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At least 703 records · Page 39Linked to original sources

PubMed2003

Cytoplasmic delivery and nuclear targeting of synthetic macromolecules.

Delivery of macromolecular drugs (e.g. antisense oligonucleotides, polymer-drug conjugates, etc.) designed to work in specific sites inside cells is complicated as macromolecules typically have access to fewer biological compartments than small molecules. To better understand the fate of macromolecules in cells and begin to alter that fate, we investigated the internalization and subcellular fate of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers and HPMA copolymer-drug conjugates in Hep G2 and A2780 cells. The subcellular fate of fluorescently labeled polymers was monitored by confocal microscopy and subcellular fractionation. Initially, the HPMA copolymers and HPMA copolymer-drug conjugates were internalized by endocytosis and remained in endosomes/lysosomes. At longer incubation times (>8 h), small amounts of the HPMA copolymers were observed to enter the cytoplasm and accumulate in the nucleus of the cells. Nuclear accumulation was confirmed after cytoplasmic microinjection. Oligonucleotides conjugated via lysosomally degradable spacers entered into the cytoplasm and nucleus of the cells faster than the polymers. The effect of the subcellular location was correlated to the toxicity of the photosensitizer, mesochlorin e(6) (Mce(6))-HPMA copolymer conjugates. The plasma membrane and late endosomes were more sensitive to damage by Mce(6). Targeting the polymer conjugates to the nucleus with the nuclear localization sequence (NLS) as well as conjugating the Mce(6) via a degradable spacer increased cell adhesion and uptake, promoted their entry into the cytoplasm and nucleus of the cells, and increased their toxicity. To further promote entry of the polymers into the cytoplasm and nucleus of the cells, the protein transduction domain, Tat peptide, was conjugated to the HPMA copolymers. This resulted in high binding to the cell membrane, but also facilitated rapid (<5 min) entry of the macromolecules into the cytoplasm and nucleus of cells. These results will prove valuable in the future design of macromolecular therapeutics.

Animals↗

PubMed2002

The use of chemically modified cyclodextrins in the development of formulations for chemical delivery systems.

Retrometabolic drug design provides a highly useful and directed approach for identifying new drug candidates with improved therapeutic indices based on predictable/controlled metabolism and/or site-targeted delivery. In the process, formulation becomes an important and integral concern especially for brain-targeting chemical delivery systems (CDS) based on the need for appropriate dosage form stability, solubility and dissolution characteristics. Adjuncts that have been useful in this regard are chemically modified, water soluble cyclodextrin derivatives such a 2-hydroxypropyl-beta-cyclodextrin (HP beta CD). These starch-derived excipients can interact with drugs via dynamic complex formation resulting in a number of beneficial pharmaceutical effects including increased apparent water solubility and stability as well as improved aesthetic and excipient compatibility properties. This cyclodextrin is approved in a number of product in the US and world-wide. HP beta CD has contributed to the development and preclinical/clinical testing of a number of CDS including E2 (estradiol)-CDS, AZT (zidovudine)-CDS, DEX (dexamethasone)-CDS and a neuropeptide CDS based on an enkephalin derivative. In these contexts, HP beta CD provided for stable and water-soluble dosage forms intended for parenteral administration.

Cyclodextrins↗

PubMed2004

Tumour-selective drug delivery via folate receptor-targeted liposomes.

Tumour cell-targeted liposomal delivery has the potential to enhance the therapeutic efficacy and reduce the toxicity of anticancer agents. Folate receptor (FR) expression is frequently amplified among human malignancies. FR is, therefore, potentially useful as a tumour marker for targeted drug delivery. FR-mediated liposomal delivery has been shown to enhance the antitumour efficacy of doxorubicin both in vitro and in vivo, and to overcome P-glycoprotein-mediated multi-drug resistance. In addition, FR-targeted liposomes have shown utility as effective delivery vehicles of genes and antisense oligodeoxyribonucleotides to FR(+) tumour cells. Both solid tumours and leukaemias can potentially benefit from FR-targeted drug delivery. Multiple mechanisms might contribute to greater therapeutic efficacy for FR-targeted liposomes, such as FR-dependent cytotoxicity and antiangiogenic activity. Further investigation of this promising drug delivery strategy is clearly warranted.

Antineoplastic Agents↗

PubMed2003

A multi-domain protein system based on the HC fragment of tetanus toxin for targeting DNA to neuronal cells.

