Li, Chunsheng; Pryma, Daniel A.; Brem, Steven; Coukos, George; Muzykantov, Vladimir R.

2014-01-01

289

Metallo-supramolecular nanogels for intracellular pH-responsive drug release.  

PubMed

A simple process is developed to fabricate metallo-supramolecular nanogels (MSNs) by the metallo-supramolecular-coordinated interaction between histidine and iron-meso-tetraphenylporphin. MSNs are composed of histidine-modified dextran (DH) and iron-meso-tetraphenylporphin (Fe-Por) and exhibit excellent biocompatibility and stability. MSNs show pH responsiveness in the intracellular mildly acidic environment, which has great potential for acid-triggered drug release delivery. In vitro drug release profiles demonstrate that the pH-dependent disassembly of MSNs to histidine and Por results in a quicker release rate of loaded-DOX at pH 5.3, while at pH 7.4 MSNs could hinder the release of loaded-DOX due to the enhanced stability of MSNs. PMID:25179405

Yao, Xuemei; Chen, Li; Chen, Xiaofei; He, Chaoliang; Zhang, Jingping; Chen, Xuesi

2014-10-01

290

PR_b-targeted delivery of tumor necrosis factor-? by polymersomes for the treatment of prostate cancer  

Microsoft Academic Search

Targeted delivery of therapeutics is an active area of research with cancer being an important target because of the necessity for new and better cancer therapies. In this study we design and assess peptide functionalized polymer vesicles, or polymersomes, self assembled from poly(ethylene oxide)-b- poly(butadiene) (PEO-PBD) diblock copolymers for the treatment of prostate cancer. PR_b, a highly effective a5b1 targeting

Döne Demirgöz; Todd O. Pangburn; Kevin P. Davis; Sangwoo Lee; Frank S. Bates; Efrosini Kokkoli

2009-01-01

291

Preparation of irinotecan-loaded folate-targeted liposome for tumor targeting delivery and its antitumor activity.  

PubMed

The purpose of this study was to investigate the in vivo distribution and antitumor activity of irinotecan (camptothecin (CPT)-11)-loaded folate-targeted liposome (F-Lip) in tumor-bearing mice following i.v. administration. Folate-poly(ethylene glycol)-distearoylphosphatidylcholine (FA-PEG-DSPE) was synthesized by amide reaction of DSPE-PEG-NH(2) and FA. F-Lip modified by FA-PEG-DSPE was prepared by an ammonium sulfate gradient. The mean particle size and entrapment efficiency of F-Lip with negative charge were 197.8 ± 4.58 nm and 91.39 ± 2.34 %, respectively. The distributions of CPT-11 and SN-38 in the tumor after i.v. administration of F-Lip, CPT-11-loaded liposomes (C-Lip), and CPT-11 injection (C-Inj) were far greater with the F-Lip group in comparison to the C-Inj and C-Lip, which might contribute to folate-meditated targeting uptake by the folate receptor on the surface of the tumor cells. The uptake of CPT-11 in the liver and rectum for two liposome groups were all markedly increased as compared to the C-Inj. Moreover, F-Lip exhibited a dose-dependent tumor growth inhibition and superior anticancer activity to C-Lip and C-Inj after i.v. administration. It also showed no significant body weight loss and much lower toxicity on the center immune organs. Therefore, F-Lip may be presented as potential candidates for tumor targeting drug delivery. PMID:22639238

Zhang, Ziqiang; Yao, Jing

2012-09-01

292

Probucol release from novel multicompartmental microcapsules for the oral targeted delivery in type 2 diabetes.  

PubMed

In previous studies, we developed and characterised multicompartmental microcapsules as a platform for the targeted oral delivery of lipophilic drugs in type 2 diabetes (T2D). We also designed a new microencapsulated formulation of probucol-sodium alginate (PB-SA), with good structural properties and excipient compatibility. The aim of this study was to examine the stability and pH-dependent targeted release of the microcapsules at various pH values and different temperatures. Microencapsulation was carried out using a Büchi-based microencapsulating system developed in our laboratory. Using SA polymer, two formulations were prepared: empty SA microcapsules (SA, control) and loaded SA microcapsules (PB-SA, test), at a constant ratio (1:30), respectively. Microcapsules were examined for drug content, zeta potential, size, morphology and swelling characteristics and PB release characteristics at pH 1.5, 3, 6 and 7.8. The production yield and microencapsulation efficiency were also determined. PB-SA microcapsules had 2.6?±?0.25% PB content, and zeta potential of -66?±?1.6%, suggesting good stability. They showed spherical and uniform morphology and significantly higher swelling at pH 7.8 at both 25 and 37°C (p?targeted delivery with a multiphasic release pattern and with good stability and uniformity. However, the release of PB from the microcapsules was not controlled, suggesting uneven distribution of the drug within the microcapsules. PMID:25168450

Mooranian, Armin; Negrulj, Rebecca; Al-Sallami, Hesham S; Fang, Zhongxiang; Mikov, Momir; Golocorbin-Kon, Svetlana; Fakhoury, Marc; Watts, Gerald F; Matthews, Vance; Arfuso, Frank; Lambros, Amanda; Al-Salami, Hani

2015-02-01

293

Target-specific delivery of doxorubicin to retinoblastoma using epithelial cell adhesion molecule aptamer  

PubMed Central

Purpose To study target-specific delivery of doxorubicin (Dox) using an RNA aptamer against epithelial cell adhesion molecule (EpCAM) in retinoblastoma (RB) cells. Methods The binding affinity of the EpCAM aptamer to RB primary tumor cells, Y79 and WERI-Rb1 cells, and Müller glial cell lines were evaluated with flow cytometry. Formation of physical conjugates of aptamer and Dox was monitored with spectrofluorimetry. Cellular uptake of aptamer-Dox conjugates was monitored through fluorescent microscopy. Drug efficacy was monitored with cell proliferation assay. Results The EpCAM aptamer (EpDT3) but not the scrambled aptamer (Scr-EpDT3) bound to RB tumor cells, the Y79 and WERI-Rb1 cells. However, the EpCAM aptamer and the scrambled aptamer did not bind to the noncancerous Müller glial cells. The chimeric EpCAM aptamer Dox conjugate (EpDT3-Dox) and the scrambled aptamer Dox conjugate (Scr-EpDT3-Dox) were synthesized and tested on the Y79, WERI-Rb1, and Müller glial cells. The targeted uptake of the EpDT3-Dox aptamer caused cytotoxicity in the Y79 and WERI-Rb1 cells but not in the Müller glial cells. There was no significant binding or consequent cytotoxicity by the Scr-EpDT3-Dox in either cell line. The EpCAM aptamer alone did not cause cytotoxicity in either cell line. Conclusions The results show that the EpCAM aptamer-Dox conjugate can selectively deliver the drug to the RB cells there by inhibiting cellular proliferation and not to the noncancerous Müller glial cells. As EpCAM is a cancer stem cell marker, this aptamer-based targeted drug delivery will prevent the undesired effects of non-specific drug activity and will kill cancer stem cells precisely in RB. PMID:23213278

Subramanian, Nithya; Raghunathan, Vaishnavi; Kanwar, Jagat R.; Kanwar, Rupinder K.; Elchuri, Sailaja V.; Khetan, Vikas

2012-01-01

294

Targeted Cytosolic Delivery of Cell-Impermeable Compounds by Nanoparticle-Mediated, Light-Triggered Endosome Disruption  

PubMed Central

Nanoparticle (NP)-mediated drug delivery typically relies on cargo release to occur passively or in response to environmental stimuli. Here we present a delivery method based on light-activated disruption of intracellular vesicles after internalization of biofunctionalized mesoporous silica nanoparticles loaded with cargo. This method combines the power of targeted delivery with the spatiotemporal control of light activation. As an example, we delivered a cell-impermeable fluorescent compound exclusively to the cytosol of multidrug resistant cancer cells in a mixed population. PMID:20446663

Febvay, Sébastien; Marini, Davide M.; Belcher, Angela M.; Clapham, David E.

2014-01-01

295

Superparamagnetic iron oxide nanoparticles (SPIONs)-loaded Trojan microparticles for targeted aerosol delivery to the lung.  

PubMed

Targeted aerosol delivery to specific regions of the lung may improve therapeutic efficiency and minimise unwanted side effects. Targeted delivery could potentially be achieved with porous microparticles loaded with superparamagnetic iron oxide nanoparticles (SPIONs)-in combination with a target-directed magnetic gradient field. The aim of this study was to formulate and evaluate the aerodynamic properties of SPIONs-loaded Trojan microparticles after delivery from a dry powder inhaler. Microparticles made of SPIONs, PEG and hydroxypropyl-?-cyclodextrin (HP?CD) were formulated by spray drying and characterised by various physicochemical methods. Aerodynamic properties were evaluated using a next generation cascade impactor (NGI), with or without a magnet positioned at stage 2. Mixing appropriate proportions of SPIONs, PEG and HP?CD allowed Trojan microparticle to be formulated. These particles had a median geometric diameter of 2.8±0.3?m and were shown to be sensitive to the magnetic field induced by a magnet having a maximum energy product of 413.8kJ/m(3). However, these particles, characterised by a mass median aerodynamic diameter (MMAD) of 10.2±2.0?m, were considered to be not inhalable. The poor aerodynamic properties resulted from aggregation of the particles. The addition of (NH4)2CO3 and magnesium stearate (MgST) to the formulation improved the aerodynamic properties of the Trojan particles and resulted in a MMAD of 2.2±0.8?m. In the presence of a magnetic field on stage 2 of the NGI, the amount of particles deposited at this stage increased 4-fold from 4.8±0.7% to 19.5±3.3%. These Trojan particles appeared highly sensitive to the magnetic field and their deposition on most of the stages of the NGI was changed in the presence compared to the absence of the magnet. If loaded with a pharmaceutical active ingredient, these particles may be useful for treating localised lung disease such as cancer nodules or bacterial infectious foci. PMID:24055690

Tewes, Frederic; Ehrhardt, Carsten; Healy, Anne Marie

2014-01-01

296

Enzyme/pH dual sensitive polymeric nanoparticles for targeted drug delivery to the inflamed colon.  

PubMed

Novel nanoparticles whose drug release profiles are controlled by both enzyme and pH were prepared for the colon-specific drug delivery using a polymeric mixture of enzyme-sensitive azo-polyurethane and pH-sensitive Eudragit S100 (ES-Azo.pu). The enzyme/pH dual sensitive nanoparticles were designed to release a drug based on a two-fold approach which specifically aimed to target drug delivery to the inflamed colon while preventing the burst release of drugs in the stomach and small intestine. Single pH-sensitive (ES) and dual sensitive (ES-Azo.pu) nanoparticles were prepared using an oil-in-water emulsion solvent evaporation method and coumarin-6 (C-6) was used as a model drug. The successful formation of ES and ES-azo.pu nanoparticles that have 214 nm and 244 nm in mean particle size, respectively, was confirmed by scanning electron microscopy and qNano. ES nanoparticles showed almost 100% of burst drug release at pH 7.4, whereas ES-Azo.pu nanoparticles prevented the burst drug release at pH 7.4, followed by a sustained release phase thereafter. Furthermore, ES-Azo.pu nanoparticles exhibited enzyme-triggered drug release in the presence of rat cecal contents obtained from a rat model of colitis. An in vivo localization study in rat gastrointestinal tract demonstrated that ES-Azo.pu nanoparticles were selectively distributed in the inflamed colon, showing 5.5-fold higher C-6 than ES nanoparticles. In conclusion, the enzyme/pH dual sensitive nanoparticles presented in this study can serve as a promising strategy for colon-specific drug delivery against inflammatory bowel disease and other colon disorders. PMID:25266978

Naeem, Muhammad; Kim, Wooseong; Cao, Jiafu; Jung, Yunjin; Yoo, Jin-Wook

2014-11-01

297

Photoactive metal carbonyl complexes as potential agents for targeted CO delivery.  

PubMed

The surprising discovery of carbon monoxide (CO) as a signaling molecule in mammalian physiology has recently raised interest in this toxic gas among researchers in biochemical and pharmaceutical community. CO is endogenously produced mainly from catabolism of heme by the enzyme heme oxygenase (HO) and participates in a myriad of anti-inflammatory, anti-proliferative, and vasoregulatory pathways. In animal models, low doses of CO have exhibited beneficial effects in suppression of organ graft rejection and safeguarding the heart during reperfusion after cardiopulmonary bypass surgery. The salutary effects of CO have naturally drawn attention of the pharmaceutical industry for its use as a cytoprotective agent. Safety-related concerns of the use of this noxious gas have prompted research in the area of syntheses of CO-releasing molecules (CORMs) and to date, several metal carbonyls (metal complexes of CO) have been employed as CORMs in promoting prolonged (and safe) delivery of low doses of CO to cellular targets. Because many carbonyl complexes release CO upon illumination, investigators have recently began to explore the possibility of "controlled CO delivery" through the use of light. During the past few years, a number of photoactive CORMs or "photoCORMs" have been synthesized that release CO upon illumination with UV or visible light. The utility of these photoCORMs in CO delivery has also been confirmed. Novel design principles for isolation of photoCORMs have started to appear in recent reports. Scrutiny of the literature reveals the emergence of a new exciting area of drug development in such efforts. The potential of photoCORMs as CO-donating pharmaceuticals along with a brief overview of the physiological roles of CO is presented in this review. PMID:24287103

Gonzales, Margarita A; Mascharak, Pradip K

2014-04-01

298

A lysosome-targeted drug delivery system based on sorbitol backbone towards efficient cancer therapy.  

PubMed

A straightforward synthetic approach was adopted for the construction of a lysosome-targeted drug delivery system (TDDS) using sorbitol scaffold (Sor) linked to octa-guanidine and tetrapeptide GLPG, a peptide substrate of lysosomal cysteine protease, cathepsin B. The main objective was to efficiently deliver the potential anticancer drug, doxorubicin to the target sites, thereby minimizing dose-limiting toxicity. Three TDDS vectors were synthesized viz., DDS1: Sor-GLPG-Fl, DDS2: Sor-Fl (control) and DDS3: Sor-GLPGC-SMCC-Dox. Dox release from DDS3 in the presence of cathepsin B was studied by kinetics measurement based on the fluorescent property of Dox. The cytotoxicity of DDS1 was assessed and found to be non-toxic. Cellular internalization and colocalization studies of all the 3 systems were carried out by flow cytometry and confocal microscopy utilizing cathepsin B-expressing HeLa cells. DDS1 and DDS3 revealed significant localization within the lysosomes, in contrast to DDS2 (control). The doxorubicin-conjugated carrier, DDS3, demonstrated significant cytotoxic effect when compared to free Dox by MTT assay and also by flow cytometric analysis. The targeted approach with DDS3 is expected to be promising, because it is indicated to be advantageous over free Dox, which possesses dose-limiting toxicity, posing risk of injury to normal tissues. PMID:25062087

Maniganda, Santhi; Sankar, Vandana; Nair, Jyothi B; Raghu, K G; Maiti, Kaustabh K

2014-09-14

299

Mechanisms and Implications of Dual-Acting Methotrexate in Folate-Targeted Nanotherapeutic Delivery  

PubMed Central

The rational design of a nanoplatform in drug delivery plays a crucial role in determining its targeting specificity and efficacy in vivo. A conventional approach relies on the surface conjugation of a nanometer-sized particle with two functionally distinct types of molecules, one as a targeting ligand, and the other as a therapeutic agent to be delivered to the diseased cell. However, an alternative simplified approach can be used, in which a single type of molecule displaying dual function as both a targeting ligand and therapeutic agent is conjugated to the nanoparticle. In this review, we evaluate the validity of this new strategy by using methotrexate, which displays multifunctional mechanisms of action. Methotrexate binds to the folate receptor, a surface biomarker frequently overexpressed in tumor cells, and also inhibits dihydrofolate reductase, an enzyme critical for cell survival and division. Thus we describe a series of fifth generation poly(amido amine) dendrimers conjugated with methotrexate, and discuss several lines of evidence supporting the efficacy of this new platform strategy based on surface plasmon resonance spectroscopy, enzyme activity assays, and cell-based studies with folate receptor (+) KB cancer cells. PMID:25590303

Wong, Pamela T.; Choi, Seok Ki

2015-01-01

300

In Vivo Fluorescence Resonance Energy Transfer Imaging for Targeted Anti-Cancer Drug Delivery Kinetics  

NASA Astrophysics Data System (ADS)

We describe an approach for the evaluation of targeted anti-cancer drug delivery in vivo. The method emulates the drug release and activation process through acceptor release from a targeted donor-acceptor pair that exhibits fluorescence resonance energy transfer (FRET). In this case, folate targeting of the cancer cells is used - 40 % of all human cancers, including ovarian, lung, breast, kidney, brain and colon cancer, over-express folate receptors. We demonstrate the reconstruction of the spatially-dependent FRET parameters in a mouse model and in tissue phantoms. The FRET parameterization is incorporated into a source for a diffusion equation model for photon transport in tissue, in a variant of optical diffusion tomography (ODT) called FRET-ODT. In addition to the spatially-dependent tissue parameters in the diffusion model (absorption and diffusion coefficients), the FRET parameters (donor-acceptor distance and yield) are imaged as a function of position. Modulated light measurements are made with various laser excitation positions and a gated camera. More generally, our method provides a new vehicle for studying disease at the molecular level by imaging FRET parameters in deep tissue, and allows the nanometer FRET ruler to be utilized in deep tissue.

