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At least 163 records · Page 9Linked to original sources
PubMed1997

Development of targeted delivery systems for nucleic acid drugs.

Our increased understanding of disease pathogenesis is the basis for developing novel nucleic acid drugs. The main challenge encountered in this development is how to maintain therapeutically meaningful concentrations of the drugs in the vicinity of their targets for the desired periods. The intrinsic difficulty arises from the fact that nucleic acid drugs are not readily transported across membranes. Hence, their delivery and transport characteristics at the whole body, organ and cellular levels need to be thoroughly examined. Liposomes and receptor-mediated polycation systems are promising carriers for their delivery in vivo. There are many barriers to be overcome for successful antisense and gene therapies. Along with other factors, disposition, stability against nucleases, binding to cell surface receptor and internalization, and intracellular trafficking affect the in vivo delivery and efficacy of nucleic acid drugs. This review article discusses the delivery and transport of these compounds.

Animals↗
PubMed2001

Water soluble polymers in tumor targeted delivery.

The rationales for the use of water soluble polymers for anticancer drug delivery include: the potential to overcome some forms of multidrug resistance, preferential accumulation in solid tumors due to enhanced permeability and retention (EPR) effect, biorecognizability, and targetability. The utility of a novel paradigm for the treatment of ovarian carcinoma in an experimental animal model, which combines chemotherapy and photodynamic therapy with polymer-bound anticancer drugs is explained. Research and clinical applications as well as directions for the future development of macromolecular therapeutics are discussed.

Animals↗
PubMed2000

Isothiocyanate-trigalactose: application for antibody-targeted delivery of diagnostic and therapeutic agents.

Radiolabeled monoclonal antibodies (MAb) and MAb-streptavidin conjugates exhibit slow blood clearance which impedes radioimmunoimaging and radioimmunotherapy. To control blood clearance and lower background levels, lesion-specific targeting proteins can be modified with galactose derivatives for liver uptake via the hepatocyte galactose receptor. In this study, an isothiocyanate-trigalactose derivative (ITC-Tgal) designed for direct coupling to protein amino groups, was synthesized and characterized. In vitro experimentation demonstrated efficient conjugation of ITC-Tgal to streptavidin (SA) and MAb Fab fragment with a corresponding decrease in protein net charge. In vivo studies were conducted with radiolabeled ITC-Tgal modified and native SA and MAb Fab fragment. ITC-Tgal modified SA and Fab fragment exhibited increased blood clearance with the liver uptake and the rate of blood clearance controlled by the extent of ITC-Tgal modification.

Animals↗
PubMed1993

Targeted delivery of a heme oxygenase inhibitor with a lyophilized liposomal tin mesoporphyrin formulation.

Tin mesoporphyrin (SnMP) is a competitive inhibitor of heme oxygenase being examined clinically for the treatment of hyperbilirubinemia. Since liposomes have been shown to target SnMP to the spleen and increase its efficacy (S. A. Landaw, G. S. Drummond, and A. Kappas, Pediatrics 84, 1091-1096, 1989), we began investigating the feasibility of the preparation and scaleup of a liposomal SnMP formulation for clinical use. SnMP liposomes were prepared by high-pressure homogenization of a suspension of SnMP and egg phosphatidylcholine (1:20, w/w) in lactose-phosphate buffer, resulting in SnMP liposomes that were less than 200 nm in diameter and had encapsulation efficiencies of up to 90% at pH 5. The SnMP liposomes could be sterile filtered and lyophilized in a 1-day cycle with retention of the encapsulation efficiency and particle size. Following injection into rats, the distribution of liposomal SnMP to spleen at 2 and 6 hr after dosing was 5-20 times higher than for aqueous SnMP. Lyophilized SnMP liposomes were also more effective than aqueous SnMP in decreasing bilirubin production in bile-cannulated rats. The results suggest the potential for producing a safe, sterile, and effective lyophilized formulation of SnMP liposomes for targeting of heme oxygenase inhibitors to the spleen.

Animals↗
PubMed1998

Targeted delivery of DNA encoding cytotoxic proteins through high-affinity fibroblast growth factor receptors.

