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At least 307 records · Page 17Linked to original sources
PubMed2004

Drug targeting to the colon with lectins and neoglycoconjugates.

Targeting of drugs to specific sites of action provides several advantages over non-targeted drugs. These include the prevention of side effects of drugs on healthy tissues and enhancement of drug uptake by targeted cells. This review will cover traditional approaches of colon drug targeting as well as the use of lectins and neoglycoconjugates for the targeted delivery. Direct and reverse targeting strategies, potential molecular targets and targeting moieties for colon drug delivery, targeted drug delivery systems (DDS) for colon delivery, anticancer DDS targeted to colon cancer are examined. Directions of future development are discussed.

Administration, Rectal↗
PubMed2002

Evolving phage vectors for cell targeted gene delivery.

We adapted filamentous phage vectors for targeted gene delivery to mammalian cells by inserting a mammalian reporter gene expression cassette (GFP) into the vector backbone and fusing the pIII coat protein to a cell targeting ligand (i.e. FGF2, EGF). Like transfection with animal viral vectors, targeted phage gene delivery is concentration, time, and ligand dependent. Importantly, targeted phage particles are specific for the appropriate target cell surface receptor. Phage have distinct advantages over existing gene therapy vectors because they are simple, economical to produce at high titer, have no intrinsic tropism for mammalian cells, and are relatively simple to genetically modify and evolve. Initially transduction by targeted phage particles was low resulting in foreign gene expression in 1-2% of transfected cells. We increased transduction efficiency by modifying both the transfection protocol and vector design. For example, we stabilized the display of the targeting ligand to create multivalent phagemid-based vectors with transduction efficiencies of up to 45% in certain cell lines when combined with genotoxic treatment. Taken together, these studies establish that the efficiency of phage-mediated gene transfer can be significantly improved through genetic modification. We are currently evolving phage vectors with enhanced cell targeting, increased stability, reduced immunogenicity and other properties suitable for gene therapy.

Animals↗
PubMed1994

Antisense DNA delivery in vivo: liver targeting by receptor-mediated uptake.

UNLABELLED: Antisense oligodeoxynucleotides coupled to asialoglycoprotein carrier molecules were evaluated in terms of their ability to accumulate preferentially in the liver and thus potentially serve as an important method to regulate liver gene expression. METHODS: Native and asialo-human alpha-1 acid glycoproteins were derivatized with low molecular weight poly(L)lysine and complexed with an antisense DNA (67 mer) complementary to the 5' end of rat serum albumin mRNA. The asialoglycoprotein antisense complex (conjugate) was characterized with respect to size, stability, and anti-sense loading, and the biodistribution of the conjugate was determined for normal rats at 5 min and 1, 6, and 24 hr after intravenous injection. In vivo stability of the anti-sense asialoglycoprotein complex was also evaluated using double-labeled (32P-antisense and 3H-glycoprotein) preparations. RESULTS: The results of the conjugate characterization studies demonstrated that at least 30% of the anti-sense DNA dissociated from the carrier after 7 min under chromatographic conditions. When the conjugate was incubated with PBS, MEM or MEM plus 10% FBS for 1 hr at 37 degrees C, about 85% of the antisense DNA was dissociated from the carrier. The results of the biodistribution studies showed that the accumulation of the asialo-glycoprotein anti-sense complex in the liver was rapid and greatly exceeded the accumulation of the sialo-glycoprotein antisense analog or antisense alone. CONCLUSION: These findings have significant implications for the targeted delivery of therapeutic antisense molecules to the liver.

Animals↗
PubMed2000

Targeted drug delivery via the folate receptor.

