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At least 613 records · Page 34Linked to original sources
PubMed2006

Bio-functional micelles self-assembled from a folate-conjugated block copolymer for targeted intracellular delivery of anticancer drugs.

In this study, a block copolymer, poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide-co-2-aminoethyl methacrylate)-b-poly(10-undecenoic acid) (P(NIPAAm-co-DMAAm-co-AMA)-b-PUA) was synthesized, and folic acid was conjugated to the hydrophilic block through the amine group in AMA. This polymer was self-assembled into micelles, which exhibited pH-induced temperature sensitivity. They were smaller in size, and possessed a better-defined core-shell structure as well as more stable hydrophobic core than the random copolymer P(NIPAAm-co-DMAAm-co-UA), and provided a shell with folate molecules. An anti-cancer drug, doxorubicin (DOX) was encapsulated into the micelles. The mean diameter of the blank and DOX-loaded micelles was less than 100 nm. DOX release was pH-dependent, being faster at low pH (endosomes/lysosomes). Therefore, DOX was readily released from the micelles into the nucleus after being taken up. More importantly, IC50 of DOX-loaded micelles with folate against folate receptor-expressing 4T1 and KB cells was much lower than that of the DOX-loaded micelles without folate (3.8 vs. 7.6 mg/L for 4T1 cells and 1.2 vs. 3.0mg/L for KB cells). In vivo experiments conducted in a 4T1 mouse breast cancer model demonstrated that DOX-loaded micelles had a longer blood circulation time than free DOX (t(1/2): 30 min and 140 min, respectively). In addition, the micelles delivered an increased amount of DOX to the tumor when compared to free DOX. These bio-functional micelles may make a promising carrier to transport anticancer drugs specifically to tumor cells and release the drug molecules inside the cells to the cytosols for improved chemotherapy.

Animals↗
PubMed2004

Potential prodrugs of non-steroidal anti-inflammatory agents for targeted drug delivery to the CNS.

Recently non-steroidal anti-inflammatory drugs (NSAIDs) have been proposed to prevent or to cure Alzheimer's disease. In this respect, we synthesized new potential prodrugs of several NSAIDs in order to increase their access to the brain. The carboxylic group of NSAIDs was attached to the 1,4-dihydro-1-methylpyridine-3-carboxylate moiety, which acts as a carrier, via an amino alcohol bridge, according to the chemical delivery approach developed by Bodor. The lipophilicity of potential prodrugs was evaluated both via traditional experimental parameters, such as partition coefficient and chromatographic R(m) value, and by predictive computational methods. From experimental parameters, all prodrugs were more lipophilic when compared to their corresponding parent compounds and consequently a better blood brain barrier (BBB) penetration is hypothesised. Prodrug lipophilicity was correlated with a calculated log P value according to Kowwin's method. The correlation between experimental Rm0 and calculated log P, determined by PLS analysis, was good for all compounds with the exception of compound 7i. In addition the BBB permeation profile of our synthesized compounds was predicted using the BBB VolSurf model and seven of the synthesized prodrugs resulted in good candidates for BBB penetration.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2006

Minimal YopB and YopD translocator secretion by Yersinia is sufficient for Yop-effector delivery into target cells.

Pathogenic Yersinia sp. utilise a common type III secretion system to translocate several anti-host Yop effectors into the cytosol of target eukaryotic cells. The secreted YopB and YopD translocator proteins are essential for this process, forming pores in biological membranes through which the effectors are thought to gain access to the cell interior. The non-secreted cognate chaperone, LcrH, also plays an important role by ensuring pre-secretory stabilisation and efficient secretion of YopB and YopD. This suggests that LcrH-regulated secretion of the translocators could be used by Yersinia to control effector translocation levels. We collected several LcrH mutants impaired in chaperone activity. These poorly bound, stabilised and/or secreted YopB and YopD in vitro. However, these mutants generally maintained stable substrates during a HeLa cell infection and these infected cells were intoxicated by translocated effectors. Surprisingly, this occurred in the absence of detectable YopB- and YopD-dependent pores in eukaryotic membranes. A functional type III translocon must therefore only require minuscule amounts of secreted translocator proteins. Based on these observations, LcrH dependent control of translocation via regulated YopB and YopD secretion would need to be exquisitely tight.

Bacterial Outer Membrane Proteins↗
PubMed2025

Gene regulation technologies for gene and cell therapy.

