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At least 523 records · Page 29Linked to original sources
PubMed1999

Neurotensin-SPDP-poly-L-lysine conjugate: a nonviral vector for targeted gene delivery to neural cells.

We report herein the synthesis of a novel DNA delivery system and in vitro evidence of its ability to transfect cell lines by binding to the high-affinity neurotensin receptor and subsequent internalization of ligand-receptor complexes. The targeting vehicle consisted of neurotensin crosslinked with poly-L-lysine via N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP). The SPDP-derivatives with either neurotensin or poly-L-lysine were purified by gel filtration. The conjugate resulting of the reaction of neurotensin-SPDP with HS-SPDP-poly-L-lysine was purified through Biogel A 1.5. The neurotensin-SPDP-poly-L-lysine conjugate was able to bind plasmidic DNAs (pSV2cat and pGreen Lantern-1) at optimal molar ratios of 1:5 and 1:6 (DNA: conjugate), respectively. The conjugate internalized those plasmids in the cell lines (N1E-115 and HT-29) bearing the high-affinity neurotensin receptor. Expression of the plasmid products, chloramphenicol acetyltransferase and green fluorescent protein, was observed in such cell lines. Both internalization and expression of the plasmids transferred by the neurotensin-SPDP-poly-L-lysine conjugate were prevented by neurotensin (1 microM) and SR-48692 (100 nM), a specific antagonist of the high-affinity neurotensin receptor. The neurotensin-SPDP-poly-L-lysine conjugate was unable to transfect cell lines lacking the neurotensin receptor (COS-7 and L-929). In rat brain, the high-affinity neurotensin receptor is expressed by specific neurons such as those of the nigrostriatal and mesolimbic dopaminergic systems. Therefore, the neurotensin-SPDP-poly-L-lysine conjugate could be a useful tool for gene delivery to those neuronal systems.

Animals↗
PubMed2007

Folate-decorated poly(lactide-co-glycolide)-vitamin E TPGS nanoparticles for targeted drug delivery.

Doxorubicin-loaded nanoparticles (NPs) of vitamin E TPGS-folate (TPGS-FOL) conjugate and doxorubicin-poly(lactide-co-glycolide)-vitamin E TPGS (DOX-PLGA-TPGS) conjugate were prepared by the solvent extraction/evaporation method for targeted chemotherapy of folate-receptor rich tumors. X-ray photoelectron spectroscopy demonstrated that folate was distributed on the NP surface while the drug molecules were entrapped in the NP matrix. The NPs were found of approximately 350nm diameter and exhibited a biphasic pattern of in vitro drug release. The cell uptake of the fluorescent NPs and the cell viability of the drug formulated in the NPs were quantitatively investigated, which were found dependent on the content of targeting TPGS-FOL conjugate. The NPs of 50% TPGS-FOL showed cellular uptake by MCF-7 cells 1.5 times higher and by C6 cells 1.7 times higher than the NPs with no TPGS-FOL component after 30min incubation. The MCF-7 cell viability was found decreased significantly from 50.8% for the drug-loaded NPs of no TPGS-FOL to 8.2% for those of 50% TPGS-FOL after incubation at 100microug concentration at 37 degrees C. The latter NPs also exhibited much lower IC(50) value than the DOX after 24h incubation, i.e., 19.4 vs. 43.7micror MCF-7 cells and 3.3 vs. >100micror C6 cells.

Animals↗
PubMed2004

Synthesis of potent taxoids for tumor-specific delivery using monoclonal antibodies.

The targeted delivery of taxoids, in the form of taxane-antibody immunoconjugates, requires the preparation of taxoids containing moieties suitable for their conjugation to monoclonal antibodies. A series of taxoids incorporating a disulfide-containing linker at various positions of the taxoid framework have been prepared to investigate the most suitable position for conjugation. A second series of taxoids modified at the C-2 position aimed at increasing the potency of these taxanes has also been prepared.

Antibodies, Monoclonal↗
PubMed2002

Studies on lactulose formulations for colon-specific drug delivery.

