Nanoparticulate systems in drug delivery and targeting.
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Antineoplastic Agents↗
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Liposomal vaccines--targeting the delivery of antigen.
Vaccines that can prime the adaptive immune system for a quick and effective response against a pathogen or tumor cells, require the generation of antigen (Ag)-specific memory T and B cells. The unique ability of dendritic cells (DCs) to activate naïve T cells, implies a key role for DCs in this process. The generation of tumor-specific CD8(+) cytotoxic T cells (CTLs) is dependent on both T cell stimulation with Ag (peptide-MHC-complexes) and costimulation. Interestingly, tumor cells that lack expression of T cell costimulatory molecules become highly immunogenic when transfected to express such molecules on their surface. Adoptive immunotherapy with Ag-pulsed DCs also is a strategy showing promise as a treatment for cancer. The use of such cell-based vaccines, however, is cumbersome and expensive to use clinically, and/or may carry risks due to genetic manipulations. Liposomes are particulate vesicular lipid structures that can incorporate Ag, immunomodulatory factors and targeting molecules, and hence can serve as potent vaccines. Similarly, Ag-containing plasma membrane vesicles (PMV) derived from tumor cells can be modified to incorporate a T cell costimulatory molecule to provide both TCR stimulation, and costimulation. PMVs also can be modified to contain IFN-gamma and molecules for targeting DCs, permitting delivery of both Ag and a DC maturation signal for initiating an effective immune response. Our results show that use of such agents as vaccines can induce potent anti-tumor immune responses and immunotherapeutic effects in tumor models, and provide a strategy for the development of effective vaccines and immunotherapies for cancer and infectious diseases.
Antigens↗
Plasma synthesis of carbon magnetic nanoparticles and immobilization of doxorubicin for targeted drug delivery.
Using dense medium plasma technology, carbon magnetic nanoparticles (CMNP) were synthesized at room temperature and atmospheric pressure. Based on results from X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy and scanning electron microscopy, we conclude that these nanoparticles are composed of spherical particles, 40-50 nm in diameter, with iron/iron oxide particles dispersed in a carbon-based host-structure. Thermal gravimetry/differential thermal gravimetry analysis shows these nanoparticles are stable to temperatures as high as 600 degrees C. The synthesized CMNP were treated by argon-plasma, aminated with ethylene diamine and subsequently activated by generating aldehyde groups on them. Free doxorubicin (DOX) molecules were then immobilized onto the surfaces of activated CMNP particles to form CMNP-DOX conjugates. The corresponding loading efficiency was determined. The in vitro antiproliferative activity of immobilized doxorubicin in the conjugates was demonstrated in tumor cell cytotoxicity assays. It is suggested that this CMNP-DOX system can be used for targeted drug-delivery systems.
Animals↗
Targeted drug delivery to C6 glioma by transferrin-coupled liposomes.
Recent advances in liposome technology have shown promise relative to the introduction of chemotherapeutic agents with reduced toxicity, extended longevity, and potential for cell-specific targeting. In this study we report the engineering of a liposomal delivery system for the chemotherapeutic drug doxorubicin. The system was targeted specifically to C6 glioma in vitro by coupling transferrin to the distal ends of liposomal polyethylene glycol (PEG) chains. The transferrin receptor is overexpressed on glioma, with the extent of overexpression correlated to the severity of the tumor. Significantly increased gliomal doxorubicin uptake was achieved by drug encapsulation within transferrin-coupled liposomes compared to other liposome populations. Doxorubicin encapsulated within transferrin-coupled liposomes exhibited 70% of free doxorubicin uptake as compared to 54, 14, and 34% for non-PEG, PEG, and albumin-coupled PEG liposomes, respectively. Competitive binding assays support the receptor-mediated mechanism of targeting. The addition of one microM free transferrin reduced the uptake of doxorubicin encapsulated within transferrin-coupled liposomes by 30%.
Animals↗
Food-derived extracellular vesicles as delivery platforms for medicine-food homology components in metabolic syndrome.