Webb, Kevin; Gaind, Vaibhav; Tsai, Hsiaorho; Bentz, Brian; Chelvam, Venkatesh; Low, Philip

2012-02-01

301

Alkali reversal of psoralen cross-link for the targeted delivery of psoralen monoadduct lesion  

SciTech Connect

Psoralen intercalates into double-stranded DNA and photoreacts mainly with thymines to form monoadducts and interstrand cross-links. The authors used an oligonucleotide model to demonstrate a novel mechanism: the reversal of psoralen cross-links by base-catalyzed rearrangement at 90/sup 0/C (BCR). The BCR reaction is more efficient than the photoreversal reaction. They show that the BCR occurs predominantly on the furan side of a psoralen cross-link. The cleavage does not result in the breaking of the DNA backbone, and the thymine based freed from the cross-link by the cleavage reaction appears to be unmodified. Similarly, BCR of the furan-side monoadduct of psoralen removed the psoralen molecule and regenerated the unaltered native oligonucleotide. The pyrone-side psoralen monoadduct is relatively resistant to BCR. One can use BCR to perform efficient oligonucleotide-directed, site-specific delivery of a psoralen monoadduct. As a demonstration of this approach, they have hybridized a 19 base long oligonucleotide vehicle containing a furan-side psoralen monoadduct to a 56 base long complementary oligonucleotide target strand and formed a specific cross-link at the target site with 365-nm UV. Subsequent BCR released the oligonucleotide vehicle and deposited the psoralen at the target site.

Yeung, A.T.; Dinehart, W.J.; Jones, B.K.

1988-08-23

302

Self-immolative polycations as gene delivery vectors and prodrugs targeting polyamine metabolism in cancer.  

PubMed

Polycations are explored as carriers to deliver therapeutic nucleic acids. Polycations are conventionally pharmacological inert with the sole function of delivering therapeutic cargo. This study reports synthesis of a self-immolative polycation (DSS-BEN) based on a polyamine analogue drug N(1),N(11)-bisethylnorspermine (BENSpm). The polycation was designed to function dually as a gene delivery carrier and a prodrug targeting dysregulated polyamine metabolism in cancer. Using a combination of NMR and HPLC, we confirm that the self-immolative polycation undergoes intracellular degradation into the parent drug BENSpm. The released BENSpm depletes cellular levels of spermidine and spermine and upregulates polyamine catabolic enzymes spermine/spermidine N(1)-acetyltransferase (SSAT) and spermine oxidase (SMO). The synthesized polycations form polyplexes with DNA and facilitate efficient transfection. Taking advantage of the ability of BENSpm to sensitize cancer cells to TNF?-induced apoptosis, we show that DSS-BEN enhances the cell killing activity of TNF? gene therapy. The reported findings validate DSS-BEN as a dual-function delivery system that can deliver a therapeutic gene and improve the outcome of gene therapy as a result of the intracellular degradation of DSS-BEN to BENSpm and the subsequent beneficial effect of BENSpm on dysregulated polyamine metabolism in cancer. PMID:25153488

Zhu, Yu; Li, Jing; Kanvinde, Shrey; Lin, Zhiyi; Hazeldine, Stuart; Singh, Rakesh K; Oupický, David

2015-02-01

303

Targeting Anticancer Drug Delivery to Pancreatic Cancer Cells Using a Fucose-Bound Nanoparticle Approach  

PubMed Central

Owing to its aggressiveness and the lack of effective therapies, pancreatic ductal adenocarcinoma has a dismal prognosis. New strategies to improve treatment and survival are therefore urgently required. Numerous fucosylated antigens in sera serve as tumor markers for cancer detection and evaluation of treatment efficacy. Increased expression of fucosyltransferases has also been reported for pancreatic cancer. These enzymes accelerate malignant transformation through fucosylation of sialylated precursors, suggesting a crucial requirement for fucose by pancreatic cancer cells. With this in mind, we developed fucose-bound nanoparticles as vehicles for delivery of anticancer drugs specifically to cancer cells. L-fucose-bound liposomes containing Cy5.5 or Cisplatin were effectively delivered into CA19-9 expressing pancreatic cancer cells. Excess L-fucose decreased the efficiency of Cy5.5 introduction by L-fucose-bound liposomes, suggesting L-fucose-receptor-mediated delivery. Intravenously injected L-fucose-bound liposomes carrying Cisplatin were successfully delivered to pancreatic cancer cells, mediating efficient tumor growth inhibition as well as prolonging survival in mouse xenograft models. This modality represents a new strategy for pancreatic cancer cell-targeting therapy. PMID:22808043

Yoshida, Makoto; Takimoto, Rishu; Murase, Kazuyuki; Sato, Yasushi; Hirakawa, Masahiro; Tamura, Fumito; Sato, Tsutomu; Iyama, Satoshi; Osuga, Takahiro; Miyanishi, Koji; Takada, Kohichi; Hayashi, Tsuyoshi; Kobune, Masayoshi; Kato, Junji

2012-01-01

304

Targeting potassium channels for increasing delivery of imaging agents and therapeutics to brain tumors  

PubMed Central

Every year in the US, 20,000 new primary and nearly 200,000 metastatic brain tumor cases are reported. The cerebral microvessels/capillaries that form the blood–brain barrier not only protect the brain from toxic agents in the blood but also pose a significant hindrance to the delivery of small and large therapeutic molecules. Different strategies have been employed to circumvent the physiological barrier posed by blood–brain tumor barrier (BTB). Studies in our laboratory have identified significant differences in the expression levels of certain genes and proteins between normal and brain tumor capillary endothelial cells (ECs). In this study, we validated the non-invasive and clinically relevant dynamic contrast enhancing-magnetic resonance imaging (DCE-MRI) method with invasive, clinically irrelevant but highly accurate quantitative autoradiography method using rat glioma model. We also showed that DCE-MRI metric of tissue vessel perfusion-permeability is sensitive to changes in blood vessel permeability following administration of calcium-activated potassium (BKCa) channel activator NS-1619. Our results show that human gliomas and brain tumor ECs that overexpress BKCa channels can be targeted for increased BTB permeability for MRI enhancing agents to brain tumors. We conclude that monitoring the outcome of increased MRI enhancing agents’ delivery to microsatellites and leading tumor edges in glioma patients would lead to beneficial clinical outcome. PMID:23755013

Khaitan, Divya; Ningaraj, Nagendra S.

2013-01-01

305

Tumor Angiogenesis Therapy Using Targeted Delivery of Paclitaxel to the Vasculature of Breast Cancer Metastases  

PubMed Central

Breast cancer aberrantly expresses tissue factor (TF) in cancer tissues and cancer vascular endothelial cells (VECs). TF plays a central role in cancer angiogenesis, growth, and metastasis and, as such, is a target for therapy and drug delivery. TF is the cognate receptor of factor VIIa (fVIIa). We have coupled PTX (paclitaxel, also named Taxol) with a tripeptide, phenylalanine-phenylalanine-arginine chloromethyl ketone (FFRck) and conjugated it with fVIIa. The key aim of the work is to evaluate the antiangiogenic effects of PTX-FFRck-fVIIa against a PTX-resistant breast cancer cell line. Matrigel mixed with VEGF and MDA-231 was injected subcutaneously into the flank of athymic nude mice. Animals were treated by tail vein injection of the PTX-FFRck-fVIIa conjugate, unconjugated PTX, or PBS. The PTX-FFRck-fVIIa conjugate significantly reduces microvessel density in matrigel (p < 0.01–0.05) compared to PBS and unconjugated PTX. The breast cancer lung metastasis model in athymic nude mice was developed by intravenous injection of MDA-231 cells expressing luciferase. Animals were similarly treated intravenously with the PTX-FFRck-fVIIa conjugate or PBS. The conjugate significantly inhibits lung metastasis as compared to the control, highlighting its potential to antagonize angiogenesis in metastatic carcinoma. In conclusion, PTX conjugated to fVIIa is a promising therapeutic approach for improving selective drug delivery and inhibiting angiogenesis. PMID:25574399

Kisiel, Walter; Lu, Yang J.; Petersen, Lars C.; Ndungu, John M.; Moore, Terry W.; Parker, Ernest T.; Sun, Aiming; Liotta, Dennis C.; El-Rayes, Bassel F.; Brat, Daniel J.; Snyder, James P.; Shoji, Mamoru

2014-01-01

306

Preparation and characterization of magnetic gene vectors for targeting gene delivery  

NASA Astrophysics Data System (ADS)

The PEI-CMD-MNPs were successfully prepared by the surface modification of magnetic Fe3O4 nanoparticles with carboxymethyl dextran (CMD) and polyethyleneimine (PEI). The PEI-CMD-MNPs polyplexes exhibited a typical superparamagnetic behavior and were well stable over the entire range of pH and NaCl concentration. These PEI-CMD-MNPs were used as magnetic gene vectors for targeting gene delivery. The prepared MNPs at different surface modification stages were characterized using Fourier transform infrared (FT-IR), thermogravimetric analysis (TGA), field emissions canning electron microscopy (FE-SEM), powder X-ray diffraction (XRD) and dynamic laser light scattering (DLS) analysis. The magnetic properties were studied by vibrating sample magnetometer (VSM). To evaluate the performance of the magnetic nanoparticles as gene transfer vector, the PEI-CMD-MNPs were used to delivery green fluorescent protein (GFP) gene into BHK21 cells. The expression of GFP gene was detected by fluorescence microscope. DNA-PEI-CMD-MNPs polyplexes absorbed by the cells were also monitored by Magnetic resonance imaging (MRI). The transfection efficiency and gene expression efficiency of that transfected with a magnet were much higher than that of standard transfection.

Zheng, S. W.; Liu, G.; Hong, R. Y.; Li, H. Z.; Li, Y. G.; Wei, D. G.

2012-10-01

307

Mannosylated Chitosan Nanoparticles for Delivery of Antisense Oligonucleotides for Macrophage Targeting  

PubMed Central

The therapeutic potential of antisense oligonucleotides (ASODN) is primarily dependent upon its safe and efficient delivery to specific cells overcoming degradation and maximizing cellular uptake in vivo. The present study focuses on designing mannosylated low molecular weight (LMW) chitosan nanoconstructs for safe ODNs delivery by macrophage targeting. Mannose groups were coupled with LMW chitosan and characterized spectroscopically. Mannosylated chitosan ODN nanoparticles (MCHODN NPs) were formulated by self-assembled method using various N/P ratio (moles of amine groups of MCH to phosphate moieties of ODNs) and characterized for gel retardation assay, physicochemical characteristics, cytotoxicity and transfection efficiency, and antisense assay. Complete complexation of MCH/ODN was achieved at charge ratio of 1:1 and above. On increasing the N/P ratio of MCH/ODN, particle size of the NPs decreased whereas zeta potential (ZV) increased. MCHODN NPs displayed much higher transfection efficiency into Raw 264.7 cells (bears mannose receptors) than Hela cells and no significant toxicity was observed at all MCH concentrations. Antisense assay revealed that reduction in lipopolysaccharide (LPS) induced serum TNF-? is due to antisense activity of TJU-2755 ODN (sequence complementary to 3?-UTR of TNF-?). These results suggest that MCHODN NPs are acceptable choice to improve transfection efficiency in vitro and in vivo. PMID:25057492

Asthana, Abhay; Kohli, Dharm Veer; Vyas, Suresh Prasad

2014-01-01

308

Fabrication of high specificity hollow mesoporous silica nanoparticles assisted by Eudragit for targeted drug delivery.  

PubMed

Hollow mesoporous silica nanoparticles (HMSNs) are one of the most promising carriers for effective drug delivery due to their large surface area, high volume for drug loading and excellent biocompatibility. However, the non-ionic surfactant templated HMSNs often have a broad size distribution and a defective mesoporous structure because of the difficulties involved in controlling the formation and organization of micelles for the growth of silica framework. In this paper, a novel "Eudragit assisted" strategy has been developed to fabricate HMSNs by utilising the Eudragit nanoparticles as cores and to assist in the self-assembly of micelle organisation. Highly dispersed mesoporous silica spheres with intact hollow interiors and through pores on the shell were fabricated. The HMSNs have a high surface area (670m(2)/g), small diameter (120nm) and uniform pore size (2.5nm) that facilitated the effective encapsulation of 5-fluorouracil within HMSNs, achieving a high loading capacity of 194.5mg(5-FU)/g(HMSNs). The HMSNs were non-cytotoxic to colorectal cancer cells SW480 and can be bioconjugated with Epidermal Growth Factor (EGF) for efficient and specific cell internalization. The high specificity and excellent targeting performance of EGF grafted HMSNs have demonstrated that they can become potential intracellular drug delivery vehicles for colorectal cancers via EGF-EGFR interaction. PMID:25617610

She, Xiaodong; Chen, Lijue; Velleman, Leonora; Li, Chengpeng; Zhu, Haijin; He, Canzhong; Wang, Tao; Shigdar, Sarah; Duan, Wei; Kong, Lingxue

2015-05-01

309

Galactosylated Chitosan Oligosaccharide Nanoparticles for Hepatocellular Carcinoma Cell-Targeted Delivery of Adenosine Triphosphate  

PubMed Central

Nanoparticles composed of galactosylated chitosan oligosaccharide (Gal-CSO) and adenosine triphosphate (ATP) were prepared for hepatocellular carcinoma cell-specific uptake, and the characteristics of Gal-CSO/ATP nanoparticles were evaluated. CSO/ATP nanoparticles were prepared as a control. The average diameter and zeta potential of Gal-CSO/ATP nanoparticles were 51.03 ± 3.26 nm and 30.50 ± 1.25 mV, respectively, suggesting suitable properties for a drug delivery system. Subsequently, the cytotoxicity of Gal-CSO/ATP nanoparticles were examined by the methyl tetrazolium (MTT) assay, and the half maximal inhibitory concentration (IC50) values were calculated with HepG2 (human hepatocellular carcinoma cell line) cells. The results showed that the cytotoxic effect of nanoparticles on HepG2 cells was low. In the meantime, it was also found that the Gal-CSO/ATP nanoparticles could be uptaken by HepG2 cells, due to expression of the asialoglycoprotein receptor (ASGP-R) on their surfaces. The presented results indicate that the Gal-CSO nanoparticles might be very attractive to be used as an intracellular drug delivery carrier for hepatocellular carcinoma cell targeting, thus warranting further in vivo or clinical investigations. PMID:23899789

Zhu, Xiu Liang; Du, Yong Zhong; Yu, Ri Sheng; Liu, Ping; Shi, Dan; Chen, Ying; Wang, Ying; Huang, Fang Fang

2013-01-01

310

Novel thermo-sensitive core-shell nanoparticles for targeted paclitaxel delivery  

NASA Astrophysics Data System (ADS)

Novel thermo-sensitive nanoparticles self-assembled from poly(N,N-diethylacrylamide- co-acrylamide)-block-poly(?-benzyl L-glutamate) were designed for targeted drug delivery in localized hyperthermia. The lower critical solution temperature (LCST) of nanoparticles was adjusted to a level between physiological body temperature (37 °C) and that used in local hyperthermia (about 43 °C). The temperature-dependent performances of the core-shell nanoparticles were systemically studied by nuclear magnetic resonance (NMR), circular dichroism (CD), fluorescence spectroscopy, dynamic light scattering (DLS), and atom force microscopy (AFM). The mean diameter of the nanoparticles increased slightly from 110 to 129 nm when paclitaxel (PTX), a poorly water-soluble anti-tumor drug, was encapsulated. A stability study in bovine serum albumin (BSA) solution indicated that the PTX loaded nanoparticles may have a long circulation time under physiological environments as the LCST was above physiological body temperature and the shell remained hydrophilic at 37 °C. The PTX release profiles showed thermo-sensitive controlled behavior. The proliferation inhibiting activity of PTX loaded nanoparticles was evaluated against Hela cells in vitro, compared with Taxol (a formulation of paclitaxel dissolved in Cremophor EL and ethanol). The cytotoxicity of PTX loaded nanoparticles increased obviously when hyperthermia was performed. The nanoparticles synthesized here could be an ideal candidate for thermal triggered anti-tumor PTX delivery system.

Li, Yuanpei; Pan, Shirong; Zhang, Wei; Du, Zhuo

2009-02-01

311

Close-packed vesicles for diclofenac skin delivery and fibroblast targeting.  