A novel, colon-targeted delivery system (CODES), which uses lactulose, was investigated in this study. Lactulose is not absorbed in the upper GI tract, but degraded to organic acids by enterobacteria in the lower gastrointestinal tract, especially the colon. A CODES consists of three components: a core containing lactulose and the drug, an inner acid-soluble material layer, and an outer layer of an enterosoluble material. When a CODES containing a pigment was introduced into the rat cecum directly after shaking in JP 2nd fluid for 3 h, pigment release was observed 1 h after introduction. A CODES containing 5-aminosalicylic acid (5-ASA) was orally administered to fasting and fed dogs to evaluate its pharmacokinetic profiles. 5-ASA was first detected in plasma after 3 h, which is the reported colon arrival time for indigestible solids, after dosing to fasting dogs. The T(max) in fed dogs was delayed by 9 h when compared to fasting dogs. This corresponds to the gastric emptying time. However, the C(max) and AUC under fed conditions were almost as same as those under fasting conditions. The results of this study show that lactulose can act as a trigger for drug release in the colon, utilizing the action of enterobacteria.

Animals↗
PubMed2006

Immunologic control of tumors by in vivo Fc gamma receptor-targeted antigen loading in conjunction with double-stranded RNA-mediated immune modulation.

Despite the expression of non-self or neo-epitopes, many tumors such as lymphoid malignancies or cancers induced by oncogenic viruses are able to gradually overcome the immune defense mechanisms and spread. Using a preclinical model of hematological malignancy, we show that Ig-associated idiotypic determinants are recognized by the immune system in a fashion that results in immune deviation, allowing tumor progression and establishment of metastases. Using gene-targeted mice, we show that anti-idiotypic MHC class I-restricted immunity is promoted by ITAM motif (ITAM+) FcgammaR, but kept in check by ITIM motif (ITIM+) FcgammaRIIB-mediated mechanisms. In addition to interfering with the functionality of ITIM+ FcgammaR, effective anti-idiotypic and antitumoral immunity can be achieved by FcgammaR-targeted delivery of epitope in conjunction with administration of stimulatory motifs such as dsRNA, correcting the ineffective response to idiotypic epitopes. The immune process initiated by FcgammaR-mediated targeting of epitope together with dsRNA, resulted in control of tumor growth, establishment of immune memory and protection against tumors bearing antigenic variants. In summary, targeted delivery of MHC class I-restricted epitopes via ITAM+ FcgammaR, in conjunction with use of TLR-binding immune stimulatory motifs such as dsRNA, overcomes suboptimal responses to idiotypic determinants and may constitute a novel approach for the treatment of a broad range of malignancies. Finally, the results shed light on the mechanisms regulating the idiotypic network and managing the diversity associated with immune receptors.

Animals↗
PubMedDate not supplied

In vitro antiproliferative activity of a medium-chain triglyceride solution of 1,25-dihydroxyvitamin D3 in HepG2 cells.

BACKGROUND: Successful targeted delivery of 1,25-dihydroxyvitamin D3 [1,25-D3] for the treatment of liver cancer would necessitate the use of an appropriate delivery agent. MATERIALS AND METHODS: Using liver cancer cell line HepG2 in culture, we examined, the possibility of using medium-chain triglyceride (MCT) as a solvent for targeted delivery of 1,25-D3. The drug was made up in either the medium or first dissolved in MCT and subsequently diluted in the medium. Cells were exposed for 1 (acute) or 5 days (chronic) to the 2 different formulations of the drug and cell proliferation was measured by [3H]thymidine and cell count methods. RESULTS: In chronic experiments, exposure of cells to the MCT containing formulation of 1,25-D3 led to significantly greater inhibition of cell proliferation. In the acute experiments where, 1 day 1,25-D3 treatment was followed by 4 days of incubation with normal medium (no drug, no MCT), inhibition of proliferation was more than 2 fold greater in cells exposed to the 1,25-D3/MCT preparation. CONCLUSION: These results indicate that, 1,25-D3 dissolved in MCT probably accumulates and then acts as a sustained release drug depot formulation, in which case it may have potential for the regional treatment of liver tumors.

Calcitriol↗
PubMed2006

Semisynthetic maytansine analogues for the targeted treatment of cancer.

Maytansine, a highly cytotoxic natural product, failed as an anticancer agent in human clinical trials because of unacceptable systemic toxicity. The potent cell killing ability of maytansine can be used in a targeted delivery approach for the selective destruction of cancer cells. A series of new maytansinoids, bearing a disulfide or thiol substituent were synthesized. The chain length of the ester side chain and the degree of steric hindrance on the carbon atom bearing the thiol substituent were varied. Several of these maytansinoids were found to be even more potent in vitro than maytansine. The targeted delivery of these maytansinoids, using monoclonal antibodies, resulted in a high, specific killing of the targeted cells in vitro and remarkable antitumor activity in vivo.

