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Limits between molecular biology and nanotechnology: Impact on medicine
Abstract
Con el advenimiento de la Nanobiotecnología, han mejorado rápidamente las perspectivas para usar nanomateriales en Imaginología médica, diagnóstico de enfermedades, liberación de fármacos, tratamiento del cáncer, terapia génica y otras áreas. Se entiende por Nanomedicina la aplicación de nanotecnologías en Medicina para el mantenimiento y mejoramiento de la vida humana. Este artículo revisa el vasto potencial de los nanosistemas (nanoliposomas, gotas cuánticas, nanopartículas, dendrímeros) en estas áreas, con aplicaciones novedosas que constantemente están siendo exploradas.
Medicine and science have been walking together through human history. With the beginning of the century, many important scientific results have emerged in nanotechnology applied to medicine. Medicine is a potential market of nano world, with revolutionary implications that could bring, i.e. the cure of cancer, or the treatment of different diseases according to the specific characteristics of each patient, achieving a substantially better quality of life of the citizens. Cuba has a great opportunity in this new area due to its scientific potential in biomedical applications and its exchange with different countries to guarantee the domain of this new technology. This article addresses the working scale of nanotechnology, as well as provides the proposed definition of this term by the leading institutions in this field. It also provides information on the different areas comprising nanomedicine and gives a brief overview of nanomedicine worldwide and in Cuba, and its possible negative implications.
Biomolecules targets with radioactive nuclides and metallic nanoparticles currently are very use in practices nuclear medicine and general medicine for diagnostic and therapeutic diseases. The investigations new drugs to need go in the direction to obtain personality doses with minimum amount of drug to utilize for not induce adverse effects. Currently is very important know respect new techniques what strengthen the use adequate of minimum concentration at level pharmaceutics in organic fluids and that enable to towards the drugs in specific site for example in Diana cell or target cells. In this text, write the relevant information respect to use of radioactive nuclides and the synthetic peptides somatostatin derivates. Furthermore includes to functionalization of gold nanoparticles.
Nanotechnology provides the sized materials that can be synthesized and function in the same general size range and Biologic structures. We have attempted to develop forms of anticancer therapeutics based on nanomaterials. Our project seeks to develop dendritic polymer nanodevices that serve as a means for the detection of cancer cells, the identification of cancer signatures, and the targeted delivery of anti-cancer therapeutics (cis-platin, methotrexate, and taxol) and contrast agents to tumor cells. Initial studies documented the synthesis and function of a targeting module, several drug delivery components, and two imaging/contrast agents. Analytical techniques have been developed and used to confirm the structure of the device. Progress has been made on the specifically triggered release of the therapeutic agent within a tumor using high-energy lasers. The work to date has demonstrated the feasibility of the nano-device concept in actual cancer cells in vitro. Peer Reviewed http://deepblue.lib.umich.edu/bitstream/2027.42/44459/1/10544_2004_Article_338256.pdf
In vitro receptor measurements in tumors were performed to evaluate the potential of the vasoactive intestinal peptide receptor (VIP-R) as an imaging tool in human cancer.
Three hundred thirty-nine human tumors were investigated for their VIP-R content by in vitro receptor autoradiography on tissue sections with 125I-VIP. For comparison, somatostatin receptors (SS-R) were measured in adjacent sections of these tumors with 125I-[Tyr3]-octreotide.
VIP-R were characterized and localized in the neoplastic cells of most breast carcinomas, breast cancer metastases, ovarian adenocarcinomas, endometrial carcinomas, prostate cancer metastases, bladder carcinomas, colonic adenocarcinomas, pancreatic adenocarcinomas, gastrointestinal squamous cell carcinomas, non-small-cell lung cancers, lymphomas, astrocytomas, glioblastomas and meningiomas. Among neuroendocrine tumors, all differentiated and one-half of undifferentiated gastroenteropancreatic tumors, pheochromocytomas, small-cell lung cancers, neuroblastomas and inactive pituitary adenomas were found to express VIP-R. In general, VIP-R were found much more frequently than SS-R, but only 5 of 19 growth hormone-producing adenomas and no medullary thyroid carcinomas or Ewing sarcomas had VIP-R. In all tumors tested, the VIP-R were of high affinity and specific for VIP and pituitary adenylate cyclase-activating peptide. No cross-competition between VIP and SS could be identified.