PubMed

Concentrated and interconnected penetration enhancer containing vesicles (PEVs) are proposed as carriers for dermal delivery of diclofenac. PEVs were prepared by using a commercial phosphatidylcholine mixture (180 mg/m) and transcutol in different amounts. Conventional liposomes were also prepared and tested as control. All vesicles showed a mean size ranging from 75 to 253 nm with fairly narrow size distribution, negative zeta potential value, and drug loading capacity between 48 and 70%. SWAXS studies showed that composition affected vesicle structure and morphology: 10 and 30% transcutol PEVs were unilamellar while liposomes and 20% transcutol PEVs were multilamellar. Rheological studies demonstrated that control liposomes and 10 and 30% transcutol containing PEVs behaved as Newtonian fluids while 20% transcutol containing PEVs showed a plastic behavior. Ex vivo (trans)dermal delivery experiments showed an improved skin deposition of diclofenac when PEVs were used. Vesicle toxicity and uptake of fibroblasts, target of inflammation treatment, were evaluated by MTT test and fluorescence microscopy. Control liposomes and PEVs were both able to interact and being internalized by the 3T3 fibroblasts at all time exposure tested. Furthermore, PEVs showed to be able to reduce the in vitro drug toxicity. PMID:23907049

Manca, Maria Letizia; Manconi, Maria; Falchi, Angela Maria; Castangia, Ines; Valenti, Donatella; Lampis, Sandrina; Fadda, Anna Maria

2013-11-01

312

Mannosylated chitosan nanoparticles for delivery of antisense oligonucleotides for macrophage targeting.  

PubMed

The therapeutic potential of antisense oligonucleotides (ASODN) is primarily dependent upon its safe and efficient delivery to specific cells overcoming degradation and maximizing cellular uptake in vivo. The present study focuses on designing mannosylated low molecular weight (LMW) chitosan nanoconstructs for safe ODNs delivery by macrophage targeting. Mannose groups were coupled with LMW chitosan and characterized spectroscopically. Mannosylated chitosan ODN nanoparticles (MCHODN NPs) were formulated by self-assembled method using various N/P ratio (moles of amine groups of MCH to phosphate moieties of ODNs) and characterized for gel retardation assay, physicochemical characteristics, cytotoxicity and transfection efficiency, and antisense assay. Complete complexation of MCH/ODN was achieved at charge ratio of 1:1 and above. On increasing the N/P ratio of MCH/ODN, particle size of the NPs decreased whereas zeta potential (ZV) increased. MCHODN NPs displayed much higher transfection efficiency into Raw 264.7 cells (bears mannose receptors) than Hela cells and no significant toxicity was observed at all MCH concentrations. Antisense assay revealed that reduction in lipopolysaccharide (LPS) induced serum TNF-? is due to antisense activity of TJU-2755 ODN (sequence complementary to 3'-UTR of TNF-?). These results suggest that MCHODN NPs are acceptable choice to improve transfection efficiency in vitro and in vivo. PMID:25057492

Asthana, Gyati Shilakari; Asthana, Abhay; Kohli, Dharm Veer; Vyas, Suresh Prasad

2014-01-01

313

PMMA/polysaccharides nanofilm loaded with adenosine deaminase inhibitor for targeted anti-inflammatory drug delivery.  

PubMed

A novel drug delivery vector, a free-standing polymeric ultrathin film (nanofilm) composed of PMMA and a polysaccharides multilayer, is presented. Chitosan and sodium alginate are alternatively deposited by spin-assisted LbL assembly onto a plasma-treated PMMA thin film. Hydrophobic anti-inflammatory drugs, an adenosine deaminase inhibitor (APP) and its fluorescent dansyl derivate (APP-Dns), are encapsulated inside the LbL multilayer using a simple casting deposition procedure. The resulting drug loaded nanofilm can be suspended in water upon dissolution of a PVA sacrificial layer. Morphological characterization of the nanofilm shows that PMMA/LbL nanofilms possess nanometric thickness (<200 nm) and very low surface roughness (1-2 nm for drug loaded nanofilms and <1 nm for blank nanofilm). Drug loaded films exhibit a diffusion controlled release mechanism following the Korsmayer-Peppas release model, confirmed by the fit of release data with a characteristic power law. Drug release is impaired through the PMMA layer, which acts effectively as a barrier for drug transport. This ultrathin polymer film can find application as a nanopatch for targeted inflammatory drug delivery to treat localized pathologies as inflammatory bowel disease. PMID:24073802

Redolfi Riva, Eugenio; Desii, Andrea; Sartini, Stefania; La Motta, Concettina; Mazzolai, Barbara; Mattoli, Virgilio

2013-10-29

314

Antibody-targeted delivery of doxorubicin entrapped in sterically stabilized liposomes can eradicate lung cancer in mice.  

PubMed

Cancer chemotherapy is limited by adverse side effects resulting from toxicities to normal tissues. Targeted delivery of drugs to diseased tissues in vivo would help to reduce these side effects. Liposomes containing lipid derivatives of polyethylene glycol have circulation times sufficiently long to allow for effective in vivo drug delivery. Polyethylene glycol liposomes, containing entrapped doxorubicin, targeted to KLN-205 squamous cell carcinoma of the lung by means of specific antibodies attached at the liposome surface were capable of reducing tumor burden to a high degree and eradicating tumor in a significant percentage of mice. PMID:8453612

Ahmad, I; Longenecker, M; Samuel, J; Allen, T M

1993-04-01

315

Targeted Drug Delivery to the Brain by MRI-guided Focused Ultrasound  

NASA Astrophysics Data System (ADS)

The effect of focused ultrasound on the absorption of liposome-encapsulated doxorubicin in the brain was investigated. By applying focused ultrasound in the presence of microbubble ultrasound contrast agent, we achieved targeted drug delivery to the brain in vivo. Tissue drug concentrations in sonicated brain corresponded with cytotoxic levels measured in various human tumors and were significantly different from those measured in unexposed contralateral control samples (p ? 0.02). In addition, increased MR signal enhancement at the focal location on contrast-enhanced T1-weighted fast spin echo images correlated with increased penetration of doxorubicin into brain tissue (r = 0.85), indicating the potential of MRI to be used as an indicator of blood-brain barrier permeability during treatment. Further investigation is required to evaluate the efficacy of this technique and to optimize its parameters for clinical application.

Treat, Lisa Hsu; McDannold, Nathan; Vykhodtseva, Natalia; Zhang, Yongzhi; Tam, Karen; Hynynen, Kullervo

2006-05-01

316

Targeted delivery of curcumin to tumors via PEG-derivatized FTS-based micellar system.  

PubMed

Curcumin and S-trans, trans-farnesylthiosalicylic acid (FTS) are two promising anticancer agents. In this study, we demonstrated that the two agents exerted significant synergy in antitumor activity in various types of cancer cells with combination indices ranging from 0.46 to 0.98 (a value of less than unity indicates synergism). We have further shown that synergistic-targeted co-delivery of the two agents can be achieved via formulating curcumin in polyethylene glycol (PEG)-derivatized FTS-based nanomicellar system. Curcumin formulated in PEG-FTS micelles had small size of around 20 nm. The nanomicellar curcumin demonstrated enhanced cytotoxicity towards several cancer cell lines in vitro. Intravenous application of curcumin-loaded micelle (20 mg kg(-1) curcumin) led to a significantly more effective inhibition of tumor growth in a syngeneic mouse breast cancer model (4T1.2) than curcumin formulated in Cremophor/EL (P?

Chen, Yichao; Zhang, Xiaolan; Lu, Jianqin; Huang, Yixian; Li, Jiang; Li, Song

2014-05-01

317

Targeted Delivery of Magnetic Cobalt Nanoparticles to the Eye Following Systemic Administration  

NASA Astrophysics Data System (ADS)

The eye offers a unique environment in the body to study progression and response to treatment of various ocular, vascular, and neurologic diseases as they occur in vivo. Due to its clear optical media, we can directly view blood vessels and nerve tissue, which often reflect the health of these tissues in the rest of the body. There are limitations to topical, periocular, or intraocular drug delivery that include access of the drug to the posterior segment of the eye and complications such as local scarring, hemorrhage, retinal detachment, cataract formation, or infection. The aim of this proof-of-concept study was to determine if systemically delivered magnetic cobalt nanoparticles (Co-MNP) could be directed to the eye of C57Bl mice via a unidirectional magnetic field. Both radioactive biodistribution studies and confocal imaging confirmed the increased presence of magnetic particles in the eye following magnetic targeting.

Dengler, Mirko; Saatchi, Katayoun; Dailey, James P.; Matsubara, Joanne; Mikelberg, Frederick S.; Häfeli, Urs O.; Yeung, Sonia N.

2010-12-01

318

Engineered nanocrystal technology: in-vivo fate, targeting and applications in drug delivery.  

PubMed

Formulation of nanocrystals is a robust approach which can improve delivery of poorly water soluble drugs, a challenge pharmaceutical industry has been facing since long. Large scale production of nanocrystals is done by techniques like precipitation, media milling and, high pressure homogenization. Application of appropriate stabilizers along with drying accords long term stability and commercial viability to nanocrystals. These can be administered through oral, parenteral, pulmonary, dermal and ocular routes showing their high therapeutic applicability. They serve to target drug molecules in specific regions through size manipulation and surface modification. This review dwells upon the in-vivo fate and varying applications in addition to the facets of drug nanocrystals stated above. PMID:24667572

Pawar, Vivek K; Singh, Yuvraj; Meher, Jaya Gopal; Gupta, Siddharth; Chourasia, Manish K

2014-06-10

319

Multi-ligand nanoparticles for targeted drug delivery to the injured vascular wall  

NASA Astrophysics Data System (ADS)

Pathological conditions like coronary artery disease, acute myocardial infarction, stroke, and peripheral artery diseases as well as cardiovascular interventions used in the treatment of coronary artery diseases such as angioplasty and stenting damage/injure the blood vessel wall, leading to inflamed or activated endothelial cells that have been implicated in events leading to thrombosis, inflammation, and restenosis. Oral administration of anti-coagulant and anti-inflammatory drugs causes systemic toxicity, bleeding, patient incompliance, and inadequate amounts of drugs at the injured area. Though drug-eluting stents have shown therapeutic benefits, complications such as in-stent restenosis and late thrombosis still remain and are a cause for concern. Rapid growth in the field of nanotechnology and nanoscience in recent years has paved the way for new targeted and controlled drug delivery strategies. In this perspective, the development of biodegradable nanoparticles for targeted intracellular drug delivery to the inflamed endothelial cells may offer an improved avenue for treatment of cardiovascular diseases. The major objective of this research was to develop "novel multi-ligand nanoparticles," as drug carriers that can efficiently target and deliver therapeutic agents to the injured/inflamed vascular cells under dynamic flow conditions. Our approach mimics the natural binding ability of platelets to injured/activated endothelial cells through glycoprotein Ib (GPIb) bound to P-selectin expressed on inflamed endothelial cells and to the subendothelium through GPIb binding to von Willebrand factor (vWF) deposited onto the injured vascular wall. Our design also exploits the natural cell membrane translocation ability of the internalizing cell peptide - trans-activating transcriptor (TAT) to enhance the nanoparticle uptake by the targeted cells. Our hypothesis is that these multi-ligand nanoparticles would show an increased accumulation at the injury site since GPIb specially binds to both P-selectin expressed on damaged endothelial cells and vWF deposited on injured subendothelium while the cell penetrating peptide -- TAT would facilitate enhanced uptake of these nanoparticles by the damaged vascular cells. To test this hypothesis, fluorescent drug loaded poly (D, L-lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG) nanoparticles (PLGA-PEG NPs) were formulated using a standard double emulsion method. We further conjugated GPIb and TAT via carbodiimide and avidin-biotin chemistry to the PLGA-PEG nanoparticles. Characterization of these nanoparticles indicated the average size to be about 200nm. Endothelial cell uptake studies indicated an optimal nanoparticle incubation time of one hour and optimal dose of 400 mug/ml. Biocompatibility results showed these particles to be non-toxic to endothelial cells. Moreover, dexamethasone release profiles from the nanoparticles demonstrated their ability to provide a sustained drug release over four weeks. Static and dynamic uptake studies of control, GPIb-conjugated, and GPIb-TAT-conjugated PLGA-PEG nanoparticles on activated endothelial cells exhibited an increased adhesion and uptake of GPIb-TAT conjugated PLGA-PEG nanoparticles compared to control nanoparticles. A similar trend of significantly higher adhesion of GPIb-TAT conjugated PLGA-PEG nanoparticles to the injured vessel wall was also observed in preliminary ex-vivo studies using the rat carotid injury model. These results suggest that "our novel multi-ligand NPs" would provide a unique active targeting strategy. This system would rapidly target and deliver therapeutic agents to the injured vascular wall under flow conditions. It could also serve as an effective therapeutic delivery system to treat the complications associated with cardiovascular diseases.

Kona, Soujanya

320

Nebulisation of Receptor-Targeted Nanocomplexes for Gene Delivery to the Airway Epithelium  

PubMed Central

Background Gene therapy mediated by synthetic vectors may provide opportunities for new treatments for cystic fibrosis (CF) via aerosolisation. Vectors for CF must transfect the airway epithelium efficiently and not cause inflammation so they are suitable for repeated dosing. The inhaled aerosol should be deposited in the airways since the cystic fibrosis transmembrane conductance regulator gene (CFTR) is expressed predominantly in the epithelium of the submucosal glands and in the surface airway epithelium. The aim of this project was to develop an optimised aerosol delivery approach applicable to treatment of CF lung disease by gene therapy. Methodology The vector suspension investigated in this study comprises receptor-targeting peptides, cationic liposomes and plasmid DNA that self-assemble by electrostatic interactions to form a receptor-targeted nanocomplex (RTN) of approximately 150 nm with a cationic surface charge of +50 mV. The aerodynamic properties of aerosolised nanocomplexes produced with three different nebulisers were compared by determining aerosol deposition in the different stages of a Next Generation Pharmaceutical Impactor (NGI). We also investigated the yield of intact plasmid DNA by agarose gel electrophoresis and densitometry, and transfection efficacies in vitro and in vivo. Results RTNs nebulised with the AeroEclipse II BAN were the most effective, compared to other nebulisers tested, for gene delivery both in vitro and in vivo. The biophysical properties of the nanocomplexes were unchanged after nebulisation while the deposition of RTNs suggested a range of aerosol aerodynamic sizes between 5.5 µm–1.4 µm cut off (NGI stages 3–6) compatible with deposition in the central and lower airways. Conclusions RTNs showed their ability at delivering genes via nebulisation, thus suggesting their potential applications for therapeutic interventions of cystic fibrosis and other respiratory disorders. PMID:22046351

Manunta, Maria D. I.; McAnulty, Robin J.; Tagalakis, Aristides D.; Bottoms, Stephen E.; Campbell, Frederick; Hailes, Helen C.; Tabor, Alethea B.; Laurent, Geoffrey J.; O'Callaghan, Christopher; Hart, Stephen L.

2011-01-01

321

Poly(NIPAm-AMPS) nanoparticles for targeted delivery of anti-inflammatory cell penetrating peptides  

NASA Astrophysics Data System (ADS)

Inflammatory diseases such as osteoarthritis and rheumatoid arthritis cause $127.8 billion in US healthcare expenditures each year and are the cause of disability for 27% of disabled persons in the United States. Current treatment options rarely halt disease progression and often result in significant unwanted and debilitating side effects. Our laboratory has previously developed a family of cell penetrating peptides (CPPs) which inhibit the activity of mitogen activated protein kinase activate protein kinase 2 (MK2). MK2 mediates the inflammatory response by activating Tristetraprline (TTP). Once activated, TTP rapidly stabilizes AU rich regions of pro-inflammatory cytokine mRNA which allows translation of pro-inflammatory cytokines to occur. Blocking MK2 with our labs CPPs yields a decrease in inflammatory activity but CPPs by are highly non specific and prone to rapid enzymatic degradation in vivo.. In order to increase the potency of MK2 inhibiting CPPs we have developed a novel nanoparticle drug carrier composed of poly(N-isopropylacrylamide-co-2-acrylamido-2-methyl-1-propanesulfonic acid). This drug carrier has been shown to have preliminary efficacy in vitro and ex vivo for suppressing pro-inflammatory cytokine production when releasing CPPs. This thesis will present progress made on three aims: Specific Aim 1) Create and validate a NIPAm based drug delivery system that mimics the binding and release previously observed between cell penetrating peptides and glycosaminoglycans. Specific Aim 2) Engineer degradability into poly(NIPAm-AMPS) nanoparticles to enable more drug to be released and qualify that system in vitro. Specific Aim 3) Validate poly(NIPAm-AMPS) nanoparticles for targeted drug delivery in an ex vivo inflammatory model. Overall we have developed a novel anionic nanoparticle system that is biocompatible and efficient at loading and releasing cell penetrating peptides to inflamed tissue. Once loaded with a CPP the nanoparticle drug complex is capable of targeting diseased tissue and preventing the production of pro-inflammatory cytokines in both in vitro and ex vivo models.