Gene therapy stands at the forefront of medical innovation, offering unique potential to treat the underlying causes of genetic disorders and broadly enable regenerative medicine. However, unregulated production of therapeutic genes can lead to decreased clinical utility due to various complications. Thus, many technologies for controlled gene expression are under development, including regulated transgenes, modulation of endogenous genes to leverage native biological regulation, mapping and repurposing of transcriptional regulatory networks, and engineered systems that dynamically react to cell state changes. Transformative therapies enabled by advances in tissue-specific promoters, inducible systems, and targeted delivery have already entered clinical testing and demonstrated significantly improved specificity and efficacy. This review highlights next-generation technologies under development to expand the reach of gene therapies by enabling precise modulation of gene expression. These technologies, including epigenome editing, antisense oligonucleotides, RNA editing, transcription factor-mediated reprogramming, and synthetic genetic circuits, have the potential to provide powerful control over cellular functions. Despite these remarkable achievements, challenges remain in optimizing delivery, minimizing off-target effects, and addressing regulatory hurdles. However, the ongoing integration of biological insights with engineering innovations promises to expand the potential for gene therapy, offering hope for treating not only rare genetic disorders but also complex multifactorial diseases.

Humans↗
PubMed1997

Synthesis of O-methylsulfonyl derivatives of D-glucose as potential alkylating agents for targeted drug delivery to the brain. Evaluation of their interaction with the human erythrocyte GLUT1 hexose transporter.

In order to obtain hydrophilic analogues of 1,4-dimethylsulfonyloxybutane (busulfan) with enhanced selectivity and improved brain penetration, we have synthesized 6-O-methylsulfonyl-D-glucose, 3-O-methylsulfonyl-D-glucose, 3,6-di-O-methylsulfonyl-D-glucose, 4-O-methylsulfonyl-D-glucose, and 4,6-di-O-methylsulfonyl-D-glucose, and we have studied their interactions with the human erythrocyte GLUT1 hexose transport system. Mesylation of OH-4 and OH-6 of glucose resulted in a slightly diminished affinity for the GLUT1 glucose transporter, whereas mesylation of OH-3 led to complete loss of affinity.

Antineoplastic Agents, Alkylating↗
PubMed2002

Targeted cytosolic delivery of hydrogel nanoparticles into HepG2 cells through engineered Sendai viral envelopes.

Hydrogel nanoparticles of cross-linked polyvinylpyrrolidone (PVP-NP) (35-50 nm in diameter) containing fluoresceinated dextran (FITC-Dx) were encapsulated in reconstituted Sendai viral envelopes containing only the fusion (F) protein (F-virosomes(1)). Incubation of these loaded F-virosomes with human hepatoblastoma cells (HepG2) in culture resulted in membrane-fusion-mediated delivery of NPs to the cell cytoplasm, as inferred from the ability of cells to internalize FITC-Dx loaded PVP-NP (PVP(f)-NP) in the presence of azide (an inhibitor of the endocytotic process). Introduction of PVP(f)-NP into the HepG2 cells was assured by selective accumulation of FITC fluorescence in the cytosolic compartment. The structural integrity of the internalized PVP(f)-NP was also confirmed by fluorescence microscopy and ultracentrifugation analysis. The potential usefulness of PVP-NP-mediated cytosolic release of water soluble drugs both in vitro and in vivo has been established for the first time.

3T3 Cells↗
PubMed1995

Biodegradable polymer microspheres for targeted drug delivery to the retinal pigment epithelium.

The authors evaluated the feasibility of biodegradable polymer microspheres of poly (L-lactic acid) and poly(glycolic acid) to deliver a substance directly to the retinal pigment epithelial (RPE) cells. The microspheres encapsulated a fluorescent dye (rhodamine 6GX) that was used as a drug marker. The dye released from the microspheres was analyzed by spectrofluorophotometry in vitro. Microspheres were administered to cultured bovine RPE cells. Phagocytosis of the microspheres by RPE cells was studied by fluorescent microscopy and transmission electron microscopy. Intracellular release of the fluorescent dye was also evaluated after phagocytosis of the microspheres. A suspension of the microspheres was administered into the subretinal space via transvitreal approach with a glass micropipette in the rabbits in vivo. The release rate of the fluorescent dye was controllable by changing the molecular weight and the monomer composition of the copolymers in vitro. Microspheres were phagocytosed by RPE cells and the dye was released intracellularly during incubation. After subretinal delivery, the microspheres were degraded in the cytoplasm of the RPE, but the fragments were observed up to four weeks. The retinal architecture overlying the delivery site was well preserved. These results suggest that it is feasible to deliver substances directly to the RPE cells with the use of polymer microspheres without damaging the neural retinal structure. This drug delivery system may enable the functions of RPE cells to be modified pharmacologically.

Animals↗
PubMed2003

Human immunodeficiency virus type 1 envelope-mediated neuropathogenesis: targeted gene delivery by a Sindbis virus expression vector.