One goal of gene therapy is the targeted delivery of therapeutic genes to defined tissues. One attractive target is the central nervous system as there are several neuronal degenerative diseases which may be amenable to gene therapy. At present there is a lack of delivery systems that are able to target genes specifically to neuronal cells. Multi-domain proteins were designed and constructed to facilitate the delivery of exogenous genes to neuronal cells. Neuronal targeting activity of the proteins was achieved by inclusion of the HC fragment of tetanus toxin (TeNT), a protein with well-characterised tropism for the central nervous system. The yeast Gal4 DNA-binding domain enabled specific binding of DNA while the translocation domain from diphtheria toxin (DT) was included to facilitate crossing of the endosomal vesicle. One multi-domain protein, containing all three of these domains, was found to transfect up to 8% of neuroblastoma N18-RE105 cells with marker genes. Monitoring the transfection by confocal microscopy indicated that this protein-DNA transfection complex is to some extent localised at the cell surface, suggesting that further improvements to translocating this membrane barrier may yield higher transfection levels. The demonstration that this multi-domain protein can target genes specifically to neuronal cells is a first step in the development of novel vectors for the delivery of genes with therapeutic potential to diseased neuronal tissues.

Animals↗

PubMed2004

Assembly of targeting complexes driven by a single-chain antibody.

Rapid development in design and production of recombinant antibodies and antibody fragments specific for cell surface markers opens new opportunities for targeted delivery of therapeutic or imaging agents. However, the progress in this field is slowed by inactivation of many antibodies by chemical conjugation of payloads and by lack of internalization of complexes formed on the cell surface. Here, we describe conversion of a non-internalizing single chain Fv (scFv) antibody P4G7 specific for vascular endothelial growth factor receptor 2 (VEGFR-2) into a targeting protein (Hu-P4G7) for assembly of a novel type of targeting complexes. Hu-P4G7 contains an N-terminal "docking" Hu-tag, a 15-aa fragment of human RNase I, capable of high affinity binding of S-protein fragment of human RNase I or bovine RNase A. Purified Hu-P4G7 and complexes of Hu-P4G7 with S-protein bind both soluble and full-length cellular VEGFR-2. To assemble targeted DNA delivery complexes, S-protein modified with a DNA condensing agent was "docked" to Hu-P4G7, and then loaded with luciferase plasmid DNA. As expected for a non-internalizing targeting protein, Hu-P4G7-based complexes did not deliver DNA in VEGFR-2 expressing cells. However, in the presence of vascular endothelial growth factor (VEGF), these complexes selectively delivered DNA into the cells overexpressing VEGFR-2 suggesting that even a non-internalizing scFv antibody can be used for targeted intracellular drug delivery.

Animals↗

PubMed2004

Targeted photodynamic therapy via receptor mediated delivery systems.

Targeted photodynamic therapy (PDT) offers the opportunity of enhancing photodynamic efficiency by directly targeting diseased cells and tissues. While antibody-conjugates have received the most attention, cellular transformations offer numerous other potent targets to exploit during the delivery of photosensitizers (PSs) for PDT. Alterations in receptor expression, increased levels of specific cell surface membrane lipids and proteins as well as changes in the cellular microenvironment all occur in diseased cells. Along with other biochemical and physiological changes that occur during diseased and malignant cell transformation, these factors have been utilized in order to improve the efficacy of PDT. Attempts have been made to either increase the uptake of the dye by the target cells and tissues or to improve subcellular localization so as to deliver the dye to photosensitive sites within the cells. This review discusses various PS bioconjugates that utilize these factors and summarizes the results obtained to date.

Blood Proteins↗

PubMed2026

Treatment of spinal injury muscle spasticity by spinal subpial AAV9-GAD65/VGAT delivery: An efficacy and safety study in rat, pig, and NHP.

The loss in segmental inhibitory GABAergic tone plays the key role in the development of spinal injury-induced muscle spasticity. We use a subpial segment-targeted delivery of adeno-associated virus vector(s) expressing GAD65 (glutamic acid decarboxylase-65) and VGAT (vesicular GABA transporter) transgenes in rats with spinal transection-induced spasticity. In treated animals, a significant suppression in spasticity was seen at 5-8 weeks after treatment. Naive rats, pigs, and non-human primates (NHPs) injected with human equivalent dose of treatment vectors and surviving for 3 weeks to 4.5 years showed normal motor function and pinch-evoked response. A significant increase in the number of VGLUT2 terminals co-expressing GAD65 and VGAT protein in vector-injected segment was seen. This corresponded with the presence of transgene-specific rat Gad2 or human GAD2 and rat Slc32a1 or human SLC32A1 mRNA signal. No spinal toxicity was noted in NHPs at 4.5 years post vector delivery. Analysis of peripheral organs (liver, spleen, and skeletal muscle) showed minimal or no detectable transgenes in pigs and NHPs. These data demonstrate that a single-time-point spinal-segment-targeted subpial delivery of GAD65/VGAT transgenes is effective in suppressing spinal injury-induced spasticity and has a favorable long-term safety profile as defined by normal neurological function and histopathology in naive pigs and NHPs.