Nonviral DNA delivery strategies for gene therapy have generally been limited by a lack of specificity and efficacy. However, ligand-mediated endocytosis can specifically deliver DNA in vitro to cells bearing the appropriate cognate receptors. Similarly, in order to circumvent problems related to efficacy, DNA must encode proteins with high intrinsic activities. We show here that the ligand basic fibroblast growth factor (FGF2) can target FGF receptor-bearing cells with DNA encoding therapeutic proteins. Delivery of genes encoding saporin, a highly potent ribosomal inactivating protein, or the conditionally cytotoxic herpes simplex virus thymidine kinase, a protein that can kill cells by activating the prodrug ganciclovir, is demonstrated. The saporin gene was codon optimized for mammalian expression and demonstrated to express functional protein in a cell-free assay. FGF2-mediated delivery of saporin DNA or thymidine kinase DNA followed by ganciclovir treatment resulted in a 60 and 75% decrease in cell number, respectively. Specificity of gene delivery was demonstrated in competition assays with free FGF2 or with recombinant soluble FGF receptor. Alternatively, when histone H1, a ligand that binds to cell surface heparan sulfate proteoglycans ("low-affinity" FGF receptors), was used to deliver DNA encoding thymidine kinase, no ganciclovir sensitivity was observed. These findings establish the feasibility of using ligands such as FGF2 to specifically deliver genes encoding molecular chemotherapeutic agents to cells.

Amino Acid Sequence↗
PubMed2005

Essential properties of drug-targeting delivery systems.

How, if at all, can drug delivery help to create ideal drugs? After four decades of trying, an effective site-specific drug-delivery system has not yet been developed. This review draws attention to the pharmacokinetic conditions that must be met to achieve a successful performance by site-selective drug-carrier delivery systems. In a drug-carrier approach, a drug is attached to a macromolecular carrier via a chemically labile linker. The carrier transports the drug to its site of action and releases it at the target site. For this simple approach to work, several fundamental conditions (nonspecific interactions, target site access, drug release and drug suitability) must be satisfied. The importance of these essential requirements, not always recognized in the development of drug-delivery systems, is discussed and illustrated by recent examples selected from the literature.

Animals↗
PubMed2006

PEGylated J591 mAb loaded in PLGA-PEG-PLGA tri-block copolymer for targeted delivery: in vitro evaluation in human prostate cancer cells.

J591 monoclonal antibody (mAb) has high affinity for prostate specific membrane antigen (PSMA) on prostate cancer (PCA) cells. We coupled polyethylene glycol-J591 (PEGylated J591) to a salicyl hydroxamic acid (SHA)-derivatized polyethylenimine (PEI)/DNA-betagal vector to investigate the specificity and efficiency of targeting PSMA in PCA cells through encapsulation. Coupling was facilitated via the high affinity interaction between phenyl(di)boronic acid (PDBA) and SHA molecules yielding J591/PEG/PEI/DNA-betagal polyplex. After encapsulation with poly(d,l-lactic-co-glycolic acid)-b-polyethylene glycol-b-poly(d,l-lactic-co-glycolic acid) (PLGA-PEG-PLGA) tri-block copolymer, 8-10-fold increment of gene transfection levels were attained at the optimum concentration of 0.25% (w/v) using Pluronic F68 tri-block copolymer as a control. The enhanced transfection efficiency was attributed to increased internalization and uptake of the radiolabeled plasmid in the presence of PLGA-PEG-PLGA tri-block copolymer. The release of plasmid DNA (pDNA) from microparticles containing SHA-PEI-complexed pDNA showed little initial burst release followed by a 5% release over 48 h. The release accelerated thereafter and approximately 60% was released after 28 days. Deconvolution confocal microscopy showed polyplex/microparticle formulation localized in the cell nucleus as opposed to the polyplex without PLGA-PEG-PLGA indicating that an optimal concentration of PLGA-PEG-PLGA tri-block copolymer can be utilized to enhance endocytic process of J591-mediated targeting of PCA cells.

Antibodies, Monoclonal↗
PubMed2003

Targeted delivery of human pro-apoptotic enzymes to tumor cells: In vitro studies describing a novel class of recombinant highly cytotoxic agents.