Bartlett, Rush Lloyd, II

322

Co-delivery of PDTC and doxorubicin by multifunctional micellar nanoparticles to achieve active targeted drug delivery and overcome multidrug resistance  

Microsoft Academic Search

Micellar nanoparticles self-assembled from copolymer folate–chitosan (FA–CS) were employed as carriers to co-deliver Pyrrolidinedithiocarbamate (PDTC) and doxorubicin (DOX) to achieve targeted DOX delivery, with a pH responsive drug release, and to overcome DOX multidrug resistance (MDR). The successful synthesis of FA–CS was determined by NMR. Average particle size was small enough to achieve longevity during systemic circulation. Lower CACs in

Li Fan; Fei Li; Haitao Zhang; Yukun Wang; Chong Cheng; Xiaoye Li; Chun-hu Gu; Qian Yang; Hong Wu; Shengyong Zhang

2010-01-01

323

Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery  

PubMed Central

Background Modular nanotransporters (MNT) are recombinant multifunctional polypeptides created to exploit a cascade of cellular processes, initiated with membrane receptor recognition to deliver selective short-range and highly cytotoxic therapeutics to the cell nucleus. This research was designed for in vivo concept testing for this drug delivery platform using two modular nanotransporters, one targeted to the ?-melanocyte-stimulating hormone (?MSH) receptor overexpressed on melanoma cells and the other to the epidermal growth factor (EGF) receptor overexpressed on several cancers, including glioblastoma, and head-and-neck and breast carcinoma cells. Methods In vivo targeting of the modular nanotransporter was determined by immuno-fluorescence confocal laser scanning microscopy and by accumulation of 125I-labeled modular nanotransporters. The in vivo therapeutic effects of the modular nanotransporters were assessed by photodynamic therapy studies, given that the cytotoxicity of photosensitizers is critically dependent on their delivery to the cell nucleus. Results Immunohistochemical analyses of tumor and neighboring normal tissues of mice injected with multifunctional nanotransporters demonstrated preferential uptake in tumor tissue, particularly in cell nuclei. With 125I-labeled MNT{?MSH}, optimal tumor:muscle and tumor:skin ratios of 8:1 and 9.8:1, respectively, were observed 3 hours after injection in B16-F1 melanoma-bearing mice. Treatment with bacteriochlorin p-MNT{?MSH} yielded 89%–98% tumor growth inhibition and a two-fold increase in survival for mice with B16-F1 and Cloudman S91 melanomas. Likewise, treatment of A431 human epidermoid carcinoma-bearing mice with chlorin e6- MNT{EGF} resulted in 94% tumor growth inhibition compared with free chlorin e6, with 75% of animals surviving at 3 months compared with 0% and 20% for untreated and free chlorin e6-treated groups, respectively. Conclusion The multifunctional nanotransporter approach provides a new in vivo functional platform for drug development that could, in principle, be applicable to any combination of cell surface receptor and agent (photosensitizers, oligonucleotides, radionuclides) requiring nuclear delivery to achieve maximum effectiveness. PMID:22346349

Slastnikova, Tatiana A; Rosenkranz, Andrey A; Gulak, Pavel V; Schiffelers, Raymond M; Lupanova, Tatiana N; Khramtsov, Yuri V; Zalutsky, Michael R; Sobolev, Alexander S

2012-01-01

324

GEN | News Highlights: Scientists Develop High-Capacity Nanoparticles for Targeted Delivery of Drug Cocktails http://www.genengnews.com/gen-news-highlights/scientists-develop-high-capacity-nanoparticles-for-targeted-delivery-of-drug-cocktails/81245016/[4/  

E-print Network

GEN | News Highlights: Scientists Develop High-Capacity Nanoparticles for Targeted Delivery of Drug Cocktails http://www.genengnews.com/gen-news-highlights/scientists-develop NEWS Blogs Podcasts Webinars Videos New Products Best of the Web Events Jobs Polls App Notes GEN

Brinker, C. Jeffrey

325

Polymersomes functionalized via ``click'' chemistry with the fibronectin mimetic peptides PR_b and GRGDSP for targeted delivery to cells with  

E-print Network

Polymersomes functionalized via ``click'' chemistry with the fibronectin mimetic peptides PRa Polymersomes were functionalized using azide-alkyne ``click'' chemistry with two targeting functionalized polymersomes to achieve targeted delivery to colon cancer cells was assessed by studying

Kokkoli, Efie

326

EGFR-mediated intracellular delivery of Pc 4 nanoformulation for targeted photodynamic therapy of cancer: in vitro studies  

Microsoft Academic Search

In photodynamic therapy (PDT), the light activation of a photosensitizer leads to the generation of reactive oxygen species that can trigger various mechanisms of cell death. Harnessing this process within cancer cells enables minimally invasive yet targeted cancer treatment. With this rationale, here we demonstrate tumor-targeted delivery of a highly hydrophobic photosensitizer Pc 4 loaded within biocompatible poly(ethylene glycol)–poly(?-caprolactone) block

Alyssa M. Master; Yizhi Qi; Nancy L. Oleinick; Anirban Sen Gupta

327

Self-complementary AAV mediates gene targeting and enhances endonuclease delivery for double-strand break repair  

Microsoft Academic Search

Adeno-associated virus (AAV) mediates gene targeting in humans by providing exogenous DNA for allelic replacement through homologous recombination. In comparison to other methods of DNA delivery or alternative DNA substrates, AAV gene targeting is reported to be very efficient, perhaps due to its single-stranded DNA genome, the inverted terminal repeats (ITRs), and\\/or the consequence of induced cellular signals on infection

M L Hirsch; L Green; M H Porteus; R J Samulski

2010-01-01

328

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

Microsoft Academic Search

The development of smart targeted nanoparticle that can deliver drugs to direct cancer cells, introduces better efficacy and\\u000a lower toxicity for treatment. We report the development and characterizations of pH-sensitive carboxymethyl chitosan modified\\u000a folic acid nanoparticles and manifest their feasibility as an effective targeted drug delivery vehicle. The nanoparticles\\u000a have been synthesized from carboxymethyl chitosan with covalently bonded bifunctional 2,2?-(ethylenedioxy)-bis-(ethylamine)

Sumanta K. Sahu; Sanjay K. Mallick; Susmita Santra; Tapas K. Maiti; Sudip K. Ghosh; Panchanan Pramanik

2010-01-01

329

ChemoRad nanoparticles: a novel multifunctional nanoparticle platform for targeted delivery of concurrent chemoradiation  

PubMed Central

Aim The development of chemoradiation – the concurrent administration of chemotherapy and radiotherapy – has led to significant improvements in local tumor control and survival. However, it is limited by its high toxicity. In this study, we report the development of a novel NP (nanoparticle) therapeutic, ChemoRad NP, which can deliver biologically targeted chemoradiation. Method A biodegradable and biocompatible lipid–polymer hybrid NP that is capable of delivering both chemotherapy and radiotherapy was formulated. Results Using docetaxel, indium111 and yttrium90 as model drugs, we demonstrated that the ChemoRad NP can encapsulate chemotherapeutics (up to 9% of NP weight) and radiotherapeutics (100 mCi of radioisotope per gram of NP) efficiently and deliver both effectively. Using prostate cancer as a disease model, we demonstrated the targeted delivery of ChemoRad NPs and the higher therapeutic efficacy of ChemoRad NPs. Conclusion We believe that the ChemoRad NP represents a new class of therapeutics that holds great potential to improve cancer treatment. PMID:20394530

Wang, Andrew Z; Yuet, Kai; Zhang, Liangfang; Gu, Frank X; Huynh-Le, Minh; Radovic-Moreno, Aleksandar F; Kantoff, Philip W; Bander, Neil H; Langer, Robert; Farokhzad, Omid C

2010-01-01

330

EGFR-Targeted Adenovirus Dendrimer Coating for Improved Systemic Delivery of the Theranostic NIS Gene  

PubMed Central

We recently demonstrated tumor-selective iodide uptake and therapeutic efficacy of combined radiovirotherapy after systemic delivery of the theranostic sodium iodide symporter (NIS) gene using a dendrimer-coated adenovirus. To further improve shielding and targeting we physically coated replication-selective adenoviruses carrying the hNIS gene with a conjugate consisting of cationic poly(amidoamine) (PAMAM) dendrimer linked to the peptidic, epidermal growth factor receptor (EGFR)-specific ligand GE11. In vitro experiments demonstrated coxsackie-adenovirus receptor-independent but EGFR-specific transduction efficiency. Systemic injection of the uncoated adenovirus in a liver cancer xenograft mouse model led to high levels of NIS expression in the liver due to hepatic sequestration, which were significantly reduced after coating as demonstrated by 123I-scintigraphy. Reduction of adenovirus liver pooling resulted in decreased hepatotoxicity and increased transduction efficiency in peripheral xenograft tumors. 124I-PET-imaging confirmed EGFR-specificity by significantly lower tumoral radioiodine accumulation after pretreatment with the EGFR-specific antibody cetuximab. A significantly enhanced oncolytic effect was observed following systemic application of dendrimer-coated adenovirus that was further increased by additional treatment with a therapeutic dose of 131I. These results demonstrate restricted virus tropism and tumor-selective retargeting after systemic application of coated, EGFR-targeted adenoviruses therefore representing a promising strategy for improved systemic adenoviral NIS gene therapy. PMID:24193032

Grünwald, Geoffrey K; Vetter, Alexandra; Klutz, Kathrin; Willhauck, Michael J; Schwenk, Nathalie; Senekowitsch-Schmidtke, Reingard; Schwaiger, Markus; Zach, Christian; Wagner, Ernst; Göke, Burkhard; Holm, Per S; Ogris, Manfred; Spitzweg, Christine

2013-01-01

331

Multifunctional receptor-targeted nanocomplexes for the delivery of therapeutic nucleic acids to the brain.  

PubMed

Convection enhanced delivery (CED) is a method of direct injection to the brain that can achieve widespread dispersal of therapeutics, including gene therapies, from a single dose. Non-viral, nanocomplexes are of interest as vectors for gene therapy in the brain, but it is essential that administration should achieve maximal dispersal to minimise the number of injections required. We hypothesised that anionic nanocomplexes administered by CED should disperse more widely in rat brains than cationics of similar size, which bind electrostatically to cell-surface anionic moieties such as proteoglycans, limiting their spread. Anionic, receptor-targeted nanocomplexes (RTN) containing a neurotensin-targeting peptide were prepared with plasmid DNA and compared with cationic RTNs for dispersal and transfection efficiency. Both RTNs were labelled with gadolinium for localisation in the brain by MRI and in brain sections by LA-ICP-MS, as well as with rhodamine fluorophore for detection by fluorescence microscopy. MRI distribution studies confirmed that the anionic RTNs dispersed more widely than cationic RTNs, particularly in the corpus callosum. Gene expression levels from anionic formulations were similar to those of cationic RTNs. Thus, anionic RTN formulations can achieve both widespread dispersal and effective gene expression in brains after administration of a single dose by CED. PMID:23948162

Kenny, Gavin D; Bienemann, Alison S; Tagalakis, Aristides D; Pugh, John A; Welser, Katharina; Campbell, Frederick; Tabor, Alethea B; Hailes, Helen C; Gill, Steven S; Lythgoe, Mark F; McLeod, Cameron W; White, Edward A; Hart, Stephen L

2013-12-01

332

Biochemically altered human erythrocytes as a carrier for targeted delivery of primaquine: an in vitro study.  

PubMed

The aim of this study was to investigate human erythrocytes as a carrier for targeted drug delivery of primaquine (PQ). The process of PQ loading in human erythrocytes, as well as the effect of PQ loading on the oxidative status of erythrocytes, was also studied. At PQ concentrations of 2, 4, 6, and 8 mg/mL and an incubation time of 2 h, the ratios of the concentrations of PQ entrapped in erythrocytes to that in the incubation medium were 0.515, 0.688, 0.697 and 0.788, respectively. The maximal decline of erythrocyte reduced glutathione content was observed at 8 mg/mL of PQ compared with native erythrocytes p < 0.001. In contrast, malondialdehyde and protein carbonyl were significantly increased in cells loaded with PQ (p < 0.001). Furthermore, osmotic fragility of PQ carrier erythrocytes was increased in comparison with unloaded cells. Electron microscopy revealed spherocyte formation with PQ carrier erythrocytes. PQ-loaded cells showed sustained drug release over a 48 h period. Erythrocytes were loaded with PQ successfully, but there were some biochemical as well as physiological changes that resulted from the effect of PQ on the oxidative status of drug-loaded erythrocytes. These changes may result in favorable targeting of PQ-loaded cells to reticulo-endothelial organs. The relative impact of these changes remains to be explored in ongoing animal studies. PMID:21544721

Alanazi, Fars K; Harisa, Gamal El-Din I; Maqboul, Ahmad; Abdel-Hamid, Magdi; Neau, Steven H; Alsarra, Ibrahim A

2011-04-01

333

EGF-functionalized single-walled carbon nanotubes for targeting delivery of etoposide  

NASA Astrophysics Data System (ADS)

To enhance the therapeutic potential of etoposide (ETO), we devised a targeted drug delivery system (TDDS) of epidermal growth factor-chitosan-carboxyl single-walled carbon nanotubes-ETO (EGF/CHI/SWNT-COOHs/ETO) using modified SWNTs (m-SWNTs) as the carrier, EGF-functionalized SWNTs (f-SWNTs) as the targeted moiety and ETO as the drug. After SWNT-COOHs were conjugated with CHI (CHI/SWNT-COOHs/ETO), they displayed high solubility and stable dispersion in aqueous solution. The drug loading capacity was approximately 25-27%. The m-SWNTs and f-SWNTs had only slight cytotoxicity. ETO was released from EGF/CHI/SWNT-COOHs/ETO at low pH and taken up by tumour cells via adenosine triphosphate (ATP)-dependent endocytosis. The cell death induced by EGF/CHI/SWNT-COOHs/ETO was as much as 2.7 times that due to ETO alone. In summary, these results demonstrated that our TDDS had a greater anticancer effect than free ETO in vitro.

Chen, Cheng; Xie, Xiao-Xia; Zhou, Qian; Zhang, Feng-Yi; Wang, Qiao-Ling; Liu, Ya-Qing; Zou, Yina; Tao, Qing; Ji, Xue-Mei; Yu, Shu-Qin

2012-02-01

334

Effect of Antigen Shedding on Targeted Delivery of Immunotoxins in Solid Tumors from a Mathematical Model  

PubMed Central

Most cancer-specific antigens used as targets of antibody-drug conjugates and immunotoxins are shed from the cell surface (Zhang & Pastan (2008) Clin. Cancer Res. 14: 7981-7986), although at widely varying rates and by different mechanisms (Dello Sbarba & Rovida (2002) Biol. Chem. 383: 69–83). Why many cancer-specific antigens are shed and how the shedding affects delivery efficiency of antibody-based protein drugs are poorly understood questions at present. Before a detailed numerical study, it was assumed that antigen shedding would reduce the efficacy of antibody-drug conjugates and immunotoxins. However, our previous study using a comprehensive mathematical model showed that antigen shedding can significantly improve the efficacy of the mesothelin-binding immunotoxin, SS1P (anti-mesothelin-Fv-PE38), and suggested that receptor shedding can be a general mechanism for enhancing the effect of inter-cellular signaling molecules. Here, we improved this model and applied it to both SS1P and another recombinant immunotoxin, LMB-2, which targets CD25. We show that the effect of antigen shedding is influenced by a number of factors including the number of antigen molecules on the cell surface and the endocytosis rate. The high shedding rate of mesothelin is beneficial for SS1P, for which the antigen is large in number and endocytosed rapidly. On the other hand, the slow shedding of CD25 is beneficial for LMB-2, for which the antigen is small in number and endocytosed slowly. PMID:25343405

Pak, Youngshang; Pastan, Ira; Kreitman, Robert J.; Lee, Byungkook

2014-01-01

335

Effect of antigen shedding on targeted delivery of immunotoxins in solid tumors from a mathematical model.  