Most human carcinomas express VIP-R, as measured by in vitro receptor autoradiography. These data represent the molecular basis for evaluation of VIP-R imaging of these tumors in vivo and predict its great potential value.
Peribronchial inflammation contributes to the pathophysiology of allergic asthma. In many vascular beds, adhesive interactions between leukocytes and the endothelial surface initiate the recruitment of circulating cells. Previous studies using OVA-induced airway hyperreactivity indicated that P-selectin, a member of the selectin family expressed by activated platelets and endothelium, contributed to both inflammation and bronchoconstriction. The current study used cockroach allergen (CRA), an allergen that induces asthmatic responses in both humans and mice, to further investigate the role of selectins in the development of peribronchial inflammation and airway hyperreactivity. P- and E-selectin mRNAs were detected in extracts of CRA-sensitized animals beginning shortly after intratracheal challenge with CRA. The P-selectin mRNA was transiently induced at early time points while up-regulation of the E-selectin mRNA was more prolonged. Mice with targeted deletions in E-selectin (E(-)), P-selectin (P(-)), and both genes (E(-)/P(-)) showed 70-85% reductions in airway hyperreactivity, peribronchial inflammation, and eosinophil accumulation. The P(-) and E(-)/P(-) groups showed the most profound reductions. The transfer of splenic lymphocytes from CRA-primed E(-)/P(-) into naive wild-type (WT) mice produced the same level of airway hyperreactivity as transfers from CRA-primed WT into naive WT hosts, indicating that peripheral immunization was similar. The observed changes in the selectin-deficient animals were not related to inadequate sensitization, because CRA priming and challenge increased serum IgE levels. Furthermore, pulmonary Th2-type cytokines and chemokines in the E-selectin(-/-) and WT animals were similar. The findings indicate that both P- and E-selectin contribute to CRA-induced peribronchial inflammation and airway hyperreactivity.
Restenosis is a serious complication of coronary angioplasty that involves the proliferation and migration of vascular smooth muscle cells (VSMCs) from the media to the intima, synthesis of extracellular matrix, and remodeling. We have previously demonstrated that tissue factor-targeted nanoparticles can penetrate and bind stretch-activated vascular smooth muscles in the media after balloon injury. In the present study, the concept of VSMC-targeted nanoparticles as a drug-delivery platform for the prevention of restenosis after angioplasty is studied.
Tissue factor-targeted nanoparticles containing doxorubicin or paclitaxel at 0, 0.2, or 2.0 mole% of the outer lipid layer were targeted for 30 minutes to VSMCs and significantly inhibited their proliferation in culture over the next 3 days. Targeting of the nanoparticles to VSMC surface epitopes significantly increased nanoparticle antiproliferative effectiveness, particularly for paclitaxel. In vitro dissolution studies revealed that nanoparticle drug release persisted over one week. Targeted antiproliferative results were dependent on the hydrophobic nature of the drug and noncovalent interactions with other surfactant components. Molecular imaging of nanoparticles adherent to the VSMC was demonstrated with high-resolution T1-weighted MRI at 4.7T. MRI 19F spectroscopy of the nanoparticle core provided a quantifiable approach for noninvasive dosimetry of targeted drug payloads.
These data suggest that targeted paramagnetic nanoparticles may provide a novel, MRI-visualizable, and quantifiable drug delivery system for the prevention of restenosis after angioplasty.
We describe the development of multifunctional nanoparticle probes based on semiconductor quantum dots (QDs) for cancer targeting and imaging in living animals. The structural design involves encapsulating luminescent QDs with an ABC triblock copolymer and linking this amphiphilic polymer to tumor-targeting ligands and drug-delivery functionalities. In vivo targeting studies of human prostate cancer growing in nude mice indicate that the QD probes accumulate at tumors both by the enhanced permeability and retention of tumor sites and by antibody binding to cancer-specific cell surface biomarkers. Using both subcutaneous injection of QD-tagged cancer cells and systemic injection of multifunctional QD probes, we have achieved sensitive and multicolor fluorescence imaging of cancer cells under in vivo conditions. We have also integrated a whole-body macro-illumination system with wavelength-resolved spectral imaging for efficient background removal and precise delineation of weak spectral signatures. These results raise new possibilities for ultrasensitive and multiplexed imaging of molecular targets in vivo.