The serine protease granzyme B (GrB, 25 kDa) can initiate apoptosis by multiple mechanisms including directly activating caspases, inducing DNA fragmentation, activating the mitochondrial death pathway, and directly cleaving the nuclear matrix. The purpose of this study was to determine whether a recombinant antibody could deliver sufficient amounts of GrB to target cells to generate an apoptotic signal. The gene sequence encoding GrB was attached to the single-chain anti-melanoma antibody scFvMEL (anti-gp240) via a flexible (G(4)S) tether. The 53-kDa GrB/scFvMEL fusion protein was expressed in bacteria and purified by metal affinity chromatography. Western blotting confirmed presence of both scFvMEL and GrB proteins. The fusion construct displayed intact GrB enzymatic activity (specific activity = 2.6 x 10(5) units/ micro mol) similar to native GrB (specific activity = 4.8 x 10(5) units/ micro mol). The construct bound specifically to human A375-M melanoma cells and delivered GrB to the cytosol as assessed by confocal microscopy. Against log-phase melanoma cells, GrB/scFvMEL demonstrated an IC(50) of 20 nM and minimal cytotoxicity to non-target cells at doses of up to 1 micro M. Coadministration of exogenous perforin (PFN) to cells resulted in a slight increase in the cytotoxic effects of the GrB/scFvMEL construct on A375 target cells and a significant increase in cytotoxicity to SKBR3 (non-target) cells. The cytotoxic effects of this fusion construct on target cells were similar to those of the previously described MEL sFv/rGel fusion toxin (IC(50) approximately 20 nM). The construct produced impressive apoptotic effects by 8 h after treatment of target cells. Mediation of the apoptotic effects of GrB/scFvMEL included caspase-3 cleavage and release of cytochrome c into the cytosolic compartment from the mitochondrial compartment. These studies demonstrate that delivery of the human pro-apoptotic pathway enzyme GrB to tumor cells may have significant therapeutic potential for cancer treatment and represents a new class of targeted therapeutic agents with a defined mechanism of action.

Antineoplastic Agents↗
PubMed2003

Targeted delivery of DNA to the mitochondrial compartment via import sequence-conjugated peptide nucleic acid.

We report that oligonucleotides can be introduced into the mitochondria of living mammalian cells by annealing them to peptide nucleic acids coupled to mitochondrial targeting peptides. These complexes are imported into the mitochondrial matrix through the outer and inner membrane import channels of isolated mitochondria. They are also imported into the mitochondria of cultured cells, provided that the cytosolic uptake of the complexes is facilitated by using synthetic polycations or membrane permeabilizing toxins. Our method now promises to provide a viable strategy for the genetic modification of the mitochondria in cultured cells, animals and patients.

Animals↗
PubMed1996

Targeted delivery of doxorubicin via sterically stabilized immunoliposomes: pharmacokinetics and biodistribution in tumor-bearing mice.

PURPOSE: To evaluate benefits in tumor localization, availability, and noncancerous organ distribution of doxorubicin (DOX) delivered via small (< or = 120 nm) sterically stabilized immunoliposomes targeted against a tumor-associated antigen in fibrosarcoma-bearing mice. METHODS: DOX-loaded liposomes were prepared with (i) specific monoclonal IgG3 antibody (32/2, D-SSIL-32/2); (ii) non-specific IgG3 (D-SSIL-IgG); or (iii) no IgG (D-SSL) on their surface. Equal DOX amounts were injected intravenously via each type of liposome into BALB/c mice carrying experimental lung metastases of a polyoma virus-induced fibrosarcoma (A9 ctc 220) expressing a polyoma virus-induced tumor-associated antigen (PAA) on their surface. Metastases occurred mainly in lung. Mice were treated at 3 stages of tumor development (micrometastases, medium-size metastases, and large, necrotic metastases). Performance evaluation was based on time-dependent quantification of DOX and DOX metabolites (DOX-M) in lung tumor, noncancerous organs, and plasma. RESULTS: (i) DOX delivered via both SSIL retained the prolonged circulation time typical of DOX delivered via D-SSL. (ii) DOX accumulation in noncancerous organs was similar for all preparations. Low levels of DOX-M were obtained for all three preparations in all organs except liver, suggesting a similar processing. (iii) Preparations differed in behavior in lung tumor depending on tumor size and microanatomy. Only at the micrometastases stage were the specifically targeted D-SSIL-32/2 superior to D-SSL and D-SSIL-IgG, delivering 2-4 times more drug into the tumor. (iv) DOX-M level in all three tumor stages was in the following order: D-SSIL-32/2 > > D-SSL > > D-SSIL-IgG, suggesting that DOX delivered as D-SSIL-32/2 is most available to tumor cells. CONCLUSIONS: The advantage of specific targeting of sterically stabilized liposomes is expressed mainly in increasing availability of DOX to tumor cells in a way which is dependent on tumor microanatomy. The impact of this advantage to therapeutic efficacy remains to be determined.

Animals↗
PubMed2003

Ocular drug delivery targeting the retina and retinal pigment epithelium using polylactide nanoparticles.