Diet-induced obesity and associated metabolic syndromes have become major global public health challenge, highlighting the urgent need for safe and effective strategies. Recently, food-derived extracellular vesicles (FDEVs) have garnered increasing attention as natural nanocarriers due to their excellent biocompatibility and specific targeted delivery capabilities. FDEVs can efficiently deliver medicine-food homology components (MFHCs) to precisely regulate lipid metabolism, inflammatory responses, and insulin sensitivity, thereby improving obesity and its metabolic abnormalities. This systematic review summarizes recent advances in the use of FDEVs as delivery vehicles for MFHCs to suppress diet-induced obesity and metabolic syndrome, with a particular focus on the underlying molecular mechanisms, including signaling pathway regulation and cellular metabolic remodeling. In addition, the clinical translational potential and industrial application prospects of FDEVs are evaluated, and key challenges related to preparation techniques, safety assessment, and large-scale production are discussed. By integrating current evidence, this review aims to provide theoretical framework and future perspectives for the development of FDEVs as a novel targeted delivery platform and treatment of metabolic diseases.
Extracellular Vesicles↗
Pharmacokinetic evaluation of guar gum-based colon-targeted drug delivery systems of mebendazole in healthy volunteers.
The pharmacokinetic evaluation of guar gum-based colon-targeted tablets of mebendazole against an immediate release tablet was carried out in human volunteers. Six healthy volunteers participated in the study and a crossover design was followed. Mebendazole was administered at a dose of 50 mg both in immediate release tablet and colon-targeted tablets. On oral administration of colon-targeted tablets, mebendazole started appearing in the plasma at 5 h, and reached the peak concentration (C(max) of 25.7+/-2.6 ng/ml) at 9.4+/-1.7 h (T(max)) whereas the immediate release tablets produced peak plasma concentration (C(max) of 37.2+/-6.8 ng/ml) at 3.4+/-0.9 h (T(max)). Colon-targeted tablets showed delayed t(max) and absorption time, and decreased C(max) and absorption rate constant when compared to the immediate release tablets. The results of the study indicated that the guar gum-based colon-targeted tablets of mebendazole did not release the drug in stomach and small intestine, but delivered the drug to the colon resulting in a slow absorption of the drug and making the drug available for local action in the colon.
Adolescent↗
Sustained-release hydroxycamptothecin polybutylcyanoacrylate nanoparticles as a liver targeting drug delivery system.
Sustained release hydroxycamptothecin polybutylcyanoacrylate nanoparticles (HCPT-PBCA-NP) associated with polybutylpyrolidone (PVP) for liver targeting were prepared by the adsorption-entrapping method. The morphology, sizes, drug loading efficiencies, release characteristics in vitro, distribution and pharmacokinetic parameters in vivo of the HCPT-PBCA-NP associated with PVP were studied. The median diameter of the particles was 81 nm and the drug loading was 1.2%. The release characteristics in vitro were in accordance with the Higuchi equation: Q = 0.0615 + 0.0940 mean square root t. 64.5% of the HCPT were concentrated in the liver at 15 min after i.v. administration of HCPT-PBCA-NP associated with PVP. The plasma drug concentration-time curve of the HCPT in rabbits was fitted to a two-compartment open model. The Vc, T 1/2 and CL were 3.5L; 147h; 0.18L x h(-1), respectively. The method of preparation presented in this paper seems to bean alternative for the preparation of PBCA-NP of poorly soluble drugs both in water and in lipid.
Animals↗
Fusogenic potential of sperm membrane lipids: nature's wisdom to accomplish targeted gene delivery.
The membrane-membrane fusion during fertilization of oocyte by spermatozoa is believed to be mainly mediated by so called "fusion proteins". In the present study we have tried to demonstrate that beside the proteins, lipid components of membrane may play an important role in fusion of oocyte with spermatozoa. Conventional membrane-membrane fusion assays were used as means to demonstrate fusogenic potential of human sperm membrane lipids. The liposomes (spermatosomes) made of the lipids isolated from sperm membrane were found to undergo strong membrane-membrane fusion as evident from fluorescence dequenching and resonance energy transfer assays. Furthermore, the fusion of these liposomes with living cells (J774 A.1 macrophage cell line) was demonstrated to result in an effective transfer of a water-soluble fluorescent probe (calcein) to cytosol of the target cell. Lastly, the liposomes were demonstrated to behave like efficient vehicles for the in vivo cytosolic delivery of the antigens to target cells resulting in elicitation of antigen specific CD8(+) T cell responses.