PubMed

Most cancer-specific antigens used as targets of antibody-drug conjugates and immunotoxins are shed from the cell surface (Zhang & Pastan (2008) Clin. Cancer Res. 14: 7981-7986), although at widely varying rates and by different mechanisms (Dello Sbarba & Rovida (2002) Biol. Chem. 383: 69-83). Why many cancer-specific antigens are shed and how the shedding affects delivery efficiency of antibody-based protein drugs are poorly understood questions at present. Before a detailed numerical study, it was assumed that antigen shedding would reduce the efficacy of antibody-drug conjugates and immunotoxins. However, our previous study using a comprehensive mathematical model showed that antigen shedding can significantly improve the efficacy of the mesothelin-binding immunotoxin, SS1P (anti-mesothelin-Fv-PE38), and suggested that receptor shedding can be a general mechanism for enhancing the effect of inter-cellular signaling molecules. Here, we improved this model and applied it to both SS1P and another recombinant immunotoxin, LMB-2, which targets CD25. We show that the effect of antigen shedding is influenced by a number of factors including the number of antigen molecules on the cell surface and the endocytosis rate. The high shedding rate of mesothelin is beneficial for SS1P, for which the antigen is large in number and endocytosed rapidly. On the other hand, the slow shedding of CD25 is beneficial for LMB-2, for which the antigen is small in number and endocytosed slowly. PMID:25343405

Pak, Youngshang; Pastan, Ira; Kreitman, Robert J; Lee, Byungkook

2014-01-01

336

Virus Capsids as Targeted Nanoscale Delivery Vessels of Photoactive Compounds for Site-Specific Photodynamic Therapy  

NASA Astrophysics Data System (ADS)

The research presented in this work details the use of a viral capsid as an addressable delivery vessel of photoactive compounds for use in photodynamic therapy. Photodynamic therapy is a treatment that involves the interaction of light with a photosensitizing molecule to create singlet oxygen, a reactive oxygen species. Overproduction of singlet oxygen in cells can cause oxidative damage leading to cytotoxicity and eventually cell death. Challenges with the current generation of FDA-approved photosensitizers for photodynamic therapy primarily stem from their lack of tissue specificity. This work describes the packaging of photoactive cationic porphyrins inside the MS2 bacteriophage capsid, followed by external modification of the capsid with cancer cell-targeting G-quadruplex DNA aptamers to generate a tumor-specific photosensitizing agent. First, a cationic porphyrin is loaded into the capsids via nucleotide-driven packaging, a process that involves charge interaction between the porphyrin and the RNA inside the capsid. Results show that over 250 porphyrin molecules associate with the RNA within each MS2 capsid. Removal of RNA from the capsid severely inhibits the packaging of the cationic porphyrins. Porphyrin-virus constructs were then shown to photogenerate singlet oxygen, and cytotoxicity in non-targeted photodynamic treatment experiments. Next, each porphyrin-loaded capsid is externally modified with approximately 60 targeting DNA aptamers by employing a heterobifunctional crosslinking agent. The targeting aptamer is known to bind the protein nucleolin, a ubiquitous protein that is overexpressed on the cell surface by many cancer cell types. MCF-7 human breast carcinoma cells and MCF-10A human mammary epithelial cells were selected as an in vitro model for breast cancer and normal tissue, respectively. Fluorescently tagged virus-aptamer constructs are shown to selectively target MCF-7 cells versus MCF-10A cells. Finally, results are shown in which porphyrin-virus-aptamer constructs selectively target and kill cancer cells versus non-cancer cells. Specifically, the results show that MS2 is a viable candidate as an addressable nanodelivery vessel of photoactive compounds, and the implications are that the nucleotide-driven packaging approach for modifying MS2 can be used to impart new functionalities for a host of diagnostic or therapeutic applications.

Cohen, Brian A.

337

Aptamer-Mediated Up-conversion Core/MOF Shell Nanocomposites for Targeted Drug Delivery and Cell Imaging  

PubMed Central

Multifunctional nanocarriers for targeted bioimaging and drug delivery have attracted much attention in early diagnosis and therapy of cancer. In this work, we develop a novel aptamer-guided nanocarrier based on the mesoporous metal-organic framework (MOF) shell and up-conversion luminescent NaYF4:Yb3+/Er3+ nanoparticles (UCNPs) core for the first time to achieve these goals. These UCNPs, chosen as optical labels in biological assays and medical imaging, could emit strong green emission under 980?nm laser. The MOF structure based on iron (III) carboxylate materials [MIL-100 (Fe)] possesses high porosity and non-toxicity, which is of great value as nanocarriers for drug storage/delivery. As a unique nanoplatform, the hybrid inorganic-organic drug delivery vehicles show great promising for simultaneous targeted labeling and therapy of cancer cells. PMID:25597762

Deng, Kerong; Hou, Zhiyao; Li, Xuejiao; Li, Chunxia; Zhang, Yuanxin; Deng, Xiaoran; Cheng, Ziyong; Lin, Jun

2015-01-01

338

Aptamer-Mediated Up-conversion Core/MOF Shell Nanocomposites for Targeted Drug Delivery and Cell Imaging.  

PubMed

Multifunctional nanocarriers for targeted bioimaging and drug delivery have attracted much attention in early diagnosis and therapy of cancer. In this work, we develop a novel aptamer-guided nanocarrier based on the mesoporous metal-organic framework (MOF) shell and up-conversion luminescent NaYF4:Yb(3+)/Er(3+) nanoparticles (UCNPs) core for the first time to achieve these goals. These UCNPs, chosen as optical labels in biological assays and medical imaging, could emit strong green emission under 980?nm laser. The MOF structure based on iron (III) carboxylate materials [MIL-100 (Fe)] possesses high porosity and non-toxicity, which is of great value as nanocarriers for drug storage/delivery. As a unique nanoplatform, the hybrid inorganic-organic drug delivery vehicles show great promising for simultaneous targeted labeling and therapy of cancer cells. PMID:25597762

Deng, Kerong; Hou, Zhiyao; Li, Xuejiao; Li, Chunxia; Zhang, Yuanxin; Deng, Xiaoran; Cheng, Ziyong; Lin, Jun

2015-01-01

339

Aptamer-Mediated Up-conversion Core/MOF Shell Nanocomposites for Targeted Drug Delivery and Cell Imaging  

NASA Astrophysics Data System (ADS)

Multifunctional nanocarriers for targeted bioimaging and drug delivery have attracted much attention in early diagnosis and therapy of cancer. In this work, we develop a novel aptamer-guided nanocarrier based on the mesoporous metal-organic framework (MOF) shell and up-conversion luminescent NaYF4:Yb3+/Er3+ nanoparticles (UCNPs) core for the first time to achieve these goals. These UCNPs, chosen as optical labels in biological assays and medical imaging, could emit strong green emission under 980 nm laser. The MOF structure based on iron (III) carboxylate materials [MIL-100 (Fe)] possesses high porosity and non-toxicity, which is of great value as nanocarriers for drug storage/delivery. As a unique nanoplatform, the hybrid inorganic-organic drug delivery vehicles show great promising for simultaneous targeted labeling and therapy of cancer cells.

Deng, Kerong; Hou, Zhiyao; Li, Xuejiao; Li, Chunxia; Zhang, Yuanxin; Deng, Xiaoran; Cheng, Ziyong; Lin, Jun

2015-01-01

340

Ultralow Protein Adsorbing Coatings from Clickable PEG Nanogel Solutions: Bene ts of Attachment under Salt-Induced Phase  

E-print Network

outperformed the best 100% PEG clickable nanogel coatings. Additional surface cross-linking of the clickable dense yet thin hydrogel coatings (surfaces with sparse covalentUltralow Protein Adsorbing Coatings from Clickable PEG Nanogel Solutions: Bene ts of Attachment

Mitra, Rob

341

Delivery  

PubMed Central

Enthusiasm greeted the development of synthetic organic insecticides in the mid-twentieth century, only to see this give way to dismay and eventually scepticism and outright opposition by some. Regardless of how anyone feels about this issue, insecticides and other pesticides have become indispensable, which creates something of a dilemma. Possibly as a result of the shift in public attitude towards insecticides, genetic engineering of microbes was first met with scepticism and caution among scientists. Later, the development of genetically modified crop plants was met with an attitude that hardened into both acceptance and hard-core resistance. Transgenic insects, which came along at the dawn of the twenty-first century, encountered an entrenched opposition. Those of us responsible for studying the protection of crops have been affected more or less by these protagonist and antagonistic positions, and the experiences have often left one thoughtfully mystified as decisions are made by non-participants. Most of the issues boil down to concerns over delivery mechanisms. © 2013 Society of Chemical Industry PMID:23852646

Miller, Thomas A

2013-01-01

342

Target-specific delivery of siRNA by stabilized calcium phosphate nanoparticles using dopa-hyaluronic acid conjugate.  

PubMed

Low cytotoxicity and high cellular gene delivery capability are among the most important prerequisites for the selection of a non-viral carrier. Although calcium phosphate (CAP) nanoparticles have been long used for animal cell transfection, its rapid and uncontrollable crystal growth and lack of tissue specificity are among the most challenging problems that limit its use in the clinic. In this study, we report the development of CAP nanoparticles stabilized by a conjugate of the mussel-inspired adhesive molecule, 3,4-dihydroxy-l-phenylalanine (dopa), and a nontoxic hydrophilic natural polymer, hyaluronic acid (HA), for targeted siRNA delivery to tumors. CAP/siRNA/dopa-HA can form compact nanoparticles that effectively protect siRNA from enzymatic degradation despite the structural drawbacks of siRNA, such as low charge density and short and rigid structure. In addition, stabilized CAP nanoparticles were able to maintain their colloidal stability in a physiological salt condition for over a week. The superior ability of CAP/siRNA/dopa-HA to maintain the integrity of encapsulated siRNA and the stability in solution of the nanoparticles allow this formulation to achieve improved intratumoral accumulation of siRNA and a high level of target gene silencing in solid tumors after systemic administration. Considering its biocompatibility, transfection efficacy, and tumor targeting capability, this stabilized calcium phosphate nanoparticle-based gene delivery platform should be considered a promising candidate carrier for systemic siRNA delivery and targeted cancer therapy. PMID:24995950

Lee, Min Sang; Lee, Jung Eun; Byun, Eunkyoung; Kim, Nak Won; Lee, Kyuri; Lee, Haeshin; Sim, Sang Jun; Lee, Doo Sung; Jeong, Ji Hoon

2014-10-28

343

Enzymatically crosslinked dendritic polyglycerol nanogels for encapsulation of catalytically active proteins.  

PubMed

The enormous potential of nanogel scaffolds for protein encapsulation has been widely recognized. However, constructing stable polymeric nanoscale networks in a facile, mild, and controllable fashion still remains a technical challenge. Here, we present a novel nanogel formation strategy using horseradish peroxidase (HRP) catalyzed crosslinking on phenolic derivatized dendritic polyglycerol (dPG) in the presence of H2O2 in an inverse miniemulsion. This "enzymatic nanogelation" approach was efficient to produce stable 200 nm dPG nanogel particles, and was performed under physiological conditions, thus making it particularly beneficial for encapsulating biological proteins. Purification of the nanogels was easy to handle and practical because there was no need for a post-quenching step. Interestingly, the use of dPG resulted in higher HRP laden nanogels than for linear polyethylene glycol (PEG) analogs, which illustrates the benefits of dendritic backbones in nanogels for protein encapsulation. In addition, the mild immobilization contributed to the enhanced thermal stability and reusability of HRP. The nanogel preparation could be easily optimized to achieve the best HRP activity. Furthermore, a second enzyme, Candida antarctica lipase B (CalB), was successfully encapsulated and optimized for activity in dPG nanogels by the same enzymatic methodology, which shows the perspective applications of such techniques for encapsulation of diverse proteins. PMID:25519490

Wu, Changzhu; Böttcher, Christoph; Haag, Rainer

2015-01-21

344

Efficient intracellular delivery and multiple-target gene silencing triggered by tripodal RNA based nanoparticles: A promising approach in liver-specific RNAi delivery.  

PubMed

RNA interference (RNAi) triggering oligonucleotides in unconventional structural format can offer advantages over conventional small interfering RNA (siRNA), enhanced cellular delivery and improved target gene silencing. With this concept, we present a well-defined tripodal-interfering RNA (tiRNA) structure that can induce simultaneous silencing of multiple target genes with improved potency. The tiRNA structure, formed by the complementary association of three single-stranded RNA units, was optimized for improved gene silencing efficacy. When combined with cationic polymers such as linear polyethyleneimine (PEI), tiRNA assembled to form a stable nano-structured complex through electrostatic interactions and induced stronger RNAi response over conventional siRNA-PEI complex. In combination with a liver-targeting delivery system, tripodal nucleic acid structure demonstrated enhanced fluorescent accumulation in mouse liver compared to standard duplex nucleic acid format. Tripodal RNA structure complexed with galactose-modified PEI could generate effective RNAi-mediated gene silencing effect on experimental mice models. Our studies demonstrate that optimized tiRNA structural format with appropriate polymeric carriers have immense potential to become an RNAi-based platform suitable for multi-target gene silencing. PMID:25251899

Sajeesh, S; Lee, Tae Yeon; Kim, Joon Ki; Son, Da Seul; Hong, Sun Woo; Kim, Soohyun; Yun, Wan Soo; Kim, Soyoun; Chang, Chanil; Li, Chiang; Lee, Dong-Ki

2014-12-28

345

A phage-targeting strategy for the design of spatiotemporal drug delivery from grafted matrices  

PubMed Central

Background The natural response to injury is dynamic and normally consists of complex temporal and spatial cellular changes in gene expression, which, when acting in synchrony, result in patent tissue repair and, in some instances, regeneration. However, current therapeutic regiments are static and most rely on matrices, gels and engineered skin tissue. Accordingly, there is a need to design next-generation grafting materials to enable biotherapeutic spatiotemporal targeting from clinically approved matrices. To this end, rather then focus on developing completely new grafting materials, we investigated whether phage display could be deployed onto clinically approved synthetic grafts to identify peptide motifs capable of linking pharmaceutical drugs with differential affinities and eventually, control drug delivery from matrices over both space and time. Methods To test this hypothesis, we biopanned combinatorial peptide libraries onto different formulations of a wound-healing matrix (Integra®) and eluted the bound peptides with 1) high salt, 2) collagen and glycosaminoglycan or 3) low pH. After three to six rounds of biopanning, phage recovery and phage amplification of the bound particles, any phage that had acquired a capacity to bind the matrix was sequenced. Results In this first report, we identify distinct classes of matrix-binding peptides which elute differently from the screened matrix and demonstrate that they can be applied in a spatially relevant manner. Conclusions We suggest that further applications of these combinatorial techniques to wound-healing matrices may offer a new way to improve the performance of clinically approved matrices so as to introduce temporal and spatial control over drug delivery. PMID:21329515

2011-01-01

346

Formulation and Evaluation of Chondroitin Sulphate Tablets of Aceclofenac for Colon Targeted Drug Delivery  

PubMed Central

The aim of the present study was to develop a single unit, site-specific matrix tablets of aceclofenac allowing targeted drug release in the colon with a microbially degradable polymeric carrier, chondroitin suphate (CS) and to coat the optimized batches with a pH dependent polymeric. The tablets were prepared by wet granulation method using starch mucilage as a binding agent and HPMC K-100 as a swellable polymer. Chondroitin Sulphate and drug and physical mixture were characterized by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The tablets were tested for their in-vitro dissolution characteristics in various simulated gastric fluids for their suitability as a colon-specific drug delivery system and also the tablets were evaluated for physicochemical properties, drug content, water percentage swelling and erosion characteristics. The dissolution data demonstrates that the 10% w/w increase in coating level of the pH dependent polymer (Eudragit L-100 and Eudragit S-100 in a ratio of 1 : 4 prevented the drug release in the simulated gastric fluid (pH 1.2-SGF) and the simulated intestinal fluid (pH 7.4-SIF). The dissolution rate of the tablet is dependent upon the concentration of Chondroitin sulphate in the simulated colonic fluid (SCF). The rapid increase in release of aceclofenac in SCF was revealed as due to the degradation of the Chondroitin sulphate membrane by bacterial enzymes. The studies confirmed that, the designed system could be used potentially as a carrier for colon delivery of aceclofenac by regulating drug release in stomach and the small intestine. PMID:24250470

Ramasamy, Thiruganesh; Subbaih Khandasamy, Umadevi; Shanmugam, Suresh; Ruttala, Himabindhu

2012-01-01

347

Formulation and evaluation of chondroitin sulphate tablets of aceclofenac for colon targeted drug delivery.  

PubMed

The aim of the present study was to develop a single unit, site-specific matrix tablets of aceclofenac allowing targeted drug release in the colon with a microbially degradable polymeric carrier, chondroitin suphate (CS) and to coat the optimized batches with a pH dependent polymeric. The tablets were prepared by wet granulation method using starch mucilage as a binding agent and HPMC K-100 as a swellable polymer. Chondroitin Sulphate and drug and physical mixture were characterized by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The tablets were tested for their in-vitro dissolution characteristics in various simulated gastric fluids for their suitability as a colon-specific drug delivery system and also the tablets were evaluated for physicochemical properties, drug content, water percentage swelling and erosion characteristics. The dissolution data demonstrates that the 10% w/w increase in coating level of the pH dependent polymer (Eudragit L-100 and Eudragit S-100 in a ratio of 1 : 4 prevented the drug release in the simulated gastric fluid (pH 1.2-SGF) and the simulated intestinal fluid (pH 7.4-SIF). The dissolution rate of the tablet is dependent upon the concentration of Chondroitin sulphate in the simulated colonic fluid (SCF). The rapid increase in release of aceclofenac in SCF was revealed as due to the degradation of the Chondroitin sulphate membrane by bacterial enzymes. The studies confirmed that, the designed system could be used potentially as a carrier for colon delivery of aceclofenac by regulating drug release in stomach and the small intestine. PMID:24250470

Ramasamy, Thiruganesh; Subbaih Khandasamy, Umadevi; Shanmugam, Suresh; Ruttala, Himabindhu

2012-01-01

348

Formulation and evaluation of niosomal nasal drug delivery system of folic acid for brain targeting.  