Sindbis virus (SIN) expression vectors offer the opportunity for studying neuropathogenesis because of their distinct neural cell tropism. Here, we demonstrate that a recombinant SIN vector expressing EGFP (SINrep5-EGFP) infected multiple cell types including neural cells from several species relevant to lentivirus pathogenesis with high levels of transgene expression. Infection of human neurons by a recombinant SIN (SINrep5-JRFL) expressing the full-length envelope from a neurovirulent human immunodeficiency virus type 1 (HIV-1) strain (JRFL) caused increased cytotoxicity compared to infection with SINrep5-EGFP (P < 0.001), while no cytotoxicity was observed among infected human astrocytes or monocytoid cells. Both human monocyte-derived macrophages (MDM) (P < 0.01) and astrocytes (P < 0.001) infected with SINrep5-JRFL released soluble neurotoxins in contrast to SINrep5-EGFP or mock-infected cells, although this was most prominent for the astrocytes. Implantation of SINrep5-JRFL into the brains of SCID/NOD mice induced neuroinflammation, neuronal loss, and neurobehavioral changes characteristic of HIV-1 infection, which were not present in SINrep5-EGFP or mock-infected animals. Thus SIN expression vectors represent novel tools for studying in vitro and in vivo HIV-1 neuropathogenesis because of their high levels of transgene expression in specific cell types within the brain.

Animals↗
PubMed1999

The comparative benefits of glaucoma filtering surgery with an electric-pulse targeted drug delivery system demonstrated in an animal model.

PURPOSE: To evaluate the safety and effectiveness of glaucoma filtering surgery performed with the adjunctive use of bleomycin administered in conjunction with electric pulses (EP). DESIGN: Experimental study in rabbits. CONTROLS AND METHODS: Trabeculectomies were performed on pigmented rabbits (2 to 2.5 kg) using the following adjunctive treatments: 5 microM of topical bleomycin and EP (5V, 50 msec, 8 pulses) (group A: B+E+, n=15); bleomycin but no EP (group B: B+E-, n=15); 5 ,uM mitomycin C (MMC) and EP (group C: M+E+, n= 10); MMC but no EP (group D: M+E-, n=10); EP alone (group E: E+, n=10); and no adjunctive treatment (group F: E-, negative control, n=10). MAIN OUTCOME MEASURES: Intraocular pressure (IOP) was measured regularly for 60 days after the operation. Bleb formation and the condition of the conjunctiva, cornea, and retina were also regularly evaluated. Histologic studies were performed by light microscopy, and retinal functions were evaluated by electroretinography. RESULTS: Postoperative IOP was significantly lower than the preoperative level in all the animals until day 7. However, in groups E and F (the negative control) it returned to the preoperative level after day 7, and in groups B, C, and D after 15 days. The IOP of group A remained lower even on day 40. The average amount IOP was lowered or increased on day 20 was -6.4 mmHg (P < 0.05) in group A; -0.2 mmHg in group B; +1.2 mmHg in group C; and -3.25 mmHg in group D. The survival rate of the filtering blebs on day 20 was significantly higher in group A than in the other groups. Clinical and histologic studies uncovered no pathologic findings in any intra- or paraocular tissues. Electroretinographic evaluation of retinal function in group A showed no apparent change over the 60 days of the study. CONCLUSION: Glaucoma filtering surgery in rabbits with the adjunctive use of bleomycin in conjunction with EP significantly lowered IOP for up to 40 days without clinically, morphologically, or functionally harming intraocular tissues.

Animals↗
PubMed2001

Assessment of target dose delivery in anal cancer using in vivo thermoluminescent dosimetry.

PURPOSE: To measure anal dose during external beam radiotherapy (EBRT) using in vivo dosimetry, to study the difference of measured from prescribed dose values, and to evaluate possible associations of such differences with acute and late skin/mucosal toxicity and anorectal function. MATERIALS: Thirty-one patients with localized anal carcinoma underwent in vivo measurements during the first EBRT session. Themoluminescent dosimeters (TLD) were placed at the center of the anal verge according to a localization protocol. No bolus was used. Patients received a median dose of 39.6 Gy (range: 36-45 Gy) by anteroposterior opposed AP/PA pelvic fields with 6 or 18 MV photons, followed by a median boost dose of 20 Gy (range: 13-24 Gy). Concomitant chemotherapy (CCT), consisting of 1-2 cycles of continuous infusion 5-fluorouracil (5-FU) and bolus mitomycin-C (MMC), was usually administered during the first weeks of the pelvic and boost EBRT courses. Acute and late skin/mucosal reactions were recorded according to the Radiation Therapy Oncology Group (RTOG) toxicity scale. Anal sphincter function was assessed using the Memorial Sloan Kettering Cancer Center (MSKCC) scale. RESULTS: TLD anal doses differed by a mean of 5.8% (SD: 5.8) in comparison to the central axis prescribed dose. Differences of at least 10% and at least 15% were observed in eight (26%) and three (9.7%) patients, respectively. TLD doses did not significantly correlate with acute or late grade 2-3 skin or mucosal toxicity. However, patients having good-fair MSKCC anal function had a significantly greater mean difference in anal TLD dose (10.5%, SD: 5.9) than patients having excellent function (3.8%, SD: 4.6) (P = 0.004). Prescribed dose values, length of follow-up, and age at diagnosis did not correlate with late sphincter function. CONCLUSIONS: These data show that AP/PA fields using megavoltage photons deliver adequate dose to the anal verge. However, in about one quarter of patients treated with this technique the anal dose varied from the prescribed dose by at least 10%. The observed correlation of TLD values and late sphincter function suggests that direct measurement of the dose delivered to the anal verge might be clinically relevant.