Metastasis is an impediment to the development of effective cancer therapies. Our understanding of metastasis is limited by our inability to follow this process in vivo. Fluorescence microscopy offers the potential to follow cells at high resolution in living animals. Semiconductor nanocrystals, quantum dots (QDs), offer considerable advantages over organic fluorophores for this purpose. We used QDs and emission spectrum scanning multiphoton microscopy to develop a means to study extravasation in vivo. Although QD labeling shows no deleterious effects on cultured cells, concern over their potential toxicity in vivo has caused resistance toward their application to such studies. To test if effects of QD labeling emerge in vivo, tumor cells labeled with QDs were intravenously injected into mice and followed as they extravasated into lung tissue. The behavior of QD-labeled tumor cells in vivo was indistinguishable from that of unlabeled cells. QDs and spectral imaging allowed the simultaneous identification of five different populations of cells using multiphoton laser excitation. Besides establishing the safety of QDs for in vivo studies, our approach permits the study of multicellular interactions in vivo.
Bleeding is clearly a major cause of morbidity and death after trauma. When bleeding is attributable to transection of major vessels, surgical repair is appropriate. Posttraumatic microvascular bleeding attributable to coagulopathy secondary to metabolic derangements, hypothermia, and depletion or dysfunction of cellular and protein components requires a different approach. Although transfusion of blood products may be necessary to replace the blood loss, it does not always correct the problem of microvascular bleeding. The type of injury, mode of care, and treatment objectives differ significantly for combat-wounded soldiers versus civilian trauma patients. Although hemorrhage is responsible for 50% of combat deaths, published information about coagulation monitoring among combat patients is very limited. These articles summarize the appropriate monitoring of hemostasis among combat trauma patients, review the unique nature of combat casualties and the medical system used to treat them, and discuss information available from civilian studies. Because the development of coagulopathy is relatively infrequent in the young, otherwise healthy, military population, the routine screening measures currently used are adequate to guide initial blood product administration. However, as new intravenous hemostatic agents are used for these patients, better laboratory measures will be required. Although hemorrhage is the leading cause of death for combat casualties, catastrophic hemorrhage is rarely a prehospital combat medical management problem because, when it occurs, it tends to cause death before medical care can be provided. In civilian environments, most seriously injured victims can be reached and transported by emergency medical services personnel within minutes; in combat, it often takes hours simply to transport casualties off the battlefield. In combat situations, even if the transport distances are small, the hazardous nature of the forward combat areas frequently prevents medical personnel from quickly reaching the wounded. Furthermore, whereas civilian blunt trauma victims may have a "golden hour," casualties with penetrating battlefield trauma often have only a "platinum 5 minutes." Because of the challenges of treating hemorrhage during combat, it is important for military medical personnel to understand their options for treating hemorrhage quickly and efficiently. These articles discuss the causes of posttraumatic microvascular bleeding and the potential treatment options for controlling catastrophic hemorrhage in combat areas.
Nanotechnology provides new materials in the nanometer range with many potential applications in clinical medicine and research. Due to their unique size-dependent properties nanomaterial such as nanoparticles offer the possibility to develop both new therapeutic and diagnostic tools. Thus, applied nanotechnology to medical problems--nanomedicine--can offer new concepts that are reviewed. The ability to incorporate drugs into nanosystems displays a new paradigm in pharmacotherapy that could be used for cell-targeted drug delivery. Nontargeted nanosystems such as nanocarriers that are coated with polymers or albumin and solid lipid particles have been used as transporter in vivo. However, nowadays drugs can be coupled to nanocarriers that are specific for cells and/or organs. Thus, drugs that are either trapped within the carriers or deposited in subsurface oil layers could be specifically delivered to organs, tumors and cells. These strategies can be used to concentrate drugs in selected target tissues thus minimizing systemic side effects and toxicity. In addition to these therapeutic options, nanoparticle-based "molecular" imaging displays a field in which this new technology has set the stage for an evolutionary leap in diagnostic imaging. Based on the recent progress in nanobiotechnology there is potential for nanoparticles and -systems to become useful tools as therapeutic and diagnostic tools in the near future.