Animals↗
Prodrugs in site-selective delivery of radiopharmaceuticals.
This paper reviews basic rules for the design of site-selective prodrugs and various modes of their activation with particular emphasis on the applications of prodrugs to targeted delivery of radiopharmaceuticals. Although many radiopharmaceuticals are "targeted" to specific tissues or organs, we will discuss only agents that are either chemically or metabolically transformed producing an active form that is retained by its target. Site-specific prodrugs of diagnostic radiopharmaceuticals are routine in the nuclear medicine applications, but the instances of targeting of radiotherapeutic prodrugs are surprisingly rare. We have concentrated on our own efforts to design and synthesize site-selective prodrugs of 5-[125I]iodo-2'-deoxyuridine (125IUdR) for cancer radiotherapy. The prodrugs of 125IUdR for targeted delivery include several derivatives with altered permeability, 3',5'-dioctanoyl, 3',5'-dioleoyl, 3'- and 5'-N-alkyl-dihydropyridyl, 3'- and 5'-N-alkyl-dihydroisoquinolyl, and 3'- and 5'-N-alkyl-dihydroacridinyl esters of 125IUdR; polymeric and macromolecular prodrugs of 125IUdR for a carrier-mediated or local delivery; metabolically trapped 125IUdR prodrugs; and glycoconjugate prodrugs for oral colon-specific delivery of 125IUDR, 125IUDR-5'-beta-d-cellobioside, 125IUDR-5'-beta-D-glucopyranoside, 125IUDR-5'-beta-D-galactopyranoside and 125IUDR-5'-beta-D-glucuronide. We also describe prodrugs of several diagnostic agents in the context of the metabolic trapping as the primary targeting modality. For various diagnostic agents the prodrug target-associated enzymes are discussed and examples of the site-specific release of the active agent are given. A brief overview of an emerging role of residualizing labels in radioimmunotherapy is included.
Animals↗
Targeted gene delivery with trisaccharide-substituted chitosan oligomers in vitro and after lung administration in vivo.
The aim of this study was to improve the gene delivery efficacy of chitosan oligomer polyplexes by introducing a trisaccharide branch that targets cell-surface lectins. For this purpose, chitosan oligomers were substituted by a trisaccharide with the N-acetylglucosamine residue at the free end, and the ability of the trisaccharide-substituted chitosan oligomers (TCO) polyplexes to transfect various cell lines in vitro and lung tissue after in vivo administration to mice was investigated. Live-cell confocal microscopy showed improved cellular uptake in HEK 293 cells (11-fold, p<0.001) for the TCO polyplexes compared with the linear chitosan oligomers. Colloidal stability was also enhanced with the substituted form, which suggests that the trisaccharide branch stabilised the polyplexes by means of a steric stabilisation mechanism. Interestingly, gene expression levels in the human liver hepatocyte (HepG2) cells were 10-fold higher with the TCO polyplexes than those mediated by polyethyleneimine. A similar improvement was obtained in a human bronchial epithelial cell line (16HBE14o-). Transfection with the TCO was significantly inhibited (by 30-80%), for all the cell lines tested, in the presence of the free trisaccharide branch, confirming lectin-mediated uptake. Finally, in vivo studies showed that, 24 h after lung administration to mice, luciferase gene expression was 4-fold higher with the TCO than with the corresponding linear chitosan oligomers.
Animals↗
Gene medicine : a new field of molecular medicine.