Animals↗

PubMed1989

Targeted and sustained delivery of aclarubicin to lymphatics by lactic acid-oligomer microsphere in rat.

We examined targeted delivery of an anticancer drug, aclarubicin (ACR), to the lymphatic system in rats by encapsulation of the drug in microsphere (MS) prepared from nontoxic and biodegradable L-lactic acid-oligomer with an average molecular weight (Mw) of 3600. ACR was released at an almost constant rate from two kinds of ACR-MSs having different size (1-5 microns and less than 1 micron) over 20 d in phosphate-buffered saline at 37 degrees C. The intraperitoneal administration of both ACR-MSs (dose of ACR; 5 mg/kg) to rats sustained an almost constant ACR level (300-400 and 400-600 ng/ml) in the lymph of the thoracic duct during over 10 d, and the ACR level in the blood was extremely low, although intraperitoneal injection of ACR alone gave lower level of ACR in the lymph than in the blood level within 12 h.

Aclarubicin↗

PubMed2002

Targeted retrograde gene delivery for neuronal protection.

The cellular heterogeneity and complex circuitry of the central nervous system make it difficult to achieve precise delivery of experimental and therapeutic agents. We report here an in vivo retrograde gene delivery strategy to target mature projection neurons using adeno-associated virus, a vector with low toxicity and the capacity for long-term gene expression. Viral delivery to axon terminal fields in the hippocampus and striatum resulted in viral internalization, retrograde transport, and transgene expression in specific projection neurons in entorhinal cortex and substantia nigra. Retrograde delivery of the anti-apoptotic gene Bcl2l (also known as Bcl-xL) protected entorhinal projection neurons from subsequent damage-induced cell death. Given the broad distribution of neurons affected by neurodegenerative diseases, gene delivery to both the terminal fields and the projection neurons through retrograde infection provides for strategic therapeutic intervention at both levels of the neural circuit. This approach may also facilitate experimental studies of defined neural circuits.

Animals↗

PubMed2003

Systemic peptide delivery via the stomach: in vivo evaluation of an oral dosage form for salmon calcitonin.

It was the aim of this study to investigate the potential of stomach targeted delivery systems for systemic peptide administration using salmon calcitonin as a model drug. Chitosan was modified by the immobilization of thiol groups utilizing 2-iminothiolane in order to obtain a chitosan-4-thiobutylamidine conjugate (chitosan-TBA). Furthermore, a chitosan-pepstatin A conjugate was synthesized by a carbodiimide mediated linkage of the pepsin inhibitor to the polymer. The protective effect of this novel conjugate for calcitonin towards pepsin was evaluated in vitro. Minitablets (5 mg) were generated by direct compression of calcitonin, chitosan, chitosan-TBA, chitosan-pepstatin A conjugate and glutathione (GSH), respectively (A, 1:0:69:20:10; B, 1:79:0:20:0; C, 1:99:0:0:0). The drug release was investigated in an artificial gastric fluid. Biofeedback studies were performed in rats by determining the decrease in plasma calcium level after oral administration. The novel chitosan-pepstatin A conjugate displayed 291+/-58 nmol inhibitor per gram polymer (mean+/-S.D., n = 5). The chitosan-inhibitor conjugate showed a very strong protective effect for salmon calcitonin towards pepsinic degradation. A controlled drug release was provided by all tested dosage forms-A, B and C. Dosage form B led only to a slight reduction of the plasma calcium level, displaying a pharmacological efficacy versus i.v. injection of 0.41%, while dosage form C did not lead to any significant effect. In contrast, dosage form A led to a decrease in the plasma calcium level of 10% for at least 12 h. The pharmacological efficacy of this formulation was determined to be 1.35%. The study suggests that stomach targeted oral delivery might be a promising novel approach for noninvasive systemic peptide administration.

Administration, Oral↗

PubMed2000

Receptor-mediated targeting of gene delivery vectors: insights from molecular mechanisms for improved vehicle design.