The folate receptor is a highly selective tumor marker overexpressed in greater than 90% of ovarian carcinomas. Two general strategies have been developed for the targeted delivery of drugs to folate receptor-positive tumor cells: by coupling to a monoclonal antibody against the receptor and by coupling to a high affinity ligand, folic acid. First, antibodies against the folate receptor, including their fragments and derivatives, have been evaluated for tumor imaging and immunotherapy clinically and have shown significant targeting efficacy in ovarian cancer patients. Folic acid, a high affinity ligand of the folate receptor, retains its receptor binding properties when derivatized via its gamma-carboxyl. Folate conjugation, therefore, presents an alternative method of targeting the folate receptor. This second strategy has been successfully applied in vitro for the receptor-specific delivery of protein toxins, anti-T-cell receptor antibodies, interleukin-2, chemotherapy agents, gamma-emitting radiopharmaceuticals, magnetic resonance imaging contrast agents, liposomal drug carriers, and gene transfer vectors. Low molecular weight radiopharmaceuticals based on folate conjugates showed much more favorable pharmacokinetic properties than radiolabeled antibodies and greater tumor selectivity in folate receptor-positive animal tumor models. The small size, convenient availability, simple conjugation chemistry, and presumed lack of immunogenicity of folic acid make it an ideal ligand for targeted delivery to tumors.

Animals↗
PubMed2003

Directed apoptosis in Cox-2-overexpressing cancer cells through expression-targeted gene delivery.

The principle of promoter-targeted gene delivery was used to direct the expression of reporter genes and inducible caspases to Cox-2-overexpressing cancer cells. The polycation poly(ethylenimine) was used in unmodified form to nonvirally deliver genes into cells, and targeting was achieved at the transcriptional level. Results demonstrated that reporter expression was reduced by an average of 89.8% in normal cells and cell lines not overexpressing Cox-2 when the strong cytomegalovirus promoter was replaced with the human Cox-2 promoter in delivered plasmids. Cocultures of normal and Cox-2-overexpressing cancer cells showed less than 0.5% reporter expression in normal fibroblast cells but over 35% reporter expression in PC3 prostate cancer cells. This targeting method was then used to direct the expression of inducible forms of caspases 3 and 9 to Cox-2-overexpressing cancer cells of the bladder and prostate. Following activation of the resulting caspase pro-forms, cells underwent apoptosis as evidenced by DNA fragmentation and cytoskeletal degradation. This result was also observed in cells resistant to apoptosis in terms of TNF-alpha initiation. Such directed apoptosis could eventually serve as a treatment for an entire class of Cox-2-overexpressing carcinomas.

Apoptosis↗
PubMed2006

Comparative evaluation of Estredox, a brain-targeted estradiol delivery system versus traditional estrogen replacement therapy.

Estredox is a novel brain-targeted delivery system for estradiol (E2). The mechanism of this estradiol-chemical delivery system (E2-CDS) is based on an interconvertible dihydropiridine <--> pyridinium salt carrier (targetor) attached to E2. After administration of the E2-CDS, the targetor moiety is oxidized to a quaternary pyridinium salt (E2-Q+). Here we demonstrate that a single i.v. injection with E2-CDS (3 mg/kg) resulted in sustained presence of E2-Q+ in three various brain regions. The sustained and gradual release of estradiol from E2-Q+ is reflected by the time-course of plasma estrogen level. At the end of repeated administration of E2-CDS (daily once 0.3 mg/kg i.v. for 10 consecutive days) we found a sharp decrease in the levels of plasma estradiol followed by a gradual decrease. The levels of E2-Q+ in the investigated brain regions decreased gradually from the first post-treatment day, however, a detectable amount of E2-Q+ was still present in the hypothalamus, striatum, and cortex even on the 24th post-treatment day. Strikingly different plasma estradiol levels were found in the groups of orchidectomized rats that received daily i.v. injections of estradiol benzoate (E2-BZ). The plasma estradiol levels in these animals were much higher compared to E2-CDS-treated animals throughout the treatment period but the level sharply dropped immediately after the treatments. In contrast to the E2-CDS-treated animals there was no estradiol in any of the brain regions of E2-BZ-treated rats on the 1st and 2nd post-treatment day. All of these data are in line with the long-lasting pharmacological effects of E2-CDS-treatment on estrogen-mediated functions in castrated rats and give further experimental support for brain-targeting estrogen-treatment approach as opposed to the traditional estrogen replacement therapy.