PubMed

Nasal mucosa offers advantages to deliver drugs to brain via olfactory route thus provides rapid onset of drug action and hence faster therapeutic effect. Therefore, various strategies have been proposed to improve the delivery of different drugs to brain including liposomes, colloidal drug carriers, micelles, chimeric peptide technology and nanotechnology through nasal route. The low blood level of folates is the primary cause of depression in Alzheimer's disease. Folic acid is a water soluble vitamin showing difficulty in crossing the blood brain barrier and thus was formulated as niosomal nasal drug delivery systems to target the brain. In the present work, folic acid niosomes were prepared using different nonionic surfactants i.e., span 20, span 60, span 80, tween 20, tween 80 and cholesterol by using lipid layer hydration technique. These were evaluated for particle size, viscosity, osmotic shock, entrapment efficiency and in vitro drug release. The influence of different formulation variables such as surfactant type, surfactant concentration, and cholesterol concentration was optimized for required size distribution, viscosity, entrapment efficiency and in vitro release. The prepared niosomes were in the size range of 3.05-5.625 µm. Niosomes prepared with span 60 and cholesterol in the ratio of 1:1 (50 mg: 50 mg) shown higher entrapment efficiency of 69.42% and better in vitro drug release of 64.2% at the end of 12 hrs and therefore considered as optimized formulation. The stability studies were carried out by storing niosomes at 4±1°C and 25±1°C and showed good stability over the period of storage. The release of drug from niosomes followed anomalous diffusion and obeyed first order release kinetics. Ex-vivo perfusion studies were also performed by using rat model, about 48.15% of drug was found to be absorbed through nasal cavity at the end of 6 hrs. PMID:23863098

Ravouru, Nagaraju; Kondreddy, Pallavi; Korakanchi, Deepthy; Haritha, M

2013-12-01

349

Ultrasound and microbubble-targeted delivery of small interfering RNA into primary endothelial cells is more effective than delivery of plasmid DNA.  

PubMed

Ultrasound and microbubble-targeted delivery (UMTD) is a promising non-viral technique for genetic-based therapy. We found that UMTD of small interfering RNA (siRNA) is more effective than delivery of plasmid DNA (pDNA). UMTD (1 MHz, 0.22 MPa) of fluorescently labeled siRNA resulted in 97.9 ± 1.5% transfected cells, with siRNA localized homogenously in the cytoplasm directly after ultrasound exposure. UMTD of fluorescently labeled pDNA resulted in only 43.0 ± 4.2% transfected cells, with localization mainly in vesicular structures, co-localizing with endocytosis markers clathrin and caveolin. Delivery of siRNA against GAPDH (glyceraldehyde-3-phosphate dehydrogenase) effectively decreased protein levels to 24.3 ± 7.9% of non-treated controls (p < 0.01). In contrast, 24 h after delivery of pDNA encoding GAPDH, no increase in protein levels was detected. Transfection efficiency, verified with red fluorescently labeled pDNA encoding enhanced green fluorescent protein, revealed that of the transfected cells, only 2.0 ± 0.7% expressed the transgene. In conclusion, the difference in localization between siRNA and pDNA after UMTD is an important determinant of the effectiveness of these genetic-based technologies. PMID:24361223

Juffermans, Lynda J M; Meijering, Bernadet D M; Henning, Robert H; Deelman, Leo E

2014-03-01

350

TARGETED LIPID BASED DRUG CONJUGATES: A NOVEL STRATEGY FOR DRUG DELIVERY  

PubMed Central

A majority of studies involving prodrugs are directed to overcome low bioavailability of the parent drug. The aim of this study is to increase the bioavailability of acyclovir (ACV) by designing a novel prodrug delivery system which is more lipophilic, and at the same time site specific. In this study, a lipid raft has been conjugated to the parent drug molecule to impart lipophilicity. Simultaneously a targeting moiety that can be recognized by a specific transporter/receptor in the cell membrane has also been tethered to the other terminal of lipid raft. Targeted lipid prodrugs i.e., biotin-ricinoleicacid-acyclovir (B-R-ACV) and biotin-12hydroxystearicacid-acyclovir (B-12HS-ACV) were synthesized with ricinoleicacid and 12hydroxystearicacid as the lipophilic rafts and biotin as the targeting moiety. Biotin-ACV (B-ACV), ricinoleicacid-ACV (R-ACV) and 12hydroxystearicacid-ACV (12HS-ACV) were also synthesized to delineate the individual effects of the targeting and the lipid moieties. Cellular accumulation studies were performed in confluent MDCK-MDR1 and Caco-2 cells. The targeted lipid prodrugs B-R-ACV and B-12HS-ACV exhibited much higher cellular accumulation than B-ACV, R-ACV and 12HS-ACV in both cell lines. This result indicates that both the targeting and the lipid moiety act synergistically towards cellular uptake. The biotin conjugated prodrugs caused a decrease in the uptake of [3H] biotin suggesting the role of sodium dependent multivitamin transporter (SMVT) in uptake. The affinity of these targeted lipid prodrugs towards SMVT was studied in MDCK-MDR1 cells. Both the targeted lipid prodrugs B-R-ACV (20.25 ± 1.74 µM) and B-12HS-ACV (23.99 ± 3.20 µM) demonstrated higher affinity towards SMVT than B-ACV (30.90 ± 4.19 µM). Further, dose dependent studies revealed a concentration dependent inhibitory effect on [3H] biotin uptake in the presence of biotinylated prodrugs. Transepithelial transport studies showed lowering of [3H] biotin permeability in the presence of biotin and biotinylated prodrugs, further indicating a carrier mediated translocation by SMVT. Overall, results from these studies clearly suggest that these biotinylated lipid prodrugs of ACV possess enhanced affinity towards SMVT. These prodrugs appear to be potential candidates for the treatment of oral and ocular herpes virus infections, because of higher expression of SMVT on intestinal and corneal epithelial cells. In conclusion we hypothesize that our novel prodrug design strategy may help in higher absorption of hydrophilic parent drug. Moreover, this novel prodrug design can result in higher cell permeability of hydrophilic therapeutics such as genes, siRNA, antisense RNA, DNA, oligonucleotides, peptides and proteins. PMID:22692074

Vadlapudi, Aswani Dutt; Vadlapatla, Ramya Krishna; Kwatra, Deep; Earla, Ravinder; Samanta, Swapan K.; Pal, Dhananjay; Mitra, Ashim K.

2012-01-01

351

siRNA delivery targeting to the lung via agglutination-induced accumulation and clearance of cationic tetraamino fullerene  

PubMed Central

The efficient treatment of lung diseases requires lung-selective delivery of agents to the lung. However, lung-selective delivery is difficult because the accumulation of micrometer-sized carriers in the lung often induces inflammation and embolization-related toxicity. Here we demonstrate a lung-selective delivery system of small interfering RNA (siRNA) by controlling the size of carrier vehicle in blood vessels. The carrier is made of tetra(piperazino)fullerene epoxide (TPFE), a water-soluble cationic tetraamino fullerene. TPFE and siRNA form sub-micrometer-sized complexes in buffered solution and these complexes agglutinate further with plasma proteins in the bloodstream to form micrometer-sized particles. The agglutinate rapidly clogs the lung capillaries, releases the siRNA into lung cells to silence expression of target genes, and is then cleared rapidly from the lung after siRNA delivery. We applied our delivery system to an animal model of sepsis, indicating the potential of TPFE-based siRNA delivery for clinical applications. PMID:24814863

MINAMI, Kosuke; OKAMOTO, Koji; DOI, Kent; HARANO, Koji; NOIRI, Eisei; NAKAMURA, Eiichi

2014-01-01

352

Biocompatible gelatin nanoparticles for tumor-targeted delivery of polymerized siRNA in tumor-bearing mice.  

PubMed

Structural modifications of the siRNA backbone improved its physiochemical properties for incorporating in gene carriers without loss of gene-silencing efficacy. These modifications provide a wider variety of choice of vector systems for siRNA delivery. We developed a tumor-targeted siRNA delivery system using polymerized siRNA (poly-siRNA) and natural polymer gelatin. The polymerized siRNA (poly-siRNA) was prepared through self-polymerization of thiol groups at the 5'-end of sense and anti-sense strands of siRNA and was encapsulated in the self-assembled thiolated gelatin (tGel) nanoparticles (NPs) with chemical cross-linking. The resulting poly-siRNA-tGel (psi-tGel) nanoparticles (average of 145 nm in diameter) protect siRNA molecules from enzymatic degradation, and can be reversibly reduced to release functional siRNA molecules in reductive conditions. The psi-tGel NPs presented efficient siRNA delivery in red fluorescence protein expressing melanoma cells (RFP/B16F10) to down-regulate target gene expression. In addition, the NPs showed low toxicity at a high transfection dose of 125 ?g/ml psi-tGel NPs, which included 1 ?M of siRNA molecules. In tumor-bearing mice, the psi-tGel NPs showed 2.8 times higher tumor accumulation than the naked poly-siRNA, suggesting tumor-targeted siRNA delivery of psi-tGel NPs. Importantly, the psi-tGel NPs induced effective tumor RFP gene silencing in vivo without remarkable toxicity. The psi-tGel NPs have great potential for a systemic siRNA delivery system for cancer therapy, based on their characteristics of low toxicity, tumor accumulation, and effective siRNA delivery. PMID:24036198

Lee, So Jin; Yhee, Ji Young; Kim, Sun Hwa; Kwon, Ick Chan; Kim, Kwangmeyung

2013-11-28

353

Effective Targeted Gene Delivery to Dendritic Cells via Synergetic Interaction of Mannosylated Lipid with DOPE and BCAT  

PubMed Central

The efficient delivery of plasmids encoding antigenic determinants into dendritic cells (DCs) that control immune response is a promising strategy for rapid development of new vaccines. In this study, we prepared a series of targeted cationic lipoplex based on two synthetic lipid components, mannose-poly(ethylene glycol, MW3000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (Mannose-PEG3000-DSPE) and O-(2R-1,2-di-O-(1'Z,9'Z-octadecadienyl)-glycerol)-3-N-(bis-2-aminoethyl)-carbamate (BCAT), that were formulated with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) for evaluation as non-viral vectors for transgene expression in DCs. First, we optimized the N:P ratio for maximum transfection and then screened the effects of mannose targeting for further enhancement of transfection levels. Our results indicate that efficient delivery of gWIZ GFP plasmid into DCs was observed for mannose compositions of ~10%, whereas low transfection efficiencies were observed with non-targeted formulations. Mannose-targeted lipofectamine complexes also showed high GFP expression levels in DCs relative to non-targeted lipofectamine controls. The best transfection performance was observed using 10 mol % Mannose-PEG3000-DSPE, 60 mol% BCAT, and 30 mol % DOPE, indicating that the most efficient delivery into DCs occurs via synergistic interaction between mannose targeting and acid-labile, fusogenic BCAT:DOPE formulations. Our data suggest that mannose-PEG3000-DSPE:BCAT:DOPE formulations may be effective gene delivery vehicles for the development of DC-based vaccines. PMID:22229467

Kim, Hee-Kwon; Wei, Huiling; Kulkarni, Aditya; Pogranichniy, Roman M.; Thompson, David H.

2012-01-01

354

Multifunctional unimolecular micelles for cancer-targeted drug delivery and positron emission tomography imaging?  

PubMed Central

A multifunctional unimolecular micelle made of a hyperbranched amphiphilic block copolymer was designed, synthesized, and characterized for cancer-targeted drug delivery and non-invasive positron emission tomography (PET) imaging in tumor-bearing mice. The hyperbranched amphiphilic block copolymer, Boltorn® H40-poly(L-glutamate-hydrazone-doxorubicin)-b-poly(ethylene glycol) (i.e., H40-P(LG-Hyd-DOX)-b-PEG), was conjugated with cyclo(Arg-Gly-Asp-D-Phe-Cys) peptides (cRGD, for integrin ?v?3 targeting) and macrocyclic chelators (1,4,7-triazacyclononane-N, N?, N?-triacetic acid [NOTA], for 64Cu-labeling and PET imaging) (i.e., H40-P(LG-Hyd-DOX)-b-PEG-OCH3/cRGD/NOTA, also referred to as H40-DOX-cRGD). The anti-cancer drug, doxorubicin (DOX) was covalently conjugated onto the hydrophobic segments of the amphiphilic block copolymer arms (i.e., PLG) via a pH-labile hydrazone linkage to enable pH-controlled drug release. The unimolecular micelles exhibited a uniform size distribution and pH-sensitive drug release behavior. cRGD-conjugated unimolecular micelles (i.e., H40-DOX-cRGD) exhibited a much higher cellular uptake in U87MG human glioblastoma cells due to integrin ?v?3-mediated endocytosis than non-targeted unimolecular micelles (i.e., H40-DOX), thereby leading to a significantly higher cytotoxicity. In U87MG tumor-bearing mice, H40-DOX-cRGD-64Cu also exhibited a much higher level of tumor accumulation than H40-DOX-64Cu, measured by non-invasive PET imaging and confirmed by biodistribution studies and ex vivo fluorescence imaging. We believe that unimolecular micelles formed by hyperbranched amphiphilic block copolymers that synergistically integrate passive and active tumor-targeting abilities with pH-controlled drug release and PET imaging capabilities provide the basis for future cancer theranostics. PMID:22281424

Xiao, Yuling; Hong, Hao; Javadi, Alireza; Engle, Jonathan W.; Xu, Wenjin; Yang, Yunan; Zhang, Yin; Barnhart, Todd E.; Cai, Weibo; Gong, Shaoqin

2012-01-01

355

Targeted delivery of cargoes into a murine solid tumor by a cell-penetrating peptide and cleavable poly(ethylene glycol) comodified liposomal delivery system via systemic administration.  

PubMed

A liposomal delivery system with a high efficiency of accumulation in tumor tissue and then transportation of the cargo into tumor cells was developed here and evaluated via systemic administration. 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)(2000) (DSPE-PEG(2000))-TAT and protective DSPE-PEG(2000) modified liposomes possessing good stability in 50% FBS (fetal bovine serum) and good uptake efficiency were used as the basic formulation (TAT-SL; SL = stealth liposome), and then longer cysteine (Cys)-cleavable PEG(5000) was incorporated to modulate the function of TAT. All of the formulations to be used in vivo had sizes in a range of 80-100 nm and were stable in the presence of 50% FBS. Optical imaging showed that the incorporation of cleavable PEG(5000) into TAT-SL (i.e., C-TAT-SL) led to much more tumor accumulation and much less liver distribution compared with TAT-SL. The in vivo delivery profiles of C-TAT-SL were investigated using DiD as a fluorescent probe. Confocal laser scanning microscopy and flow cytometry showed that C-TAT-SL had a 48% higher (p < 0.001) delivery efficiency in the absence of Cys and a 130% higher (p < 0.001) delivery efficiency in the presence of Cys than the control (SL), indicating the successful targeted delivery of cargo was achieved by C-TAT-SL via systemic administration especially with a subsequent administration of Cys. PMID:21981683

Kuai, Rui; Yuan, Wenmin; Li, Wanyu; Qin, Yao; Tang, Jie; Yuan, Mingqing; Fu, Ling; Ran, Rui; Zhang, Zhirong; He, Qin

2011-12-01

356

Multifunctional Nanocarriers for diagnostics, drug delivery and targeted treatment across blood-brain barrier: perspectives on tracking and neuroimaging  

PubMed Central

Nanotechnology has brought a variety of new possibilities into biological discovery and clinical practice. In particular, nano-scaled carriers have revolutionalized drug delivery, allowing for therapeutic agents to be selectively targeted on an organ, tissue and cell specific level, also minimizing exposure of healthy tissue to drugs. In this review we discuss and analyze three issues, which are considered to be at the core of nano-scaled drug delivery systems, namely functionalization of nanocarriers, delivery to target organs and in vivo imaging. The latest developments on highly specific conjugation strategies that are used to attach biomolecules to the surface of nanoparticles (NP) are first reviewed. Besides drug carrying capabilities, the functionalization of nanocarriers also facilitate their transport to primary target organs. We highlight the leading advantage of nanocarriers, i.e. their ability to cross the blood-brain barrier (BBB), a tightly packed layer of endothelial cells surrounding the brain that prevents high-molecular weight molecules from entering the brain. The BBB has several transport molecules such as growth factors, insulin and transferrin that can potentially increase the efficiency and kinetics of brain-targeting nanocarriers. Potential treatments for common neurological disorders, such as stroke, tumours and Alzheimer's, are therefore a much sought-after application of nanomedicine. Likewise any other drug delivery system, a number of parameters need to be registered once functionalized NPs are administered, for instance their efficiency in organ-selective targeting, bioaccumulation and excretion. Finally, direct in vivo imaging of nanomaterials is an exciting recent field that can provide real-time tracking of those nanocarriers. We review a range of systems suitable for in vivo imaging and monitoring of drug delivery, with an emphasis on most recently introduced molecular imaging modalities based on optical and hybrid contrast, such as fluorescent protein tomography and multispectral optoacoustic tomography. Overall, great potential is foreseen for nanocarriers in medical diagnostics, therapeutics and molecular targeting. A proposed roadmap for ongoing and future research directions is therefore discussed in detail with emphasis on the development of novel approaches for functionalization, targeting and imaging of nano-based drug delivery systems, a cutting-edge technology poised to change the ways medicine is administered. PMID:20199661

2010-01-01

357

Hyaluronic acid based self-assembling nanosystems for CD44 target mediated siRNA delivery to solid tumors  

PubMed Central

Anticancer therapeutics employing RNA interference mechanism holds promising potentials for sequence-specific silencing of target genes. However targeted delivery of siRNAs to tumor tissues and cells and more importantly, their intracellular release at sites of interest still remains a major challenge that needs to be addressed before this technique could become a clinically viable option. In the current study, we have engineered and screened a series of CD44 targeting hyaluronic acid (HA) based self-assembling nanosystems for targeted siRNA delivery. The HA polymer was functionalized with lipids of varying carbon chain lengths/nitrogen content, as well as polyamines for assessing siRNA encapsulation. From the screens, several HA-derivatives were identified that could stably encapsulate/complex siRNAs and form self-assembled nanosystems, as determined by gel retardation assays and dynamic light scattering. Many HA derivatives could transfect siRNAs into cancer cells overexpressing CD44 receptors. Interestingly, blocking the CD44 receptors on the cells using free excess soluble HA prior to incubation of cy3-labeled-siRNA loaded HA nano-assemblies resulted in >90% inhibition of the receptor mediated uptake, confirming target specificity. In addition, SSB/PLK1 siRNA encapsulated in HA-PEI/PEG nanosystems demonstrated dose dependent and target specific gene knockdown in both sensitive and resistant A549 lung cancer cells overexpressing CD44 receptors. More importantly, these siRNA encapsulated nanosystems demonstrated tumor selective uptake and target specific gene knock down in vivo in solid tumors as well as in metastatic tumors. The HA based nanosystems thus portend to be promising siRNA delivery vectors for systemic targeting of CD44 overexpressing cancers including tumor initiating (stem-) cells and metastatic lesions. PMID:23410679

Ganesh, Shanthi; Iyer, Arun K.; Morrissey, David V.; Amiji, Mansoor M.