One way to deliver transgenes to cells in a selective manner is to target the delivery vehicles, or vectors, to specific cell-surface receptors as a first step toward ultimate transport of the gene to the nucleus for expression. While selective delivery, although often to undesired cell types, occurs naturally for some viral vectors and can be achieved for nonviral vehicles, current understanding and control of the delivery mechanism is inadequate for many therapeutic applications. The complicated nature of receptor-mediated transgene uptake and transport requires improved analysis to more effectively evaluate delivery vehicles. As receptor-mediated pathways for gene delivery typically involve vector binding, internalization, subcellular trafficking, vesicular escape, nuclear translocation, and unpackaging for transcription, each of these processes offer mechanisms that can be exploited to enhance targeted gene delivery via properly designed vehicles. For the purpose of this review, current targeted gene delivery vehicles are divided into three approaches: viral, synthetic, and hybrid vectors. Each approach possesses advantages as well as disadvantages at the present time for in vitro and in vivo application, and provides particular challenges to overcome in order to gain significantly improved targeted delivery properties. Quantitative experiments and mathematical modeling of the gene delivery pathway will serve to provide insight into molecular mechanisms and rate-limiting steps for effective gene expression. Information on molecular mechanisms obtained by such methodologies can then be applied to specific vectors, whether viral, synthetic, or hybrid, allowing for the creation of targeted, effective, and safe gene therapeutics.

Animals↗

PubMed1999

Polymer conjugates for tumour targeting and intracytoplasmic delivery. The EPR effect as a common gateway?

Tumour capillaries are frequently hyperpermeable compared with normal vasculature, and thus they offer a much sought-after gateway for targeted delivery of cancer chemotherapy. Phase I clinical trials reported recently describe the first synthetic polymer-drug conjugate to be tested in man. N-(2-Hydroxypropyl)methacrylamide copolymer-doxorubicin (PK1, FCE 28068) displayed antitumour activity in chemotherapy-refractory patients, considerably reduced toxicity compared with doxorubicin, and evidence of tumour-selective targeting. With increasing understanding of the vector- and tumour-related factors that govern vascular permeability, non-viral vectors are being designed for tumour-selective targeting and subsequent intracytoplasmic delivery of macromolecular medicines such as genes, antisense oligonucleotides, proteins and peptides.

Journal Article↗

PubMed1990

A redox-based system that enhances delivery of estradiol to the brain: pharmacokinetic evaluation in the dog.

The pharmacokinetics of a dihydropyridine-pyridinium salt-type chemical delivery system (CDS) for brain-targeted delivery of estradiol (E2) were examined in dogs. Parameters evaluated in vitro included stability in buffers and biological fluids and plasma protein binding. In vivo studies examined drug and metabolite concentrations in plasma, urine, and cerebrospinal fluid as well as in selected brain regions. The administered lipophilic E2-CDS disappeared very quickly from plasma and was not detected in urine. The oxidized drug form, E2-Q+, was excreted unchanged or as a conjugate in the urine for as long as 2 weeks. Plasma levels were below assay detection limits at later times. Pharmacokinetic analysis of urine E2-Q+ levels allowed estimation of a half-life of 2.2 days. Amounts of E2-Q+ excreted into the urine were proportional to the dose but averaged only 13.9% of the dose, indicating that other routes of excretion must be considered. CSF levels were below the limit of detection for both E2-CDS and E2-Q+, however, brain tissue concentrations of E2-Q+ were similar in several brain regions of individual animals examined 1 or 3 days after drug dosing.

Animals↗

PubMedDate not supplied

Targeting of drugs and vaccines to the gut.

Targeted delivery to the gastrointestinal tract requires a multi-disciplinary approach to research involving contributions from polymer and material scientists, gastroenterologists, pharmaceutical scientists and technologists. Intestinal delivery is important not only for drugs that act locally, but also for those with systemic activity. In particular, there is considerable interest in the oral delivery of peptides and it is felt that the colon may provide an advantageous absorption site for such molecules. The different targeting mechanisms available to the pharmaceutical scientist to provide site-specific delivery in the gastrointestinal tract will be critically assessed. Delivery systems and targeting agents, which are being developed for the delivery of drugs, may also be exploited for the delivery of vaccines, since many of the delivery problems are common to both areas. Recent developments in the design of oral antigen formulations will be discussed in this review.

Administration, Oral↗

PubMed2000

Targeted synthetic gene delivery vectors.