Nanomaterials are engineered structures with at least one dimension of 100 nanometers or less. These materials are increasingly
being used for commercial purposes such as fillers, opacifiers, catalysts, semiconductors, cosmetics, microelectronics, and
drug carriers. Materials in this size range may approach the length scale at which some specific physical or chemical interactions
with their environment can occur. As a result, their properties differ substantially from those bulk materials of the same
composition, allowing them to perform exceptional feats of conductivity, reactivity, and optical sensitivity. Possible undesirable
results of these capabilities are harmful interactions with biological systems and the environment, with the potential to
generate toxicity. The establishment of principles and test procedures to ensure safe manufacture and use of nanomaterials
in the marketplace is urgently required and achievable.
During the last few years, research on toxicologically relevant properties of engineered nanoparticles has increased tremendously. A number of international research projects and additional activities are ongoing in the EU and the US, nourishing the expectation that more relevant technical and toxicological data will be published. Their widespread use allows for potential exposure to engineered nanoparticles during the whole lifecycle of a variety of products. When looking at possible exposure routes for manufactured Nanoparticles, inhalation, dermal and oral exposure are the most obvious, depending on the type of product in which Nanoparticles are used. This review shows that (1) Nanoparticles can deposit in the respiratory tract after inhalation. For a number of nanoparticles, oxidative stress-related inflammatory reactions have been observed. Tumour-related effects have only been observed in rats, and might be related to overload conditions. There are also a few reports that indicate uptake of nanoparticles in the brain via the olfactory epithelium. Nanoparticle translocation into the systemic circulation may occur after inhalation but conflicting evidence is present on the extent of translocation. These findings urge the need for additional studies to further elucidate these findings and to characterize the physiological impact. (2) There is currently little evidence from skin penetration studies that dermal applications of metal oxide nanoparticles used in sunscreens lead to systemic exposure. However, the question has been raised whether the usual testing with healthy, intact skin will be sufficient. (3) Uptake of nanoparticles in the gastrointestinal tract after oral uptake is a known phenomenon, of which use is intentionally made in the design of food and pharmacological components. Finally, this review indicates that only few specific nanoparticles have been investigated in a limited number of test systems and extrapolation of this data to other materials is not possible. Air pollution studies have generated indirect evidence for the role of combustion derived nanoparticles (CDNP) in driving adverse health effects in susceptible groups. Experimental studies with some bulk nanoparticles (carbon black, titanium dioxide, iron oxides) that have been used for decades suggest various adverse effects. However, engineered nanomaterials with new chemical and physical properties are being produced constantly and the toxicity of these is unknown. Therefore, despite the existing database on nanoparticles, no blanket statements about human toxicity can be given at this time. In addition, limited ecotoxicological data for nanomaterials precludes a systematic assessment of the impact of Nanoparticles on ecosystems.
Tuberculosis is a leading killer of young adults worldwide and the global scourge of multi-drug resistant tuberculosis is reaching epidemic proportions. It is endemic in most developing countries and resurgent in developed and developing countries with high rates of human immunodeficiency virus infection. This article reviews the current situation in terms of drug delivery approaches for tuberculosis chemotherapy. A number of novel implant-, microparticulate-, and various other carrier-based drug delivery systems incorporating the principal anti-tuberculosis agents have been fabricated that either target the site of tuberculosis infection or reduce the dosing frequency with the aim of improving patient outcomes. These developments in drug delivery represent attractive options with significant merit, however, there is a requisite to manufacture an oral system, which directly addresses issues of unacceptable rifampicin bioavailability in fixed-dose combinations. This is fostered by the need to deliver medications to patients more efficiently and with fewer side effects, especially in developing countries. The fabrication of a polymeric once-daily oral multiparticulate fixed-dose combination of the principal anti-tuberculosis drugs, which attains segregated delivery of rifampicin and isoniazid for improved rifampicin bioavailability, could be a step in the right direction in addressing issues of treatment failure due to patient non-compliance.
In approving drug-eluting stents, the FDA obliged manufacturers to track all subjects in their pivotal clinical trials for 5 years. Dr. Miriam Shuchman discusses the recent data that challenge the golden reputation of drug-eluting stents.