PURPOSE: To study the kinetics of polylactide (PLA) nanoparticle (NP) localization within the intraocular tissues and to evaluate their potential to release encapsulated material. METHODS: A single intravitreous injection (5 micro L) of an NP suspension (2.2 mg/mL) encapsulating either Rh-6G (Rh) or Nile red (Nr) was performed. Animals were killed at various times, and the NPs localization within the intraocular tissues was studied by environmental scanning electron microscopy (ESEM), confocal microscopy, light microscopy histology, fluorescence microscopy, and immunohistochemistry. Eyes injected with blank NPs, free Rh, or PBS solution were used as the control. RESULTS: ESEM showed the flow of the NPs from the site of injection into the vitreous cavity and their rapid settling on the internal limiting membrane. Histology demonstrated the anatomic integrity of the injected eyes and showed no toxic effects. A mild inflammatory cell infiltrate was observed in the ciliary body 6 hours after the injection and in the posterior vitreous and retina at 18 to 24 hours. The intensity of inflammation decreased markedly by 48 hours. Confocal and fluorescence microscopy and immunohistochemistry showed that a transretinal movement of the NPs was gradually taking place with a later localization in the RPE cells. Rh encapsulated within the injected NPs diffused and stained the retina and RPE cells. PLA NPs were still present within the RPE cells 4 months after a single intravitreous injection. CONCLUSIONS: Intravitreous injection of PLA NPs appears to result in transretinal movement, with a preferential localization in the RPE cells. Encapsulated Rh diffuses from the NPs and stains the neuroretina and the RPE cells. The findings support the idea that specific targeting of these tissues is feasible. Furthermore, the presence of the NPs within the RPE cells 4 months after a single injection shows that a steady and continuous delivery of drugs can be achieved.

Animals↗
PubMed2004

Enhancement of the antiangiogenic activity of interleukin-12 by peptide targeted delivery of the cytokine to alphavbeta3 integrin.

We engineered a fusion protein, mrIL-12vp [mouse recombinant interleukin (IL)-12 linked to vascular peptide], linking the vascular homing peptide CDCRGDCFC (RGD-4C), a ligand for alphavbeta3 integrin, to mrIL-12 to target IL-12 directly to tumor neovasculature. The fusion protein stimulated IFN-gamma production in vitro and in vivo, indicating its biological activity was consistent with mrIL-12. Immunofluorescence techniques showed mrIL-12vp specifically bound to alphavbeta3 integrin-positive cells but not to alphavbeta3 integrin-negative cells. In corneal angiogenesis assays using BALB/c mice treated with either 0.5 microg/mouse/d of mrIL-12vp or mrIL-12 delivered by subcutaneous continuous infusion, mrIL-12vp inhibited corneal neovascularization by 67% compared with only a slight reduction (13%) in angiogenesis in the mrIL-12-treated animals (P = 0.008). IL-12 receptor knockout mice given mrIL-12vp showed a marked decrease in the area of corneal neovascularization compared with mice treated with mrIL-12. These results indicate that mrIL-12vp inhibits angiogenesis through IL-12-dependent and IL-12-independent mechanisms, and its augmented antiangiogenic activity may be due to suppression of endothelial cell signaling pathways by the RGD-4C portion of the fusion protein. Mice injected with NXS2 neuroblastoma cells and treated with mrIL-12vp showed significant suppression of tumor growth compared with mice treated with mrIL-12 (P = 0.03). Mice did not show signs of IL-12 toxicity when treated with mrIL-12vp, although hepatic necrosis was present in mrIL-12-treated mice. Localization of IL-12 to neovasculature significantly enhances the antiangiogenic effect, augments antitumor activity, and decreases toxicity of IL-12, offering a promising strategy for expanding development of IL-12 for treatment of cancer patients.

Angiogenesis Inhibitors↗
PubMed2000

Targeted delivery of DNA encoding herpes simplex virus type-1 glycoprotein D enhances the cellular response to primary viral challenge.

Intravenous injection of plasmid DNA encoding herpes simplex virus type-1 glycoprotein D (gD-1) complexed with asialoorosomucoid-poly-L-lysine (gD-ASOR) targets foreign DNA to the liver, leading to hepatic expression of gD-1. BALB/c mice were given two intravenous injections of gD-ASOR, pBK-ASOR (plasmid lacking the gD-1 gene but complexed with ASOR), or PBS. The skin was inoculated with 1 x 10(4) PFU of HSV-1 or sham-inoculated, and analyzed for infectious virus and cellular infiltration 1, 3, and 5 days after inoculation. Prior immunization with gD-ASOR led to significantly lower (P < 0.05) viral titers in the skin 5 days after inoculation compared with controls. Infiltration of the skin at the site of inoculation by polymorphonuclear neutrophils (PMNs), T cells, B cells, dendritic cells, and macrophages was monitored immunohistochemically. Significantly higher numbers (P < 0.05) of CD4+ and CD8+ T cells, dendritic cells, and macrophages responded to HSV-1 challenge in mice immunized with gD-ASOR than in mice immunized with pBK-ASOR or PBS. The response by PMNs and B cells was indistinguishable among the treatment groups. These results suggest that BALB/c mice sensitized to gD-1 following gD-ASOR immunization develop an enhanced T-cell response to primary HSV-1 infection.