Animals↗
PubMed1994

Long-circulating (sterically stabilized) liposomes for targeted drug delivery.

Anticancer chemotherapy is limited by adverse side-effects resulting from toxicities to normal tissues. Targeted delivery of drugs to diseased tissues in vivo would help to reduce these side-effects. Liposomes containing lipid derivatives of polyethylene glycol (sterically stabilized liposomes) have circulation times that are sufficiently long to allow for effective in vivo drug delivery, and are discussed in this review by Theresa Allen. Sterically stabilized liposomes, containing entrapped doxorubicin, targeted to squamous cell lung carcinoma by means of specific antibodies attached at the liposome surface are capable of reducing tumour burden to a significant extent and eradicating tumour in a significant percentage of mice.

Animals↗
PubMed2000

The pilosebaceous unit: a pivotal route for topical drug delivery.

The hair follicle, hair shaft and sebaceous gland are collectively known as the pilosebaceous unit. The pilosebaceous unit is a complex, dynamic, 3-D structure, which is the site of unique biochemical, metabolical and immunological events. Ongoing research has focused on the hair follicle as a potential route for both localized and systemic drug delivery. Targeted drug delivery to the specific sites of hair follicle has paved ways to treat several dermatological abnormalities that are known to originate at the hair follicle. In recent studies, topical liposomes have been shown to target the drug to the pilosebaceous unit. This review describes general aspects of pilosebaceous unit, follicular delivery, with particular emphasis on studies which have demonstrated targeted follicular delivery via liposomes.

Administration, Topical↗
PubMed2002

Targeted drug delivery to the central nervous system via phosphonate derivatives (anionic delivery system for testosterone).

An anionic chemical delivery system (aCDS) has been developed and applied to deliver testosterone (T) to the central nervous system (CNS). The delivery of a target compound is achieved through the use of a specific targetor moiety which is an (acyloxy)alkyl-phosphonate-type functional group. The T-aCDS readily penetrates biological membranes by passive transport due to its increased lipophilicity and enters the target organ. Hydrolytic cleavage by esterases provides a negatively charged, hydrophilic intermediate phosphonate compound (TP-), which is "locked in" the CNS and should provide sustained, site-specific release of the drug. In vitro and in vivo investigations in rats showed that methyl-pivaloyloxymethyl-17-testosterylphosphonate (T-aCDS) might function as an anionic chemical delivery system of testosterone. The concentration of T-aCDS decreased fairly rapidly in vitro. The half-lives (t1/2) in different organs are as follows: blood 4.48 min (r = 0.9388), lung 5.53 min (r = 0.9661), liver 2.82 min (r = 0.9498), and brain 7.37 min (r = 0.9972). Simultaneously with the disappearance of T-aCDS, testosterone-phosphonate (TP-) appeared as a main metabolite in increasing concentration. In vivo evaluations (tail vein 11.3 mg/kg in DMSO) found maximum T-aCDS brain levels 5-10 min after administration; they fell under the borderline of detectability (< 0.1 microgram/g) after 60 min. Maximum concentration of the decomposition product (TP-) was obtained at 30 min after administration; it did not decrease significantly during the study. Even if the phosphonate derivative of the secondary, hindered hydroxyl group in this product was fairly resistant to phosphorolytic attack, the design principle can work for other compounds.

Animals↗
PubMed1996

Targeted drug delivery for boron neutron capture therapy.