With the advent of nanotechnology, the prospects for using engineered nanomaterials with diameters of < 100 nm in industrial applications, medical imaging, disease diagnoses, drug delivery, cancer treatment, gene therapy, and other areas have progressed rapidly. The potential for nanoparticles (NPs) in these areas is infinite, with novel new applications constantly being explored. The possible toxic health effects of these NPs associated with human exposure are unknown. Many fine particles generally considered "nuisance dusts" are likely to acquire unique surface properties when engineered to nanosize and may exhibit toxic biological effects. Consequently, the nuisance dust may be transported to distant sites and could induce adverse health effects. In addition the beneficial uses of NPs in drug delivery, cancer treatment, and gene therapy may cause unintentional human exposure. Because of our lack of knowledge about the health effects associated with NP exposure, we have an ethical duty to take precautionary measures regarding their use. In this review we highlight the possible toxic human health effects that can result from exposure to ultrafine particles (UFPs) generated by anthropogenic activities and their cardiopulmonary outcomes. The comparability of engineered NPs to UFPs suggests that the human health effects are likely to be similar. Therefore, it is prudent to elucidate their toxicologic effect to minimize occupational and environmental exposure. Highlighting the human health outcomes caused by UFPs is not intended to give a lesser importance to either the unprecedented technologic and industrial rewards of the nanotechnology or their beneficial human uses.
Purpose. Aim of the study was the evaluation of the potential of novel tetanus toxoid (TT) loaded nanoparticles (NP) for electing an immune response in mice against TT.
Methods. Six week-old female Balb/c mice were immunized by oral (p.o.), nasal (i.n.) and intraperitoneal (i.p.) application of TT NP loaded by adsorption. As polymer a novel polyester, sulfobutylated poly(vinyl alcohol)-graft-poly(lactide-co-glycolide), SB(43)-PVAL-g-PLGA was used. Blood samples were collected 4 and 6 weeks after immunization and assayed for serum IgG- as well as IgA antibody titers by ELISA. NP formulations varying in size and loading were compared to alum adsorbates as well as to TT solutions.
Results. Both, p.o. and i.n. administration of TT associated NP increased serum titers up to 3 103 (IgG) and 2 103 (IgA). While small NP induced significantly higher titers then larger ones after oral administration, intermediate NP induced antibodies after nasal application. Of the mucosal routes investigated, i.n. seems to be more promising compared to p.o. immunization.
Conclusions. Antigen loaded NP prepared from surface modified polyesters combined with CT show considerable potential as a vaccine delivery system for mucosal immunization. The results warrant further experiments to explore in more detail the potential use of NP as mucosal vaccine delivery system.
Nanoparticles are polymeric particles in the nanometer size range whereas microparticles are particles in the micrometre size range. Both types of particle are used as drug carriers into which drugs or antigens may be incorporated in the form of solid solutions or solid dispersions or onto which these materials may be absorbed or chemically bound. These particles have been shown to enhance the delivery of certain drugs across a number of natural and artificial membranes. In addition, the particles were shown to accumulate in areas of the intestine that appear to be the Peyer's patches. Possibly because of the combination of both effects these particles were able to significantly improve the bioavailability of some drugs after peroral administration in comparison with solutions. Recently nanoparticles coated with polysorbate 80 enabled the passage of small peptides and other drugs across the blood-brain barrier and the exhibition of a pharmacological effect after intravenous injection. Without the use of this type of nanoparticles the drugs did not cross this barrier and yielded no effect.
The early bactericidal activity (EBA) of a liposomal preparation of amikacin (MiKasome) with a long plasma half-life of 120-200 h was examined in seven patients with newly diagnosed, smear-positive pulmonary tuberculosis. Liposomal amikacin was given in slow iv infusions of 30 mg total amikacin/kg body weight on three successive days. Cfu counts were set up on 16 h sputum collections preceding the first dose and following each dose and were used for calculating the EBA. Despite the high concentrations of total amikacin, >1000 mg/L, obtainable in plasma, no evidence of EBA was obtained. In view of the considerable activity of liposomal amikacin in experimental murine tuberculosis, this finding indicates that liberation of amikacin from the long-life liposomes occurs only in macrophages that are not usually present in the vicinity of the large extracellular clumps of bacilli in the cavity caseum.
Great progress in the development of molecular biology techniques has been seen since the discovery of the structure of deoxyribonucleic acid (DNA) and the implementation of a polymerase chain reaction (PCR) method. This started a new era of research on the structure of nucleic acids molecules, the development of new analytical tools, and DNA-based analyses. The latter included not only diagnostic procedures but also, for example, DNA-based computational approaches. On the other hand, people have started to be more interested in mimicking real life, and modeling the structures and organisms that already exist in nature for the further evaluation and insight into their behavior and evolution. These factors, among others, have led to the description of artificial organelles or cells, and the construction of nanoscale devices. These nanomachines and nanoobjects might soon find a practical implementation, especially in the field of medical research and diagnostics. The paper presents some examples, illustrating the progress in multidisciplinary research in the nanoscale area. It is focused especially on immunogenetics-related aspects and the wide usage of DNA molecules in various fields of science. In addition, some proposals for nanoparticles and nanoscale tools and their applications in medicine are reviewed and discussed.