Animals↗
PubMed2005

Targeted drug delivery to macrophages in parasitic infections.

Successful homing of drugs to the desired biological compartment of the host usually depends on the intrinsic properties of the drug molecules. However, it can always be manipulated by appropriate designing of the carrier/delivery system, as little can be done to influence the target and its surroundings. Various carrier systems have emerged to deliver drugs to macrophages, albeit the efficacy, reliability and selectivity of these carriers are still in question. To date, the most extensively studied carriers are liposomes and microspheres. In fact, physicochemical properties of these carriers can alter their efficacy and specificity to a great extent. These properties include hydrophilicity, surface charge, composition, concentration, and presence of various target specific ligands on their surface. Incidentally, the particulate nature of these vehicles may facilitate passive homing of the entrapped drug molecules to the macrophages, which may harbour many of the important pathogens in their intracellular compartments, such as Mycobacterium sps, Leishmania and dengue virus etc., belonging to three different major classes of microbes. Moreover, macrophages upon interaction with particulate drug delivery vehicles may act as secondary drug depot, thus helping in localized delivery of the drug at the infected site. In the present article, a comprehensive review of literature is presented on the suitability of some lipid-based and polymeric materials as vehicles in delivery of drugs to macrophages in parasitic infections.

Animals↗
PubMed1998

Drug delivery and targeting.

When a pharmaceutical agent is encapsulated within, or attached to, a polymer or lipid, drug safety and efficacy can be greatly improved and new therapies are possible. This has provided the impetus for active study of the design of degradable materials, intelligent delivery systems and approaches for delivery through different portals in the body.

Drug Administration Routes↗
PubMed2000

Inhaled aerosolization of all-trans-retinoic acid for targeted pulmonary delivery.

Retinoids have shown promising activity for both cancer chemoprevention and as a treatment for emphysema. However, chronic oral administration of these drugs is limited by systemic side effects, including hepatic dysfunction, skeletal malformations, hyperlipidemia. hypercalcemia, and other reactions. In order to improve the pulmonary targeting of this potentially useful therapy, we developed a system for aerosolization of retinoids that substantially increased their local bioavailability. We compared the biodistribution and pharmacokinetics of an inhaled formulation of all-trans-retinoic acid (all-trans-RA), which was packaged in a metered dose inhaler, following both intratracheal (IT) and intravenous (IV) administration in male Sprague-Dawley rats. After drug administration, anesthetized animals were killed at 5 min, and at 1, 2, 4, 6 and 24 h. Plasma and emulsified samples of liver and lung tissues were dissected, extracted, and frozen prior to measurement of all-trans-RA concentration by high-performance liquid chromatography (HPLC). Aerosolization and IT injection of all-trans-RA resulted in a significantly longer pulmonary half-life of the drug (both 5-17 h), lower peak serum concentrations (aerosol 71 +/- 31 ng/ml, IT 68 +/- 50 ng/ml), and lower liver levels (aerosol 111 +/- 28 ng/g, IT 753 +/- 350 ng/g) than the same dose administered IV (2 h, 838 +/- 56 ng/ml, 4,258 +/- 1,006 ng/g, respectively; P < 0.05 for each comparison). Histologic examination of lungs and trachea showed no focal irritation attributable to the drug after single-dose administration. These results suggest that aerosolization of retinoids may offer a practical alternative to systemic oral administration for chemoprevention trials or treatment of lung diseases. This method may substantially increase the therapeutic index of these compounds by reducing systemic complications associated with long-term dosing.

Administration, Inhalation↗
PubMedDate not supplied

Peptide targeting and delivery across the blood-brain barrier utilizing synthetic triglyceride esters: design, synthesis, and bioactivity.

As an approach to the development of therapeutically useful peptide pharmaceuticals that can penetrate the blood-brain barrier, we have designed and demonstrated the application of a carrier-targeting system. We have developed a prodrug design strategy that is designed to utilize membrane-bound enzymes whereby release of a bioactive peptide from a highly lipophilic triglyceride peptide-carrier is achieved in situ, thus attaining high localized concentrations of the bioactive peptide. Following localization of such a system, normal peptidase and lipase action is utilized to release the active peptide (deltorphin II) intact and in high concentration. At present, the exact mechanisms are unclear, but the observed results in which analgesia is observed following peripheral administration suggest that the active peptide is able to cross the blood-brain barrier and sustain prolonged periods of analgesia as determined by antinociception tests by release of the bioactive peptide. In vitro tests of binding and bioactivity by the peptide conjugate show essentially no potency in either target or control analogues, but potent antinociceptive effects are observed following peripheral administration.