PURPOSE: Boron neutron capture therapy (BNCT) is a form of radiochemotherapy that is becoming increasingly important for the treatment of malignant gliomas, malignant melanomas and other forms of cancer. Targeted delivery of boron to tumors is a critical prerequisite for successful BNCT. METHODS: Strategies that involve synthetic chemical approaches and biochemical and biophysical approaches are employed to meet this requirement. Compounds developed for targeting to tumors include borocaptate sodium (BSH) and p-boronophenylalanine (BPA) which are currently in clinical use. RESULTS: Boronated porphyrins, nucleosides, nucleotides and other boronated compounds show potentials as targeting molecules. Conjugation of boron compounds to macromolecules such as monoclonal antibodies, epidermal growth factor and dextran is also employed for active or passive tumor targeting. CONCLUSIONS: Boron delivery via microparticulate carriers such as liposomes, high density lipoproteins and microcapsules is also attractive for its potential application in BNCT.

Animals↗
PubMed2026

Engineering CRISPR nanoplatforms to deplete cancer stem cells: Delivery checkpoints, target plasticity, and clinical viability.

Cancer stem cells (CSCs) sustain tumor initiation, therapy resistance, and relapse, yet evade durable control because they switch phenotype, enter quiescence, shelter within protective niches, resist drug efflux, and share markers with normal stem cells. Programmable CRISPR editing can disable intracellular self-renewal dependencies that antibodies and small molecules cannot reach, whereas only nanoscale carriers can confine such editing to intended cells; neither component alone solves the CSC problem. This review reframes CSC-directed CRISPR nanomedicine as an integrated design problem. We examine why target plasticity defeats static single-marker targeting; the sequential delivery checkpoints spanning blood stability, organ selection, tumor penetration, CSC recognition, endosomal escape, and productive editing; and advanced architectures including organ-selective lipid nanoparticles, biomimetic and vesicle carriers, metal-organic frameworks, and logic-gated systems. Genotoxicity, immunogenicity, incomplete depletion, manufacturing reproducibility, and absent CSC-specific clinical evidence remain limiting. Clinical viability, not imminent cure, is the realistic near-term objective.

Neoplastic Stem Cells↗
PubMedDate not supplied

Design and development of multiparticulate system for targeted drug delivery to colon.

A multiparticulate system combining pH-sensitive property and specific biodegradability for colon-targeted delivery of metronidazole has been investigated. Cross-linked chitosan microspheres were prepared from an emulsion system using liquid paraffin as the external phase and solution of chitosan in acetic acid as the disperse phase. The multiparticulate system was prepared by coating cross-linked chitosan microspheres exploiting Eudragit L-100 and S-100 as pH-sensitive polymers. Morphology and surface characteristics of the formulations were determined by scanning electron microscopy. Particle size of the chitosan microspheres was determined by optical microscopy while that of coated microspheres was determined by particle size analyzer. In vitro drug-release studies were performed in conditions simulating stomach-to-colon transit in presence and absence of rat caecal contents. The size of the microspheres was small and they were efficiently microencapsulated within Eudragit microspheres, forming a multireservoir system. By coating the microspheres with Eudragit pH-dependant release profiles were obtained. No release was observed at acidic pH; however, when it reached the pH where Eudragit starts solublizing there was continuous release of drug from the formulation. Further, the release of drug was found to be higher in the presence of rat caecal contents, indicating the susceptibility of chitosan matrix to colonic enzymes released from rat caecal contents.

Animals↗
PubMed2002

The role of the transferrin-transferrin-receptor system in drug delivery and targeting.

Exploration of the potential of site-specific and target-oriented drug delivery systems has gained interest recently. Indeed, the efficient cellular mechanism of transferrin uptake has been exploited for the delivery not only of anticancer drugs and proteins, but also of therapeutic genes into proliferating malignant cells that overexpress transferrin receptors. In particular, the transferrin receptor offers great promise in the delivery of therapeutic agents across the blood-brain barrier to the brain.

Animals↗
PubMedDate not supplied

Efficient intracellular delivery of oligonucleotides formulated in folate receptor-targeted lipid vesicles.