Adult↗
PubMed2003

Targeted gene delivery into HepG2 cells using complexes containing DNA, cationized asialoorosomucoid and activated cationic liposomes.

Unilamellar activated cationic liposomes containing 3beta[N-(N',N'-dimethylaminopropane)-carbamoyl] cholesterol, dioleoyl phosphatidylethanolamine (DOPE) and the N-hydroxysuccinimide ester of cholesteryl hemisuccinate (4:5:1, molar ratio) have been prepared and their DNA-binding capacity has been assessed in a gel retardation assay. Ternary complexes composed of activated cationic liposomes, carbodiimide-cationized asialoorosomucoid (Me+AOM) and pRSVL plasmid DNA were assembled for receptor-mediated DNA delivery into cells expressing the asialoglycoprotein receptor (ASGP-R). Binding of complexes in which Me+AOM was replaced by fluoresceinated Me+AOM (FMe+AOM) to the human hepatocellular cell line HepG2 at 4 degrees C was severely reduced by co-incubation with asialoorosomucoid (AOM). Moreover, assemblies containing liposomes, pRSVL DNA and Me+AOM (8:1:4, w/w/w) promoted high levels of luciferase activity in this cell line (1.3 x 10(7) relative light units/mg soluble cell protein). Assays conducted in the presence of a hundred-fold excess of the ligand AOM afforded considerably lower levels of transfection (2.5 x 10(5) relative light units/mg soluble cell protein). In contrast, the highest level of luciferase activity achieved with liposome, pRSVL DNA, AOM complexes was only a quarter of the best levels obtained with liposome, pRSVL DNA, Me+AOM assemblies. These findings strongly support the notion that complexes gain entry into hepatocyte-derived cells by ASGP-R mediation and that they are potentially useful gene carriers to liver hepatocytes.

Asialoglycoprotein Receptor↗
PubMed2001

Targeted drug delivery systems 6: Intracellular bioreductive activation, uptake and transport of an anticancer drug delivery system across intestinal Caco-2 cell monolayers.

We demonstrate transport across, intracellular accumulation and bioreductive activation of a conformationally constrained, anticancer drug delivery system (the CH(3)-TDDS) using Caco-2 cell monolayers (CCMs) as an in vitro model of the human intestinal mucosa. Reverse-phase High Performance Liquid Chromatography (HPLC) coupled with UV detection was used to detect CH(3)-TDDS, the bioreduction product (lactone) and the released drug (melphalan methyl ester; MME). Upon incubation of the CH(3)-TDDS with the apical (AP) surface of 21-day-old CCM, we observed rapid decrease in the AP concentration of the CH(3)-TDDS (60%/hr) as a result of cellular uptake. Rapid intracellular accumulation of the CH(3)-TDDS was followed by bioreductive activation to deplete the cellular levels of CH(3)-TDDS. The drug part (MME) and lactone, as well as CH(3)-TDDS, were detected in the basolateral (BL) chamber. Intracellular Caco-2 levels of TDDS and lactone were also detectable. Bioreductive activation of the CH(3)-TDDS was additionally confirmed by formation of lactone after incubation of the CH(3)-TDDS in the presence of freshly prepared Caco-2 cell homogenates. During transport studies of melphalan or MME alone (as control), the intact drug was not detected in the intracellular compartment or in the BL chamber. These observations demonstrate that CH(3)-TDDS has potential for improving intestinal delivery of MME. TDDS could be useful in facilitating oral absorption of MME as well as the oral delivery of other agents.

Antineoplastic Agents↗
PubMed2002

Synthesis of cholesterol-carborane conjugate for targeted drug delivery.

The cholesterol-carborane conjugate has been designed and synthesized to selectively deliver boron to tumor cells by means of reconstituted low-density lipoprotein. The chemical stability and cytotoxicity of the new compound have been examined. Several methods have been evaluated for incorporation of the compound into LDL.

Antineoplastic Agents↗