Dendrimers are synthetic, highly branched, mono-disperse macromolecules of nanometer dimensions. Started in the mid-1980s, the research investigations into the synthetic methodology, physical and chemical properties of these macromolecules are increasing exponentially with growing interest in this field. Potential applications for dendrimers are now forthcoming. Properties associated with these dendrimers such as uniform size, water solubility, modifiable surface functionality and available internal cavities make them attractive for biological and drug-delivery applications.
In the past year, significant advances have been made in the synthesis and study of glycodendrimers and peptide dendrimers. Application of these dendrimers to the study of carbohydrate-protein and protein-protein interactions has facilitated the understanding of these processes. In addition, dendrimers show great promise as DNA- and drug-delivery systems.
In this study, injectable microemulsions of vincristine (M-VCR) were prepared and its pharmacokinetics, acute toxicity and antitumor effects were evaluated. In M-VCR, the surfactants were PEG-lipid and cholesterol, the oil phase was a vitamin E solution of oleic acid and VCR. The particle size distribution and zeta potential of M-VCR were measured by the laser light dynamic scattering method. The VCR-loading efficiency was measured by Sephadex G50 column chromatography. The stability of M-VCR was monitored by particle size, VCR-loading efficiency and VCR content changes of M-VCR stored at 7 degrees C. The pharmacokinetics, acute toxicity and antitumor effects of M-VCR were studied in C57BL/6 mice bearing mouse murine histocytoma M5076 tumors. When stored at 7 degrees C in the dark for 1 year, the average diameter and VCR-loading efficiency of M-VCR changed from 138.1+/-1.2 nm and 94.6+/-4.7% to 127.1+/-2.4 nm and 91.3+/-4.8% (n=3), respectively, while 7.4+/-0.3% VCR decomposition was observed (n=3). The plasma AUC of M-VCR was significantly greater than that of free VCR (F-VCR). The heart, spleen and liver AUC(0.08-12 h) of M-VCR were significantly smaller than those of F-VCR while the kidney AUC(0.08-12 h) of M-VCR was significantly greater than that of F-VCR. The tumor AUC(0.08-12 h) of M-VCR was significantly greater than that of F-VCR. M-VCR had lower acute toxicity and greater potential antitumor effects than F-VCR in M5076 tumor-bearing C57BL/6 mice. M-VCR is a useful tumor-targeting microemulsion drug delivery system.
The worldwide emergence of nanoscale science and engineering was marked by the announcement of the National Nanotechnology Initiative (NNI) in January 2000. Recent research on biosystems at the nanoscale has created one of the most dynamic science and technology domains at the confluence of physical sciences, molecular engineering, biology, biotechnology and medicine. This domain includes better understanding of living and thinking systems, revolutionary biotechnology processes, the synthesis of new drugs and their targeted delivery, regenerative medicine, neuromorphic engineering and developing a sustainable environment. Nanobiosystems research is a priority in many countries and its relevance within nanotechnology is expected to increase in the future.
Biodegradable poly(isobutylcyanoacrylate) nanocapsules have been recognized as a promising carrier for oral administration of peptides and proteins. In the present study, we investigate the fate of insulin-loaded nanocapsules by fluorescence and transmission electron microscopy (TEM) after intragastric force-feeding to rats.
Insulin-, Texas-red-labeled insulin, or gold-labeled insulin-loaded nanocapsules were first characterized. Rats received a single dose of nanocapsules (diameter 60-300 nm, 57 IU insulin/kg) by intragastric force-feeding. After 90 min, ileum was isolated and prepared for fluorescence and transmission electron microscopy.
Nanocapsules were observed on both sides of the gut epithelium and in blood capillaries. In M-cell-free epithelium, apparently intact nanocapsules could be seen in the underlying tissue, suggesting they could cross the epithelium and carry the encapsulated peptide. In M-cell-containing epithelium, nanocapsules appeared degraded in the vicinity of macrophages. It is noteworthy that intestinal absorption of nanocapsules was observed without artifacts forcing the nanocapsules to stay in the gut.