In this study, a novel lipid vector has been developed for targeted delivery of oligodeoxynucleotides (ODN) to tumors that overexpress folate receptor. This is based on a method developed by Semple et al. (1), which utilizes an ionizable aminolipid (1,2-dioleoyl-3-(dimethylammonio)propane, DODAP) and an ethanol-containing buffer system for encapsulating large quantities of polyanionic ODN in lipid vesicles. Folate is incorporated into the lipid vesicles via a distearoylphosphatidylethanolamine-poly(ethylene glycol) (DSPE-PEG) spacer. These vesicles are around 100-200 nm in diameter with an ODN entrapment efficiency of 60-80%. Folate mediated efficient delivery of ODN to KB cells that overexpress folate receptor. Uptake of folate-targeted lipidic ODN by KB cells is about 8-10-fold more efficient than that of lipidic ODN without a ligand or free ODN. This formulation is resistant to serum. Thus, targeted delivery of ODN via this novel lipid vector may have potential in treating tumors that overexpress folate receptors.

Base Sequence↗
PubMed2001

Synthesis of RGD analogs as potential vectors for targeted drug delivery.

RGD analogs bind to integrin receptors with high affinity and therefore have the potential to be used as vectors for the targeted delivery of pharmaceutical agents to designated sites. Critical to this application is the ability to synthesize RGD analogs with different side chain functional groups that allow for the ready tethering of pharmaceutical agents without sacrificing their affinity for the target receptor significantly. A series of RGD analogs intended to be used as delivery vectors of pharmaceutical agents were prepared and evaluated for their ability to inhibit platelet aggregation by binding to glycoprotein IIb/IIIa. Among them, compound 11 showed the lowest IC50 against platelets activated by ADP. It was found that such RGD analogs could tolerate side chain modification fairly well with various functional groups attached such as amide, amine, ester, protected amine and poly(ethylene glycol). The fact that the compound with a side chain modification of poly(ethylene glycol) retained high affinity for glycoprotein IIb/IIIa (IC50 150 nM) suggests the feasibility of tethering fairly large pharmaceutical agents to such RGD analogs without significant sacrifice of their affinity to the intended receptor.

Drug Delivery Systems↗
PubMed2006

FGF-1 as a possible carrier for targeted drug delivery.

Delivery of anticancer chemotherapeuticals to tumor cells raises many problems due to pronounced systemic side effects. Targeted delivery using specific monoclonal antibodies has been postulated; however, monoclonal antibodies very often produce immune response in the human body. Chimeric and humanized antibodies have some advantages over monoclonals, but still some side effects can be observed. Because some tumor cells (e.g., breast cancer cells) overexpress fibroblast growth factor receptors, it is possible to use these receptors for drug targeting. We think that growth factors of human origin can be used for drug delivery to tumor cells. Fibroblast growth factor-1 (FGF-1) is especially suitable as drug carrier because it can cross the barrier of the cell membrane and reach the cytosol and, further, it is translocated to the cell nucleus. One possible approach for anticancer therapy is to use biotinylated growth factors linked to avidin/ streptavidin-coated liposomes. Another possibility is to link drug molecules or radioisotopes directly to growth factors. Thus, we wanted to determine if FGF-1 retains its biological activity after chemical modification, and if it is able to bind its receptors and if it can be internalized by the cells. For this purpose we have biotinylated recombinant human FGF-1 and we have verified that it retains its biological activities in NIH/3T3 and MDA-MB-453 cells and it is able to enter the target cells.

Animals↗
PubMed1996

Macromolecular carrier systems for targeted drug delivery: pharmacokinetic considerations on biodistribution.

This review article describes the current status and future perspectives of site-specific drug delivery by means of macromolecular carrier systems. Basic aspects and recent advances of targeted delivery of 1) conventional drugs, 2) protein drugs, and 3) gene medicines including antisense oligonucleotides and plasmid DNA, are reviewed from a pharmacokinetic perspective. Successful in vivo application of macromolecular carrier systems requires pharmacokinetic considerations at whole body, organ, cellular and subcellular levels. The integration of simultaneous research progress in the multidisciplinary fields such as biochemistry, cell and molecular biology, pharmacology, and pharmacokinetics will accelerate the emergence of marketed drugs with macromolecular carrier systems.

Animals↗