Animals↗
PubMed1996

Retroviral targeted delivery.

The systemic delivery of genes will open new applications for gene therapy. The deployment of retroviral vectors for this purpose is being considered and requires the development of retroviral vectors with a defined target cell specificity of infection. Several reports have recently described attempts to engineer the envelope protein of murine retroviruses in order to expand the host range and enable them to infect specific human cells. The strategies are based on the introduction of binding sites specific for receptors on the surface of target cells. Although the attempts to manipulate the specificity of viral target cell recognition are ambitious and promising, they are not without pitfalls. We summarize the results obtained and the difficulties encountered.

Gene Products, env↗
PubMed1992

Targeted delivery of human recombinant superoxide dismutase by chemical modification with mono- and polysaccharide derivatives.

Four types of superoxide dismutase (SOD) derivatives such as SOD-carboxymethyl dextran conjugate, SOD-diethylaminoethyl dextran conjugate, galactosylated SOD and mannosylated SOD were synthesized and their potential for selective targeting to organs or cells was evaluated in mice by pharmacokinetic analysis. All SOD derivatives retained 50 to 80% of the original enzymatic activity and were stable during incubation with mouse serum retaining enzymatic activity greater than 80% for 3 hr. After intravenous injection, native SOD was rapidly excreted into urine and no significant accumulation was observed in the organs except the kidney. SOD-carboxymethyl dextran conjugate gave a long plasma half-life because of impaired glomerular filtration and tissue interaction. By contrast, galactosylated-SOD and mannosylated-SOD were very rapidly eliminated from the circulation and taken up by parenchymal and nonparenchymal cells of the liver, respectively, via receptor-mediated endocytosis. These uptake processes were nonlinear and hepatic uptake clearance decreased as the dose increased, although almost complete extraction was obtained at a dose of 0.1 mg/kg. Furthermore, the accumulation in kidney of both glycosylated SODs was drastically decreased due to reduced renal proximal tubular reabsorption and also enhanced hepatic clearance. SOD-diethylaminoethyl dextran conjugate also rapidly disappeared from plasma and distributed into liver, but its accumulation occurred due to electrostatic interaction and was nonspecific in cellular distribution. These results suggest the possibility of controlling the in vivo fate of SOD at a cellular level by chemical modification utilizing sugar moieties with varied physicochemical and/or biological characteristics.

Animals↗
PubMed2003

Protein Therapy: in vivo protein transduction by polyarginine (11R) PTD and subcellular targeting delivery.

Protein Therapy is a newly developed method, which allows proteins, peptides and biologically active compounds to penetrate across the plasma membrane of eukaryotic cells by a polyarginine (most efficiently by 11-arginine, 11R) protein transduction domain. This method enables us to control the localization of targeted substances in subcellular compartments, such as the nuclei, mitochondria and post-synaptic density. The method is very efficient and applicable not only to cultured cells but also to tissue slices and the whole animal. Brain, heart, skeletal muscle, liver, pancreas and lymphocytes are efficient target organs and tissues for Protein Therapy. The method is therefore a very useful strategy in the post-genomic era. In this mini-review, the development of Protein Therapy and its application for cancer cells and neuroscience study will be shown.

Animals↗
PubMed2001

Targeted delivery of drugs to the gastrointestinal tract.

The oral route is attractive for drug administration because it is associated with patient acceptability, less stringent production conditions, and lower costs. However, gastrointestinal destruction of labile molecules and low levels of absorption generally render oral delivery of peptides and proteins ineffective. Several strategies have the potential to enhance the efficacy of orally administered drugs. Bioadhesion is an approach for increasing interaction between drugs and the mucosae. Bioadhesive systems can be nonspecific, achieving adhesion via mechanical processes or specific systems that recognize receptors on epithelial cells. Lectins are one group of specific bioadhesives with many suitable properties for targeting of cells in the gastrointestinal tract (GIT). This review assesses the potential of lectins in the delivery of drugs and vaccines to the GIT.

Adhesiveness↗