2013-01-01

358

Intracellular delivery of redox cycler-doxorubicin to the mitochondria of cancer cell by folate receptor targeted mitocancerotropic liposomes.  

PubMed

Cancer cells reflect higher level of ROS in comparison to the normal cell, so they become more vulnerable to further oxidative stress induced by exogenous ROS-generating agents. Through this a novel therapeutic strategy has evolved, which involves the delivery of redox cycler-doxorubicin (DOX) to the mitochondria of cancer cell where it acts as a source of exogenous ROS production. The purpose of this study is to develop a liposomal preparation which exhibits a propensity to selectively target cancer cell along with the potential of delivering drug to mitochondria of cell. We have rendered liposomes mitocancerotropic (FA-MTLs) by their surface modification with dual ligands, folic acid (FA) for cancer cell targeting and triphenylphosphonium (TPP) cations for mitochondria targeting. The cytotoxicity, ROS production and cell uptake of doxorubicin loaded liposomes were evaluated in FR (+) KB cells and found to be increased considerably with FA-MTLs in comparison to folic acid appended, mitochondria targeted and non-targeted liposomes. As confirmed by confocal microscopy, the STPP appended liposomes delivered DOX to mitochondria of cancer cell and also showed higher ROS production and cytotoxicity in comparison to folic acid appended and non-targeted liposomes. Most importantly, mitocancerotropic liposomes showed superior activity over mitochondria targeted liposomes which confirm the synergistic effect imparted by the presence of dual ligands - folic acid and TPP on the enhancement of cellular and mitochondrial delivery of doxorubicin in KB cells. PMID:22531856

Malhi, Sarandeep Singh; Budhiraja, Abhishek; Arora, Sumit; Chaudhari, Kiran R; Nepali, Kunal; Kumar, Raj; Sohi, Harmik; Murthy, Rayasa S R

2012-08-01

359

Ultralow protein adsorbing coatings from clickable PEG nanogel solutions: Benefits of attachment under salt-induced phase separation conditions and comparison with PEG/albumin nanogel coatings  

PubMed Central

Clickable nanogel solutions were synthesized by using the copper catalyzed azide/alkyne cycloaddition (CuAAC) to partially polymerize solutions of azide and alkyne functionalized poly(ethylene glycol) (PEG) monomers. Coatings were fabricated using a second click reaction: a UV thiol-yne attachment of the nanogel solutions to mercaptosilanated glass. Because the CuAAC reaction was effectively halted by the addition of a copper-chelator, we were able to prevent bulk gelation and limit the coating thickness to a single monolayer of nanogels in the absence of the solution reaction. This enabled the inclusion of kosmotropic salts, which caused the PEG to phase-separate and nearly double the nanogel packing density, as confirmed by Quartz Crystal Microbalance with Dissipation (QCM-D). Protein adsorption was analyzed by single molecule counting with total internal reflection fluorescence (TIRF) microscopy and cell adhesion assays. Coatings formed from the phase-separated clickable nanogel solutions attached with salt adsorbed significantly less fibrinogen than other 100% PEG coatings tested, as well as poly-L-lysine-g-PEG (PLL-g-PEG) coatings. However, PEG/albumin nanogel coatings still outperformed the best 100% PEG clickable nanogel coatings. Additional surface crosslinking of the clickable nanogel coating in the presence of copper further reduced levels of fibrinogen adsorption closer to those of PEG/albumin nanogel coatings. However, this step negatively impacted long-term resistance to cell adhesion and dramatically altered the morphology of the coating by atomic force microscopy (AFM). The main benefit of the click strategy is that the partially polymerized solutions are stable almost indefinitely, allowing attachment in the phase-separated state without danger of bulk gelation, and thus, producing the best performing 100% PEG coating that we have studied to date. PMID:23441808

Donahoe, Casey D.; Cohen, Thomas L.; Li, Wenlu; Nguyen, Peter K.; Fortner, John D.; Mitra, Robi D.; Elbert, Donald L.

2013-01-01

360

Functionalized nanoscale oil bodies for targeted delivery of a hydrophobic drug  

NASA Astrophysics Data System (ADS)

Effective formulations of hydrophobic drugs for cancer therapies are challenging. To address this issue, we have sought to nanoscale artificial oil bodies (NOBs) as an alternative. NOBs are lipid-based particles which consist of a central oil space surrounded by a monolayer of oleosin (Ole)-embedded phospholipids (PLs). Ole was first fused with the anti-HER2/neu affibody (Ole-ZH2), and the resulting hybrid protein was overproduced in Escherichia coli. ZH2-displayed NOBs were then assembled by sonicating the mixture containing plant oil, PLs, and isolated Ole-ZH2 in one step. To illustrate their usefulness, functionalized NOBs were employed to encapsulate a hydrophobic anticancer drug, Camptothecin (CPT). As a result, these CPT-loaded NOBs remained stable in serum and the release of CPT at the non-permissive condition exhibited a sustained and prolonged profile. Moreover, plain NOBs were biocompatible whereas CPT-loaded NOBs exerted a strong cytotoxic effect on HER2/neu-positive cells in vitro. Administration of xenograft nude mice with CPT-loaded NOBs also led to the regression of solid tumors in an effective way. Overall, the result indicates the potential of NOBs for targeted delivery of hydrophobic drugs.

Chiang, Chung-Jen; Lin, Che-Chin; Lu, Tzu-Li; Wang, Hesin-Fu

2011-10-01

361

Applicator for in-vitro ultrasound-activated targeted drug delivery  

NASA Astrophysics Data System (ADS)

Reducing toxicity and improving uptake of cancer drugs in tumors are important goals of targeted drug delivery (TDD). Ultrasonic drug release from various encapsulants has been a focus of many research groups. However, a single standard ultrasonic device, viable for use by biologists, is not currently present in the market. The device reported here is designed to allow investigation of the impact of ultrasound on cellular uptake and cell viability in-vitro. In it, single-element transducers with different operating frequencies are mounted below a standard 96-well plate. The plate is moved above the transducers, such that each line of wells can be sonicated at a different frequency. To assess the device, 96-well plates were seeded with cells and sonicated using different ultrasonic parameters, with and without doxorubicin. Cell viability was measured by colorimetric MTT assay and the uptake of doxorubicin by cells was also determined. The device proved to be highly viable in preliminary tests; it demonstrated that change in ultrasonic parameters produces different effect on cells. For example, increase in uptake of doxorubicin was demonstrated following ultrasound application. The growing interest in ultrasound-activated TDD emphasizes the need for standardization of the ultrasound device and the one reported here may offer some indications of how that may be achieved. It is planned to further improve the prototype by increasing the number of ultrasonic frequencies and degrees of freedom for each transducer.

Gerold, B.; Gourevich, D.; Volovick, A.; Xu, D.; Arditti, F.; Prentice, P.; Cochran, S.; Gnaim, J.; Medan, Y.; Wang, L.; Melzer, A.

2012-10-01

362

Ultrasound-targeted Microbubble Destruction-mediated Gene Delivery Into Canine Livers  

PubMed Central

Ultrasound (US) was applied to a targeted canine liver lobe simultaneously with injection of plasmid DNA (pDNA)/microbubble (MB) complexes into a portal vein (PV) segmental branch and occlusion of the inferior vena cava (IVC) to facilitate DNA uptake. By using a 1.1 MHz, 13 mm diameter transducer, a fivefold increase in luciferase activity was obtained at 3.3 MPa peak negative pressure (PNP) in the treated lobe. For more effective treatment of large tissue volumes in canines, a planar unfocused transducer with a large effective beam diameter (52?mm) was specifically constructed. Its apodized dual element configuration greatly reduced the near-field transaxial pressure variations, resulting in a remarkably uniform field of US exposure for the treated tissues. Together with a 15 kW capacity US amplifier, a 692-fold increase of gene expression was achieved at 2.7?MPa. Transaminase and histology analysis indicated minimal tissue damage. These experiments represent an important developmental step toward US-mediated gene delivery in large animals and clinics. PMID:23732985

Noble, Misty L; Kuhr, Christian S; Graves, Scott S; Loeb, Keith R; Sun, Samuel S; Keilman, George W; Morrison, Kyle P; Paun, Marla; Storb, Rainer F; Miao, Carol H

2013-01-01

363

Preparation and in vitro evaluation of mebeverine HCl colon-targeted drug delivery system.  

PubMed

Mebeverine HCl is a water soluble drug commonly used to treat irritable bowel syndrome by acting directly on the smooth muscles of the colon. This work was aimed at the formulation and in vitro evaluation of a colon-targeted drug delivery system containing mebeverine HCl. Matrix tablets were prepared using ethyl cellulose (EC), Eudragit RL 100 either solely or in combination by wet granulation technique. Dissolution was carried out in 0.1 N HCl for 2?h followed by pH 6.8 phosphate buffer for eight hours. Uncoated forms released more than 5% drug in 0.1 N HCl therefore, Eudragit L100 was used as a coat. The results indicated very slow release profile. As a result, single retardant was used to prepare the matrix and coated by Eudragit L 100. The matrix containing 7% Eudragit RL 100 and 6% of binder was subjected to further studies to assess the effect of different coats (Eudragit L 100-55 and cellulose acetate phthalate) and different binders (pectin and sodium alginate) on the release profile. Eudragit L 100 and pectin were the best coating agent and binder, respectively. The final formula was stable and it can be concluded that the prepared system has the potential to deliver mebeverine HCl in vivo to the colon. PMID:20429815

Abdullah, Ghassan Z; Abdulkarim, Muthanna F; Chitneni, Mallikarjun; Mutee, Ahmed F; Ameer, Omar Z; Salman, Ibrahim M; Noor, Azmin M

2011-08-01

364

Temporal Multiscale Approach for Nanocarrier Motion with Simultaneous Adhesion and Hydrodynamic Interactions in Targeted Drug Delivery  

PubMed Central

We present a fluctuating hydrodynamics approach and a hybrid approach combining fluctuating hydrodynamics with generalized Langevin dynamics to resolve the motion of a nanocarrier when subject to both hydrodynamic interactions and adhesive interactions. Specifically, using these approaches, we compute equilibrium probability distributions at constant temperature as well as velocity autocorrelation functions of the nanocarrier subject to thermal motion in a quiescent Newtonian fluid medium, when tethered by a harmonic spring force mimicking a tether due to a single receptor-ligand bond. We demonstrate that the thermal equipartition of translation, rotation, and spring degrees of freedom are preserved by our formalism while simultaneously resolving the nature of the hydrodynamic correlations. Additionally, we evaluate the potential of mean force (or free energy density) along a specified reaction coordinate to faciltate extensive conformational sampling of the nanocarrier motion. We show that our results are in excellent agreement with analytical results and Monte Carlo simulations, thereby validating our methodologies. The frameworks we have presented provide a comprehensive platform for temporal multiscale modeling of hydrodynamic and microscopic interactions mediating nanocarrier motion and adhesion in vascular targeted drug delivery. PMID:23853388

Radhakrishnan, R.; Uma, B.; Liu, J.; Ayyaswamy, P. S.; Eckmann, D. M.

2012-01-01

365

The Biology of the Sodium Iodide Symporter and its Potential for Targeted Gene Delivery  

PubMed Central

The sodium iodide symporter (NIS) is responsible for thyroidal, salivary, gastric, intestinal and mammary iodide uptake. It was first cloned from the rat in 1996 and shortly thereafter from human and mouse tissue. In the intervening years, we have learned a great deal about the biology of NIS. Detailed knowledge of its genomic structure, transcriptional and post-transcriptional regulation and pharmacological modulation has underpinned the selection of NIS as an exciting approach for targeted gene delivery. A number of in vitro and in vivo studies have demonstrated the potential of using NIS gene therapy as a means of delivering highly conformal radiation doses selectively to tumours. This strategy is particularly attractive because it can be used with both diagnostic (99mTc, 125I, 124I) and therapeutic (131I, 186Re, 188Re, 211At) radioisotopes and it lends itself to incorporation with standard treatment modalities, such as radiotherapy or chemoradiotherapy. In this article, we review the biology of NIS and discuss its development for gene therapy. PMID:20201784

Hingorani, M.; Spitzweg, C.; Vassaux, G.; Newbold, K.; Melcher, A.; Pandha, H.; Vile, R.; Harrington, K.

2013-01-01

366

Intrinsically water-stable keratin nanoparticles and their in vivo biodistribution for targeted delivery.  

PubMed

Highly water-stable nanoparticles of around 70 nm and capable of distributing with high uptake in certain organs of mice were developed from feather keratin. Nanoparticles could provide novel veterinary diagnostics and therapeutics to boost efficiency in identification and treatment of livestock diseases to improve protein supply and ensure safety and quality of food. Nanoparticles could penetrate easily into cells and small capillaries, surpass detection of the immune system, and reach targeted organs because of their nanoscale sizes. Proteins with positive and negative charges and hydrophobic domains enable loading of various types of drugs and, hence, are advantageous over synthetic polymers and carbohydrates for drug delivery. In this research, the highly cross-linked keratin was processed into nanoparticles with diameters of 70 nm under mild conditions. Keratin nanoparticles were found supportive to cell growth via an in vitro study and highly stable after stored in physiological environments for up to 7 days. At 4 days after injection, up to 18% of the cells in kidneys and 4% of the cells in liver of mice were penetrated by the keratin nanoparticles. PMID:25174826

Xu, Helan; Shi, Zhen; Reddy, Narendra; Yang, Yiqi

2014-09-17

367

Novel thermo/pH sensitive nanogels composed from poly(N-vinylcaprolactam) for controlled release of an anticancer drug.  