Synthetic gene delivery vehicles have made significant progress in the past decade in demonstrating strong potential for targeted delivery to specific cells, low toxicity and immunogenicity and large carrying capacity. However, significant advances must still be made to increase the efficiency of both polymer and lipid vehicles. Furthermore, techniques to generate more effective targeting moieties for a variety of cell types, as well as means to consistently assemble vectors containing these targeting ligands, are areas for further improvement. This review focuses on significant recent advances in generating a number of novel targeted vectors, and discusses progress in the development of new genetic and chemical systems to enhance the targeting, assembly and biocompatibility of synthetic vectors.

Animals↗

PubMed2003

Current strategies and future directions of antiangiogenic tumor therapy.

Neovascularization is a prerequisite for progressive growth of most tumors and their metastases. Therefore, inhibition of angiogenesis could be one of the most promising strategies that might lead to the development of novel anticancer therapy. New blood vessels forming in tumors can be avoided by interfering the process of angiogenesis through suppressing the proangiogenic signal or augmenting the antiangiogenic factors. Concentrated efforts in this area have lead to the discovery of many proangiogenic factors as well as their inhibitors, and antiangiogenic factors. For the established tumor vasculature, tumor vasculature-targeted delivery of antiangiogenic substances and endothelial cell vaccines has been explored. Although some antiangiogenic drugs are currently in clinical development, for future reason, more efficient therapeutic methods, including antiangiogenic gene therapy strategy, targeted drug delivery system, and the combination of antiangiogenic agents with immunotherapy, chemotherapy or radiotherapy are being explored. With the development of tumor model assessment system, clinical use of the above antiangiogenic tumor therapy methods could be achieved.

Angiogenesis Inhibitors↗

PubMedDate not supplied

Polycefin, a new prototype of a multifunctional nanoconjugate based on poly(beta-L-malic acid) for drug delivery.

A new prototype of nanoconjugate, Polycefin, was synthesized for targeted delivery of antisense oligonucleotides and monoclonal antibodies to brain tumors. The macromolecular carrier contains: 1. biodegradable, nonimmunogenic, nontoxic beta-poly(L-malic acid) of microbial origin; 2. Morpholino antisense oligonucleotides targeting laminin alpha4 and beta1 chains of laminin-8, which is specifically overexpressed in glial brain tumors; 3. monoclonal anti-transferrin receptor antibody for specific tissue targeting; 4. oligonucleotide releasing disulfide units; 5. L-valine containing, pH-sensitive membrane disrupting unit(s), 6. protective poly(ethylene glycol); 7. a fluorescent dye (optional). Highly purified modules were conjugated directly with N-hydroxysuccinimidyl ester-activated beta-poly(L-malic acid) at pendant carboxyl groups or at thiol containing spacers via thioether and disulfide bonds. Products were chemically validated by physical, chemical, and functional tests. In vitro experiments using two human glioma cell lines U87MG and T98G demonstrated that Polycefin was delivered into the tumor cells by a receptor-mediated endocytosis mechanism and was able to inhibit the synthesis of laminin-8 alpha4 and beta1 chains at the same time. Inhibition of laminin-8 expression was in agreement with the designed endosomal membrane disruption and drug releasing activity. In vivo imaging showed the accumulation of intravenously injected Polycefin in brain tumor tissue via the antibody-targeted transferrin receptor-mediated endosomal pathway in addition to a less efficient mechanism known for high molecular mass biopolymers as enhanced permeability and retention effect. Polycefin was nontoxic to normal and tumor astrocytes in a wide range of concentrations, accumulated in brain tumor, and could be used for specific targeting of several biomarkers simultaneously.

Animals↗

PubMed2004

Targeted nucleic acid delivery into tumors: new avenues for cancer therapy.

Unique properties of tumors, such as abnormalities in the cell cycle and apoptosis, migration and metastasis, neoangiogenesis or unique antigen profiles are targets for therapeutic anti-cancer strategies. Beyond the selection of such strategies, additional specificity for the targeted tumor tissue can be accomplished in cancer gene therapy in several ways. Upon systemic administration, appropriately packaged therapeutic nucleic acid may be preferentially transported into the tumor tissue (targeted delivery); formulation can mediate the intracellular uptake of the nucleic acid into the nucleus of target cells only (transductional targeting); and/or the use of specific promotor/enhancer elements can restrict transcription of therapeutic genes to the target cells only (transcriptional targeting). Options for physical and biological targeting of nucleic acid formulations into tumors and therapeutic approaches are reviewed.

Animals↗