Analgesia↗
PubMed2006

Breath actuated device improves delivery to target sites beyond the nasal valve.

OBJECTIVES: The objective was to compare nasal deposition patterns achieved with a conventional hand actuated spray pump and a novel breath actuated bidirectional prototype device housing the same spray pump (OptiMist, OptiNose AS, Oslo, Norway). STUDY DESIGN AND METHODS: The bidirectional delivery device exploits the posterior connection between the nasal passages persisting when the velum automatically closes during oral exhalation. The deposition and clearance patterns achieved with the two devices were compared in nine healthy subjects by scintigraphy after administration of Tc-aerosols. RESULTS: Compared with traditional spray pump delivery, the OptiMist device provided significantly (P < .004) larger initial and cumulative deposition (area under the deposition vs. time curve) in the upper posterior segment of the nasal passage, housing the sinus ostia and the olfactory region, and significantly lower deposition (P < .004) in the anterior segment, lined by nonciliated squamous epithelium. Furthermore, intersubject reproducibility of the initial and cumulative deposition was higher for the OptiMist device both in the upper posterior segment and the entire nose. CONCLUSIONS: Compared with a spray pump, the novel breath actuated bidirectional device provides significantly larger deposition in the clinically important regions beyond the nasal valve and reduced anterior deposition. These striking differences provide new opportunities for improved therapy of chronic rhinosinusitis and polyposis as well as extended use of the nose for delivery of drugs from the nose into the brain.

Administration, Intranasal↗
PubMedDate not supplied

Targeted gene delivery with a low molecular weight glycopeptide carrier.

A low molecular weight glycopeptide carrier was prepared by coupling a tyrosinamide-triantennary oligosaccharide to dp19 poly-L-lysine resulting in a 1:1 conjugate. The glycopeptide carrier complexed with plasmid DNA as evidenced by displacement of intercalated dye, light scattering by condensed DNA, and immobility of complexed DNA upon agarose gel electrophoresis. DNA-carrier complexes were endocytosed into HepG2 cells via the asialoglycoprotein receptor due to recognition of terminal galactose residues on the oligosaccharide. The resulting luciferase reporter gene expression was dramatically influenced by the solubility of complexes, the extent of complexation, and the presence of the lysosomotropic agent chloroquine. The results suggest that low molecular weight glycopeptides may be suitable for further development as well-defined DNA carriers for receptor-mediated gene delivery in vivo.

Carbohydrate Sequence↗
PubMed1997

Colloidal systems for tumor targeting.

The potential and limitations of targeted delivery of anticancer agents with colloidal particulate carriers is the subject of this contribution. Because over the years liposomes have gained the most attention as carrier system in the category of colloidal carrier systems, this paper focuses on the utility of the liposomal system for tumor targeting. It is imperative that an intended therapeutic application of liposomes should be well matched with the liposome behavior in vivo. Therefore, the in vivo fate of the first-generation liposomes and the more recently developed second-generation liposomes (surface-modified liposomes such as the immunoliposomes and long-circulating liposomes) is analyzed in terms of accessibility of target sites, time-, and site-controlled drug release and potential target sites for rational targeted delivery are discussed. A few examples of areas in cancer chemotherapy, with a strong rationale for the use of liposomes, are given. It is concluded that, although several options are available on the drawing board, issues such as tumor cell heterogeneity, access to the target site, shedding of antigens, and target site-specific release of the liposome-associated drug need to be addressed early in the development process.

Animals↗
PubMed2006

Genospheres: self-assembling nucleic acid-lipid nanoparticles suitable for targeted gene delivery.