Based on TEM observations, this study shows the intestinal absorption of biodegradable nanocapsules leading to the transport of insulin across the epithelium mucosa. The fate of the nanocapsules appeared different depending on the presence or the absence of M cells in the intestinal epithelium.
Biomaterials that successfully integrate into surrounding tissue should match not only the tissue's mechanical properties, but also its topography. The cellular response to a biomaterial may be enhanced in synthetic polymer formulations by mimicking the surface roughness created by the associated nano-structured extra-cellular matrix components of natural tissue. As a first step towards this endeavor, the goal of the present in vitro study was to use these design parameters to develop a synthetic, nano-structured, polymeric biomaterial that promotes cell adhesion and growth for vascular applications. In a novel manner, poly(lactic-co-glycolic acid) (PLGA) (50/50wt% mix) was synthesized to possess a range (from micron to nanometer) of surface features. Reduction of surface features was accomplished by treating conventional PLGA with various concentrations of NaOH for select periods of time. Results from cell experiments indicated that, compared to conventional PLGA, NaOH treated PLGA enhanced vascular smooth muscle cell adhesion and proliferation. However, PLGA prepared by soaking in NaOH decreased endothelial cell adhesion and proliferation compared to conventional PLGA. After further investigation, this finding was determined to be a result of chemical (and not topographical) changes during polymer synthesis. Surface chemistry effects were removed while retaining nano-structured topography by using polymer/elastomer casting methods. Results demonstrated that endothelial and smooth muscle cell densities increased on nano-structured cast PLGA. For these reasons, the present in vitro study provided the first evidence that nano-structured surface features can significantly improve vascular cell densities; such design criteria can be used in the synthesis of the next-generation of more successful tissue-engineered vascular grafts.
Background
Allergic subjects produce relatively low amounts of IFN-γ, a pleiotropic Th-1 cytokine that downregulates Th2-associated airway inflammation and hyperresponsiveness (AHR), the hallmarks of allergic asthma. Adenovirus-mediated IFN-γ gene transfer reduces AHR, Th2 cytokine levels and lung inflammation in mice, but its use would be limited by the frequency of gene delivery required; therefore, we tested chitosan/IFN-γ pDNA nanoparticles (CIN) for in situ production of IFN-γ and its in vivo effects.
Methods
CIN were administered to OVA-sensitized mice to investigate the possibility of using gene transfer to modulate ovalbumin (OVA)-induced inflammation and AHR.
Results
Mice treated with CIN exhibit significantly lower AHR to methacholine challenge and less lung histopathology. Production of IFN-γ is increased after CIN treatment while the Th2-cytokines, IL-4 and IL-5, and OVA-specific serum IgE are reduced compared to control mice. AHR and eosinophilia are also significantly reduced by CIN therapy administered therapeutically in mice with established asthma. CIN was found to inhibit epithelial inflammation within 6 hours of delivery by inducing apoptosis of goblet cells. Experiments performed on STAT4-defective mice do not show reduction in AHR with CIN treatment, thus implicating STAT4 signaling in the mechanism of CIN action.
Conclusion
These results demonstrate that mucosal CIN therapy can effectively reduce established allergen-induced airway inflammation and AHR.
SPI-077 and SPI-077 B103 are formulations of cisplatin encapsulated in pegylated STEALTH liposomes that accumulate in tumors. However, the extent to which active platinum (Pt) is released from the liposome is unknown. Thus, we evaluated the disposition of encapsulated and released Pt in plasma and tumors after administration of STEALTH liposomal and nonliposomal cisplatin.
Cisplatin (10 mg/kg), SPI-077 (10 mg/kg), and SPI-077 B103 (5 mg/kg) were administered i.v. to mice bearing B16 murine melanoma tumors. Microdialysis probes were placed into the right and left sides of each tumor, and serial samples were collected from tumor extracellular fluid (ECF) after administration of each agent. After each microdialysis procedure, tumor samples were obtained at each probe site to measure total Pt and Pt-DNA adducts. In a separate study, serial plasma samples (three mice per time point) were obtained. Unbound Pt in tumor ECF and plasma, and total Pt in tumor homogenates were measured by flameless atomic absorption spectrophotometry. Area under the tumor ECF (AUC(ECF)) concentration versus time curves of unbound Pt were calculated. Intrastrand GG (Pt-GG) and AG (Pt-AG) Pt-DNA adducts were measured via (32)P-postlabeling.