Gene therapy has emerged as a new concept of therapeutic strategies to treat diseases which do not respond to the conventional therapies. The principle of gene therapy is to introduce genetic materials into patient cells to produce therapeutic proteins in these cells. Gene therapy is now at the stage where a number of dinical trials have been carried out to patients with gene-deficiency disease or cancer. Genetic materials for gene therapy are generally composed of gene expression system and gene delivery system. For the dinical application of gene therapy in a way which conventional drugs are used, researches have been focused on the design of gene delivery system which can offer high transfection efficiency with minimal toxicity. Currently, viral delivery systems generally provide higher transfection efficiency compared with non-viral delivery systems while non-viral delivery systems are less toxic, less immunogenic and manufacturable in large scale compared with viral systems. Recently, novel strategies towards the design of new non-viral delivery system, combination of viral and non-viral delivery systems and targeted delivery system have been extensively studied. The continued effort in this area will lead us to develop gene medicine as 'gene as a drug' in the near future.
Clinical Trials as Topic↗
From Gene Function to Precision Intervention: CRISPR/Cas9 and Stem Cell-Based Strategies as Emerging Disease-Modifying Approaches in PMOS.
Polyendocrine metabolic ovarian syndrome (PMOS) is a complex endocrine-metabolic disorder affecting up to 18% of women worldwide and remains the leading cause of anovulatory infertility. Despite extensive research, current treatments primarily target symptoms, including menstrual irregularities, hyperandrogenism, and metabolic dysfunction, without addressing the underlying molecular and tissue-level disturbances. Advances in multi‑omic profiling have identified disruptions across neuroendocrine, metabolic, inflammatory, and extracellular matrix pathways, alongside genetic susceptibility at loci such as DENND1A, CYP17A1, LHCGR, FSHR, IRS1, and PPARG. However, the functional roles of many variants remain unresolved. CRISPR/Cas9 gene editing enables precise interrogation of these pathways, while stem cell-based platforms, including mesenchymal stem cells (MSCs), exosomes, and gene-edited induced pluripotent stem cells (iPSCs), may serve as complementary platforms for regeneration and disease modeling. Preclinical studies demonstrate that MSCs and their derivatives modulate inflammation, restore ovarian structure, and improve metabolic parameters, while iPSC-based models enable patient-specific investigation of steroidogenic and metabolic abnormalities. Translational challenges remain, including targeted delivery, off-target effects, phenotypic heterogeneity, and regulatory considerations. Integrating CRISPR‑based functional genomics with stem cell research may shift PMOS management from symptom‑focused care to targeted, mechanism‑driven interventions that could modify the course of PMOS (Graphical Abstract).
Humans↗
Characterization of biodegradable drug delivery vehicles with the adhesive properties of leukocytes II: effect of degradation on targeting activity.
The site-specific expression of selectins (P- and E-selectin) on endothelial cells of blood vessels during inflammation provides an opportunity for the targeted delivery of anti-inflammatory drugs to sites of chronic inflammation. It is well documented that the selectins mediate the initial interaction (rolling) of leukocytes in an inflamed vessel by binding to carbohydrate-presenting counter-receptors displayed on leukocytes. Previous work in our laboratory has shown that artificial capsules with the adhesive properties of leukocytes can be made by attaching leukocyte adhesive ligands to polymer microspheres (Biomaterials 23(10) (2002) 2167). Specifically, we showed that drug-loaded poly (lactic-co-glycolic-acid) (PLGA) microspheres coated with biotinylated-Sialyl LewisX (sLeX), a carbohydrate that serves as a ligand to selectins, mimic the adhesive behavior of leukocytes on selectins in flow chambers, displaying slow rolling under flow, suggesting that these drug-loaded particles can potentially target inflammatory sites in vivo. Since the effectiveness of this delivery system might depend on the degradation of polymer microspheres as well as the degradation of sLeX molecules, we measured the effect of polymer and ligand degradation on the adhesiveness of microspheres over time. We show that degrading sLeX microspheres maintain the ability to recognize selectin surfaces under flow for at least 2 weeks and that the ability to sustain recognition depends upon the extent at which microspheres are loaded. We also show that microsphere rolling velocity increases as microsphere degrade and that this increase is due to a combination of increase in average microsphere size and loss of sLeX molecules on microsphere surface--a result of microsphere degradation confirmed by flow cytometry. Control experiments show that microsphere, not sLeX, degradation limits the lifetime of our targeted delivery system; therefore, factors affecting degradation such as type of polymer, type of drug, extent of drug loading and microsphere size, provide an opportunity for engineering the time-scale of activity for the delivery system.