We describe the assembly of a cationic lipid-nucleic acid nanoparticle from a liquid monophase containing water and a water miscible organic solvent where both lipid and DNA components are separately soluble prior to their combination. Upon removal of the organic solvent, stable and homogenously sized (70-100 nm) lipid-nucleic acid nanoparticles (Genospheres) were formed. The low accessibility (<15%) of the nanoparticle-encapsulated DNA to a DNA intercalating dye indicated well-protected nucleic acids and high DNA incorporation efficiencies. It was demonstrated that Genospheres could be stably stored under a variety of conditions including a lyophilized state where no appreciable increase in particle size or DNA accessibility was observed following reconstitution. Finally, Genospheres were made target-specific by insertion of an antibody-lipopolymer (anti-HER2 scFv (F5)-PEG-DSPE) conjugate into the particle. The target specificity (>100-fold) in HER2 overexpressing SK-BR-3 breast cancer cells was dependent on the degree of PEGylation, where the incorporation of high amounts of PEG-lipid on the particle surface (up to 5 mol%) had only a minor effect on the transfection activity of the targeted Genospheres. In summary, this work describes a novel, readily scalable method for preparing highly stable immunotargeted nucleic acid delivery vehicles capable of achieving a high degree of specific transfection activity.

DNA↗
PubMed2005

[Inhibitory effect of polyethylenimine-mediated transfection of suicide gene HSV-tk with an ovarian-specific promoter on growth of ovarian cancer cell line SKOV3].

BACKGROUND & OBJECTIVE: Improving the transfection efficiency and targeted delivery of gene vector are 2 critical problems in the field of gene therapy. Polycationic polyethylenimine (PEI), as a new kind of gene vector, provides an effective solution. This study aimed to investigate the antitumor and targeted delivery effects of PEI-mediated transfection of suicide gene HSV-tk regulated by ovarian-specific promoter OSP1 on human ovarian carcinoma cell line SKOV3. METHODS: SKOV3 cells were separately transfected with PEI, liposome DOTAP, and naked DNA mediated by plasmid pGL3-Luc; the transfection efficiency was measured by relative luciferase unit (RLU). SKOV3 cells and human hepatocellular carcinoma cell line SMMC7721 were transfected with pOSP1-HSVtk mediated by PEI. Cytotoxicity of ganciclovir (GCV) to SKOV3 and SMMC7721 cells was measured by MTT assay; the concentration of GCV in SKOV3 cells was detected by high performance liquid chromatography (HPLC). Cell apoptosis was detected by flow cytometry (FCM) and TdT-mediated dUTP nick end labeling (TUNEL) technique. RESULTS: RLU was significantly higher in PEI group than in DOTAP and naked DNA groups (187.35+/-6.48 vs. 45.74+/-5.98, and 0.03+/-0.00,P<0.01). Evident GCV cytotoxicity was observed in SKOV3 cells, but negligible in SMMC7721 cells. The concentration of GCV in SKOV3 cells was gradually decreased with treatment prolonging. FCM showed that the apoptotic rate of pOSP1-HSVtk-transfected SKOV3 cells was increased when exposed to GCV for 24, 48, and 72 h [(8.42+/-0.76)%, (18.50+/-1.78)%, (34.80+/-3.46)%]. A lot of apoptotic SKOV3 cells were detected by TUNEL. CONCLUSION: PEI-mediated transfection of suicide gene regulated by ovarian-specific promoter has an in vitro tissue-specific killing effect on ovarian cancer cells, which may improve the efficiency and the targeting of gene therapy.

Adenocarcinoma↗
PubMed2004

A synthetic peptide containing loop 4 of nerve growth factor for targeted gene delivery.

BACKGROUND: Gene delivery vectors that restrict the expression of a therapeutic gene to a particular type of cells are critical to gene therapy in a complex structure, such as the central nervous system. We constructed a nonviral vector for targeted gene transfer to cells expressing nerve growth factor (NGF) receptor TrkA. METHODS AND RESULTS: The vector was a synthetic chimeric peptide composed of a targeting moiety derived from NGF loop 4 and a DNA-binding moiety of 10 lysine residues. The peptide activated signal transduction pathways of the NGF receptor TrkA in PC12 cells and supported the survival of the cells after serum deprivation. After forming complexes with plasmid DNA, the peptide dose-dependently increased reporter gene expression in PC12 cells, which could be inhibited by excess NGF. The peptide-mediated gene expression was not affected in PC12 cells by co-incubation with a blocking antibody against the low-affinity NGF receptor p75 and was significantly enhanced in NIH3T3 cells stably transfected with TrkA cDNA, suggesting the involvement of the high-affinity NGF receptor TrkA without the participation of p75. Moreover, the peptide did not assist gene transfer in TrkA-poor, but TrkB- and/or TrkC-positive primary cerebellar granule neurons and primary cortical glial cells. CONCLUSIONS: The chimeric peptide reported will be useful in gene delivery to and gene therapy of the nervous system and other tissues/organs with cells expressing TrkA.

Animals↗