PubMed

A series of novel nanogels (NGs) with both pH and thermoresponsive properties were synthesised by free radical emulsion polymerisation of N-vinyl caprolactam (VCL) and acrylamidoglycolic acid (AGA). 5-Flurouracil, an anti cancer drug, was successfully loaded into these nanogels via equilibrium swelling method. The encapsulation efficiency of 5-FU was found up to 61%. Here we present the novel potential drug delivery system showing both pH and temperature release of 5-FU. Fourier transforms infrared spectroscopy (FTIR), and differential scanning calorimetric (DSC) examined the structure and morphology of the NGs. Transmission electron microscopy (TEM) indicates the diameter of the NGs to be about 50 nm. The size distribution of NGs was investigated using dynamic light scattering (DLS), the average diameter and polydispersity is 57 nm and 0.194. Interestingly, the in vitro release studies of 5-FU demonstrated the dual nature (pH and temperature) of NGs. The cumulative release data were analysed using an emperical equation to compute the diffusion exponent (n); whose values suggest Fickian diffusion. PMID:23107966

Madhusudana Rao, K; Mallikarjuna, B; Krishna Rao, K S V; Siraj, S; Chowdoji Rao, K; Subha, M C S

2013-02-01

368

Targeted delivery of tissue plasminogen activator by binding to silica-coated magnetic nanoparticle  

PubMed Central

Background and methods Silica-coated magnetic nanoparticle (SiO2-MNP) prepared by the sol-gel method was studied as a nanocarrier for targeted delivery of tissue plasminogen activator (tPA). The nanocarrier consists of a superparamagnetic iron oxide core and an SiO2 shell and is characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, superconducting quantum interference device, and thermogravimetric analysis. An amine-terminated surface silanizing agent (3-aminopropyltrimethoxysilane) was used to functionalize the SiO2 surface, which provides abundant –NH2 functional groups for conjugating with tPA. Results The optimum drug loading is reached when 0.5 mg/mL tPA is conjugated with 5 mg SiO2-MNP where 94% tPA is attached to the carrier with 86% retention of amidolytic activity and full retention of fibrinolytic activity. In vitro biocompatibility determined by lactate dehydrogenase release and cell proliferation indicated that SiO2-MNP does not elicit cytotoxicity. Hematological analysis of blood samples withdrawn from mice after venous administration indicates that tPA-conjugated SiO2-MNP (SiO2-MNP-tPA) did not alter blood component concentrations. After conjugating to SiO2-MNP, tPA showed enhanced storage stability in buffer and operation stability in whole blood up to 9.5 and 2.8-fold, respectively. Effective thrombolysis with SiO2-MNP-tPA under magnetic guidance is demonstrated in an ex vivo thrombolysis model where 34% and 40% reductions in blood clot lysis time were observed compared with runs without magnetic targeting and with free tPA, respectively, using the same drug dosage. Enhanced penetration of SiO2-MNP-tPA into blood clots under magnetic guidance was confirmed from microcomputed tomography analysis. Conclusion Biocompatible SiO2-MNP developed in this study will be useful as a magnetic targeting drug carrier to improve clinical thrombolytic therapy. PMID:23055726

Chen, Jyh-Ping; Yang, Pei-Ching; Ma, Yunn-Hwa; Tu, Su-Ju; Lu, Yu-Jen

2012-01-01

369

Thermoresponsive Gelatin Nanogels Sahil Sandesh Gandhi, Huan Yan, and Chanjoong Kim*  

E-print Network

Thermoresponsive Gelatin Nanogels Sahil Sandesh Gandhi, Huan Yan, and Chanjoong Kim* Chemical thermoresponsive gelatin nanogel that shows a volume transition at 32 °C. A thermally induced volume reduction of more than 30� is observed due to the helix to random coil transition of gelatin chains confined

Kim, Chanjoong

370

Efficient Management of Fruit Pests by Pheromone Nanogels  

PubMed Central

Environment-friendly management of fruit flies involving pheromones is useful in reducing the undesirable pest populations responsible for decreasing the yield and the crop quality. A nanogel has been prepared from a pheromone, methyl eugenol (ME) using a low-molecular mass gelator. This was very stable at open ambient conditions and slowed down the evaporation of pheromone significantly. This enabled its easy handling and transportation without refrigeration, and reduction in the frequency of pheromone recharging in the orchard. Notably the involvement of the nano-gelled pheromone brought about an effective management of Bactrocera dorsalis, a prevalent harmful pest for a number of fruits including guava. Thus a simple, practical and low cost green chemical approach is developed that has a significant potential for crop protection, long lasting residual activity, excellent efficacy and favorable safety profiles. This makes the present invention well-suited for pest management in a variety of crops. PMID:23416455

Bhagat, Deepa; Samanta, Suman K.; Bhattacharya, Santanu

2013-01-01

371

Efficient management of fruit pests by pheromone nanogels.  

PubMed

Environment-friendly management of fruit flies involving pheromones is useful in reducing the undesirable pest populations responsible for decreasing the yield and the crop quality. A nanogel has been prepared from a pheromone, methyl eugenol (ME) using a low-molecular mass gelator. This was very stable at open ambient conditions and slowed down the evaporation of pheromone significantly. This enabled its easy handling and transportation without refrigeration, and reduction in the frequency of pheromone recharging in the orchard. Notably the involvement of the nano-gelled pheromone brought about an effective management of Bactrocera dorsalis, a prevalent harmful pest for a number of fruits including guava. Thus a simple, practical and low cost green chemical approach is developed that has a significant potential for crop protection, long lasting residual activity, excellent efficacy and favorable safety profiles. This makes the present invention well-suited for pest management in a variety of crops. PMID:23416455

Bhagat, Deepa; Samanta, Suman K; Bhattacharya, Santanu

2013-01-01

372

CD40-targeted dendritic cell delivery of PLGA-nanoparticle vaccines induce potent anti-tumor responses.  

PubMed

Dendritic cells (DC) play a prominent role in the priming of CD8(+) T cells. Vaccination is a promising treatment to boost tumor-specific CD8(+) T cells which is crucially dependent on adequate delivery of the vaccine to DC. Upon subcutaneous (s.c.) injection, only a small fraction of the vaccine is delivered to DC whereas the majority is cleared by the body or engulfed by other immune cells. To overcome this, we studied vaccine delivery to DC via CD40-targeting using a multi-compound particulate vaccine with the aim to induce potent CD8(+) T cell responses. To this end, biodegradable poly(lactic-co-glycolic acid) nanoparticles (NP) were formulated encapsulating a protein Ag, Pam3CSK4 and Poly(I:C) and coated with an agonistic ?CD40-mAb (NP-CD40). Targeting NP to CD40 led to very efficient and selective delivery to DC in vivo upon s.c. injection and improved priming of CD8(+) T cells against two independent tumor associated Ag. Therapeutic application of NP-CD40 enhanced tumor control and prolonged survival of tumor-bearing mice. We conclude that CD40-mediated delivery to DC of NP-vaccines, co-encapsulating Ag and adjuvants, efficiently drives specific T cell responses, and therefore, is an attractive method to improve the efficacy of protein based cancer vaccines undergoing clinical testing in the clinic. PMID:25465442

Rosalia, Rodney A; Cruz, Luis J; van Duikeren, Suzanne; Tromp, Angelino T; Silva, Ana L; Jiskoot, Wim; de Gruijl, Tanja; Löwik, Clemens; Oostendorp, Jaap; van der Burg, Sjoerd H; Ossendorp, Ferry

2015-02-01

373

“All in the mind”? Brain-targeting chemical delivery system of 17?-estradiol (Estredox) produces significant uterotrophic side effect  

PubMed Central

Here we revisit the peculiarly named redox chemical delivery system concept. This unique prodrug approach has long been claimed to be capable of targeting 17?-estradiol (E2), which has numerous beneficial central effects, into the brain without detrimental peripheral hormonal exposure. Using a well-established protocol to monitor E2’s antidepressant–like effect, we show that the administration of this chemical delivery system incorporated into hydroxypropyl-?-cyclodextrin (i.e., Estredox), indeed, triggers a transient antidepressant-like behavior in ovariectomized mice. At the same time, even an acute dose of the carefully purified chemical delivery system produces significant circulating E2 levels and uterotrophic side effects for several days after drug administration. For the first time, we also unequivocally show by liquid chromatography coupled with tandem mass spectrometry that the uterus of the Estredox-treated animals contains a large quantity of E2 compared to that of the control group. These thus far unexposed yet consequential peripheral side effects brought about by Estredox call for a thorough and unbiased reassessment of the extent of brain-targeting of the hormone via the chemical delivery system approach. PMID:24380028

Prokai-Tatrai, Katalin; Szarka, Szabolcs; Nguyen, Vien; Sahyouni, Fatima; Walker, Cary; White, Shastazia; Talamantes, Tatjana; Prokai, Laszlo

2013-01-01

374

New mechanisms for non-porative ultrasound stimulation of cargo delivery to cell cytosol with targeted perfluorocarbon nanoparticles  

NASA Astrophysics Data System (ADS)

The cell membrane constitutes a major barrier for non-endocytotic intracellular delivery of therapeutic molecules from drug delivery vehicles. Existing approaches to breaching the cell membrane include cavitational ultrasound (with microbubbles), electroporation and cell-penetrating peptides. We report the use of diagnostic ultrasound for intracellular delivery of therapeutic bulky cargo with the use of molecularly targeted liquid perfluorocarbon (PFC) nanoparticles. To demonstrate the concept, we used a lipid with a surrogate polar head group, nanogold-DPPE, incorporated into the nanoparticle lipid monolayer. Melanoma cells were incubated with nanogold particles and this was followed by insonication with continuous wave ultrasound (2.25 MHz, 5 min, 0.6 MPa). Cells not exposed to ultrasound showed gold particles partitioned only in the outer bilayer of the cell membrane with no evidence of the intracellular transit of nanogold. However, the cells exposed to ultrasound exhibited numerous nanogold-DPPE components inside the cell that appeared polarized inside intracellular vesicles demonstrating cellular uptake and trafficking. Further, ultrasound-exposed cells manifested no incorporation of calcein or the release of lactate dehydrogenase. These observations are consistent with a mechanism that suggests that ultrasound is capable of stimulating the intracellular delivery of therapeutic molecules via non-porative mechanisms. Therefore, non-cavitational adjunctive ultrasound offers a novel paradigm in intracellular cargo delivery from PFC nanoparticles.

Soman, N. R.; Marsh, J. N.; Lanza, G. M.; Wickline, S. A.

2008-05-01

375

Dynamics in thermo-responsive nanogel crystals undergoing melting.  

PubMed

We report here the dynamics in thermo-responsive poly(N-isopropylacrylamide) (PNIPAM) nanogel crystals undergoing melting/freezing and verify the applicability of the dynamical criterion for melting/freezing proposed by Löwen et al. [Phys. Rev. Lett. 70, 1557 (1993)]. According to this criterion the ratio of long time diffusion coefficient (D(L)) to short time diffusion coefficients (D(S)) is ~0.1 for colloidal particles in suspension undergoing melting/freezing. Static and dynamic light scattering techniques have been employed to identify the melting/freezing transition of PNIPAM nanogel colloidal crystals of two different volume fractions ? = 0.49 and 0.79 and to measure D(L) and D(S) across the melting. In dense PNIPAM nanogel crystals undergoing melting, the ratio D(L)/D(S) is found to be less than 0.1 for the first time and this deviation is higher in the suspension with higher ?. We also show that the deviation is genuine by measuring D(L)/D(S) on shear melted charged silica colloidal liquid undergoing freezing. The mean square displacement at shorter times, close to the melting, shows subdiffusive behavior. The subdiffusive behavior, arising due to the overlap of the dangling polymer chains between shells of the neighboring particles, is argued to be the reason for the observed deviation. PMID:24089798

Joshi, R G; Tata, B V R; Brijitta, J

2013-09-28

376

Conjugation of enzyme on superparamagnetic nanogels covered with carboxyl groups.  

PubMed

Alpha-chymotrypsin (CT) as model enzyme was conjugated onto the novel carboxyl-functionalized superparamagnetic nanogels, prepared via facile photochemical in situ polymerization, by using 1-ethyl-3-(3-dimethylaminepropyl) carbodiimide (EDC) as coupling reagent. The obtained magnetic immobilized enzyme was characterized by use of photo correlation spectroscopy (PCS), Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD) measurement, thermogravimetric (TG) analysis and vibrating sample magnetometer (VSM) measurement. PCS result showed that the immobilized enzyme was 68 nm in diameter while the magnetic nanogels with carboxyl groups were only 38 nm; enzyme immobilization led to pronounced change in size. Superparamagnetic properties were retained for Fe3O4 after enzyme immobilization while slightly reducing its value of saturation magnetization. Immobilization and surface coating did not induce phase change of Fe3O4 by XRD analysis. The binding capacity was 30 mg enzyme/g and 37.5 mg enzyme/g nanogel determined by TG analysis and BCA protein assay, respectively. Specific activity of the immobilized CT was calculated to be 0.77 U/(mg min), 82.7% as that of the free form. PMID:17241826

Hong, Jun; Xu, Dongmei; Gong, Peijun; Ma, Hongjuan; Dong, Li; Yao, Side

2007-05-01

377

Dynamics in thermo-responsive nanogel crystals undergoing melting  

NASA Astrophysics Data System (ADS)

We report here the dynamics in thermo-responsive poly(N-isopropylacrylamide) (PNIPAM) nanogel crystals undergoing melting/freezing and verify the applicability of the dynamical criterion for melting/freezing proposed by Löwen et al. [Phys. Rev. Lett. 70, 1557 (1993)]. According to this criterion the ratio of long time diffusion coefficient (DL) to short time diffusion coefficients (DS) is ˜0.1 for colloidal particles in suspension undergoing melting/freezing. Static and dynamic light scattering techniques have been employed to identify the melting/freezing transition of PNIPAM nanogel colloidal crystals of two different volume fractions ? = 0.49 and 0.79 and to measure DL and DS across the melting. In dense PNIPAM nanogel crystals undergoing melting, the ratio DL/DS is found to be less than 0.1 for the first time and this deviation is higher in the suspension with higher ?. We also show that the deviation is genuine by measuring DL/DS on shear melted charged silica colloidal liquid undergoing freezing. The mean square displacement at shorter times, close to the melting, shows subdiffusive behavior. The subdiffusive behavior, arising due to the overlap of the dangling polymer chains between shells of the neighboring particles, is argued to be the reason for the observed deviation.

Joshi, R. G.; Tata, B. V. R.; Brijitta, J.

2013-09-01

378

Method for tracking nanogel particles in vivo and in vitro.  

PubMed

Hydrogels made of N-isopropylacrylamide (NIPA) can be synthesized in the form of highly monodispersed nanoparticles. After synthesis, NIPA hydrogel nanoparticles (nanogels) can be labeled by Alexa Fluor 488 carboxylic acid, 2,3,5,6-tetrafluorophenyl ester through amine-terminated functional groups. This choice of dye is complementary to other biological labeling methods for in vivo studies. When the nanogel/dye nanoparticles are injected into rabbits, they can be imaged via tissue sectioning and confocal microscopy, while nanoparticle concentration can be determined by fluorescent microplate assays. Time-course persistence of nanoparticles in the circulatory system can be readily tracked by direct assay of plasma and urine samples using 485 nm excitation and 538 emission wavelengths to keep background fluorescence to nearly the same level as that found using an empty well. Depending upon how the nanoparticles are injected, circulatory system concentrations can reach high concentrations and diminish to low levels or gradually increase and gradually decrease over time. Injection in the femoral artery results in a rapid spike in circulating nanogel/dye concentration, while injection into the renal artery results in a more gradual increase. PMID:18348139

Seal, Brandon L; Lien, Yeong-Hau H; Mazar, Carla; Salkini, Mohamad W; Cai, Tong; Hu, Zhibing; Marquez, Manuel; Garcia, Antonio A

2008-07-01

379

Geometrical characteristics of polyelectrolyte nanogel particles and their polyelectrolyte complexes studied by dynamic and static light scattering.  

PubMed

The geometric characteristics of nanogel particles in aqueous solutions were studied by determining their ratios of radius of gyration (mean-square radius; Rg) to hydrodynamic radius (Rh), Rg/Rh, derived from static light scattering and dynamic light scattering experiments, respectively. The various nanogel samples studied included ones composed of lightly cross-linked N-isopropylacrylamide (NIPA) polymer, NIPA-based anionic or cationic copolymers, and amphoteric terpolymers. Polyelectrolyte complexes between anionic or cationic nanogels and oppositely charged polyions or nanogels having opposite charges were also studied. Most NIPA and NIPA-based polyelectrolyte nanogels in a swollen state had Rg/Rh values >0.775, which is the theoretically predicted value for a solid sphere. In a collapsed state, one may expect nanogel particles to be spherical in shape; however, this was not the case for a variety of nanogel samples, either with or without charges. These data were consistent with the idea that the surfaces of these nanogel particles were decorated with attached dangling chains. The Rg/Rh data from polyelectrolyte-nanogel complexes, however, indicated different structures from this. It was found that most of the polyelectrolyte-nanogel complex particles had Rg/Rh approximately 0.775. This suggested that the complexed nanogel particles were spherical in shape and that there were no dangling surface chains. PMID:17559254

Kokufuta, Etsuo; Ogawa, Kazuyoshi; Doi, Ryo; Kikuchi, Rie; Farinato, Raymond S

2007-07-26

380

Targeted Quantum Dot Conjugates for siRNA Delivery Austin M. Derfus,,  

E-print Network

tools and therapeutic modalities. Multifunctional platforms combining therapeutic and diagnostic imaging these principles to the delivery of small interfering RNA (siRNA) therapeutics, where systemic delivery is hampered as a scaffold, siRNA and tumor-homing peptides (F3) were conjugated to functional groups on the particle

Bhatia, Sangeeta