Anti-Inflammatory Agents↗
Mechanism of binding and internalization of ICAM-1-derived cyclic peptides by LFA-1 on the surface of T cells: a potential method for targeted drug delivery.
PURPOSE: Peptides derived from the Domain 1 of the adhesion molecule ICAM-1(1-21) are being developed as targeting ligands for LFA-1 receptors expressed on activated T cells. This work aims to elucidate the binding and internalization of ICAM-1-derived cyclic peptides (cIBL, cIBC, and cIBR) to LFA-1. METHODS: Ninety-six-well plates coated with soluble LFA-1 (sLFA-1) were used to characterize the binding of FITC-labeled peptide. An anti-CD11a antibody to the I-domain of LFA-1 was used to inhibit the binding of these peptides, which was quantified using a fluorescence plate reader. An unrelated FITC-labeled cyclic peptide was used as a negative control, and PE-labeled anti-CD11a antibodies (PE-R3.2 and PE-R7.1) were used as positive controls. Peptide binding to cell surface LFA-1 was visualized using colocalization of FITC-cIBR peptide and PE-labeled anti-CD18 antibody (LFA-1 beta-subunit) on SKW-3 T cells by fluorescent microscopy. Inhibition of ICAM-1 binding to LFA-1 by peptides was evaluated using a Biacore assay. Binding and internalization of FITC-labeled peptides were evaluated by flow cytometry and confocal microscopy at 4 degrees C and 37 degrees C. RESULTS: These FITC-labeled cyclic peptides bind to sLFA-1 and can be blocked by an anti-CD11a antibody to the I-domain, suggesting that their binding site is on the I-domain of LFA-1. The FITC-cIBR peptide was localized with an anti-CD18 antibody on the surface of T cells, indicating that the FITC-cIBR peptide binds to LFA-1 on the cell surface. Flow cytometry and confocal microscopy demonstrated that FITC-labeled peptides were internalized in a temperature-dependent manner. Biacore analysis demonstrated that these peptides did not inhibit sICAM-1 from binding to immobilized sLFA-1. However, the binding properties of the soluble forms of LFA-1 and ICAM-1 may not correlate to their interaction at the cell surface. CONCLUSIONS: Cyclic ICAM-1-derived peptides (cIBL, cIBC, and cIBR) bind to the I-domain of LFA-1 and are internalized by LFA-1 receptors on the surface of T cells. Therefore, these peptides could be used to target and deliver drugs to the cytoplasmic domain of T cells.
Cell Line, Tumor↗
Stable integration of large (>100 kb) PAC constructs in HaCaT keratinocytes using an integrin-targeting peptide delivery system.
Transfer of large DNA constructs in gene therapy studies is being recognised for its importance in maintaining the natural genomic environment of the gene of interest and providing tissue-specific regulation and control. However, methods used to deliver such constructs have been poorly studied. We used a receptor-mediated, integrin-targeting transfection system enhanced by liposomes, to deliver a 110 kb PAC (P1-based artificial chromosome) to HaCaT keratinocytes. The PAC contained the collagen VII locus, an EGFP (enhanced green fluorescent protein) reporter gene and the puromycin resistance gene (pac) to allow selection of stably transfected cells. Analysis of puromycin resistant and EGFP-expressing colonies by Western blot showed that collagen VII production increased dramatically after transfection, indicating successful transfer of a large fully functional genomic locus. Fluorescent in situ hybridisation (FISH) and Southern blot analysis revealed that the PAC had integrated as at least one copy per cell. EGFP expression has persisted for 35 weeks, suggesting stable transgene expression. We conclude that the integrin-targeting peptide method of gene delivery is an effective means of stably delivering large DNA constructs to human keratinocytes and could be of benefit for genomic gene therapy approaches.
Anti-Bacterial Agents↗
Folate-conjugated methoxy poly(ethylene glycol)/poly(epsilon-caprolactone) amphiphilic block copolymeric micelles for tumor-targeted drug delivery.
Amphiphilic block copolymers composed of methoxy poly(ethylene glycol) (MPEG) and poly(epsilon-caprolactone) (PCL) were synthesized and then conjugated with folic acid to produce a folate-receptor-targeted drug carrier for tumor-specific drug delivery. Folate-conjugated MPEG/PCL micelles containing the anticancer drug paclitaxel were prepared by micelle formation in aqueous medium. The size of the folate-conjugated MPEG/PCL micelles formed was about 50-130 nm, depending on the molecular weight of block copolymers, and was maintained at less than 150 nm even after loading with paclitaxel. The in vitro release profile of the paclitaxel from the MPEG/PCL micelles exhibited no initial burst release and showed sustained release. Paclitaxel-loaded folate-conjugated MPEG/PCL micelles (PFOL50) exhibited much higher cytotoxicity for cancer cells, such as MCF-7 and HeLa cells, than MPEG/PCL micelles without the folate group (PMEP50). Confocal image analysis revealed that fluorescent paclitaxel-loaded PFOL50 micelles were endocytosed into MCF-7 cells through the interaction with overexpressed folate receptors on the surface of the cancer cells.
Antineoplastic Agents, Phytogenic↗
Enhancing and targeting nucleic acid delivery by magnetic force.
Insufficient contact of inherently highly active nucleic acid delivery systems with target cells is a primary reason for their often observed limited efficacy. Physical methods of targeting can overcome this limitation and reduce the risk of undesired side effects due to non-target site delivery. The authors and others have developed a novel means of physical targeting, exploiting magnetic force acting on nucleic acid vectors associated with magnetic particles in order to mediate the rapid contact of vectors with target cells. Here, the principles of magnetic drug and nucleic acid delivery are reviewed, and the facts and potentials of the technique for research and therapeutic applications are discussed. Magnetically enhanced nucleic acid delivery - magnetofection - is universally applicable to viral and non-viral vectors, is extraordinarily rapid, simple and yields saturation level transfection at low dose in vitro. The method is useful for site-specific vector targeting in vivo. Exploiting the full potential of the technique requires an interdisciplinary research effort in magnetic field physics, magnetic particle chemistry, pharmaceutical formulation and medical application.
Animals↗
A versatile system for receptor-mediated gene delivery permits increased entry of DNA into target cells, enhanced delivery to the nucleus and elevated rates of transgene expression.
We have developed a method for stabilisation of polyelectrolyte gene delivery vectors by crosslinking their surfaces with biodegradable multivalent copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA). The resulting nanoparticulate vectors resist attack by serum proteins and can be modified for cell-specific delivery by incorporation of targeting ligands onto the polymer coating. Here we show that vascular endothelial growth factor (VEGF), transferrin and basic fibroblast growth factor (bFGF) can each be linked to polyHPMA-coated poly(L-lysine)/DNA complexes. All ligand-targeted complexes demonstrated increased uptake into receptor-positive cells (measured using plasmids containing 32P-dCTP), that could be antagonised with excess free ligand. Targeted complexes also showed increased transfection, resistant to inhibition by serum, suggesting the possibility of effective application in vivo. Analysis using fluorescence microscopy confirmed enhanced uptake of ligand-targeted complexes (using Texas Red-labelled plasmid DNA), although VEGF- and transferrin-targeted complexes were restricted to cytoplasmic or perinuclear distributions. In contrast, bFGF-targeted complexes showed efficient delivery into the nucleus, with accumulation of more than 100000 plasmids per cell within distinct intranuclear compartments. This method permits versatile targeting of genes to selected cells and may also permit manipulation of intracellular trafficking. It should find several important applications in gene delivery systems both in vitro and in vivo.
Cell Nucleus↗