Mean+/-SD peak concentrations of total Pt in tumor homogenates after administration of cisplatin, SPI-077, and SPI-077 B-103 were 3.2+/-1.9, 11.9+/-3.0, and 3.5+/-0.3 microg/g, respectively. After cisplatin, mean+/-SD AUC(ECF) of unbound Pt was 0.72+/-0.46 microg/ml.h. There was no detectable unbound Pt in tumor ECF after SPI-077 or SPI-077 B-103 treatment. Mean+/-SD peak concentration of Pt-GG DNA adducts after administration of cisplatin, SPI-077, and SPI-077 B-103 were 13.1+/-3.3, 3.5+/-1.3, and 2.1+/-0.3 fmol Pt/microg DNA, respectively.
This study suggests that more SPI-077 and SPI-077 B103 distribute into tumors, but release less Pt into tumor ECF, and form fewer Pt-DNA adducts than does cisplatin.
Nanotechnology, a multidisciplinary scientific undertaking, involves creation and utilization of materials, devices or systems on the nanometer scale. The field of nanotechnology is currently undergoing explosive development on many fronts. The technology is expected to create innovations and play a critical role in various biomedical applications, not only in drug delivery, but also in molecular imaging, biomarkers and biosensors. Target-specific drug therapy and methods for early diagnosis of pathologies are the priority research areas where nanotechnology would play a vital role. This review considers different nanotechnology-based drug delivery and imaging approaches, and their economic impact on pharmaceutical and biomedical industries.
The purpose is to evaluate the feasibility and safety of aerosol administration of the topoisomerase I inhibitor, 9-nitrocamptothecin, in a liposome formulation, and to recommend a dosage for a Phase II trial for an 8-week daily treatment schedule.
Patients with primary or metastatic lung cancer received aerosolized liposomal 9-nitrocamptothecin for 5 consecutive days/week for 1, 2, 4, or 6 weeks followed by 2 weeks of rest to determine feasibility. For the Phase I part, the dose was increased stepwise from 6.7 up to 26.6 micro g/kg/day Monday to Friday for 8 weeks followed by 2 weeks of rest.
Twenty-five patients received treatment. The mean baseline forced expiratory volume in 1 second for all patients was 85% of predicted. A dose-limiting toxicity was chemical pharyngitis seen after 1 week in 2 of 2 patients at 26.6 micro g/kg/day. At 20.0 micro g/kg/day, grade 2 and 3 fatigue prompting a dose reduction was seen after 4 weeks in 2 of 4 patients. Grade 2 toxic effects included nausea/vomiting (9 patients), cough and bronchial irritation (6 patients), fatigue (5 patients), anemia (4 patients), neutropenia (2 patients), anorexia (1 patient), and skin rash around the face mask (1 patient). 9-Nitro-20(S)-camptothecin (9NC) was absorbed systemically. Partial remissions were observed in 2 patients with uterine cancer, and stabilization occurred in 3 patients with primary lung cancer.
Aerosol administration of liposomal 9NC was found to be feasible and safe. 9NC delivered as an aerosol was detected in patient's plasma shortly after the start of treatment. The recommended dose for Phase II studies is 13.3 micro g/kg/day (equivalent to 0.5 mg/m(2)/day), which constitutes two consecutive 30-min nebulizations/day from a nebulizer reservoir with 4 mg of 9NC in 10 ml of sterile water, Monday to Friday for 8 weeks every 10 weeks.
Drug delivery is an interdisciplinary area of research that aims at making the administration of complex new drugs feasible, as well as adding critical value to the drugs that are currently in the market. At present, one of the most attractive areas of research in drug delivery is the design of nanomedicines consisting of nanosystems that are able to deliver drugs to the right place, at appropriate times. The goal of the present article is to review the advances we have made in the development and characterization of nanosystems intended to be used as drug carriers for mucosal administration. These nanocarriers are able to protect the associated drug against degradation and facilitate its transport across critical and specific barriers. Some of them, are further able to release the associated drug to the target tissue in a controlled manner. These nanocarriers have been made of safe materials, including synthetic biodegradable polymers, lipids and polysaccharides. A number of nanotechnologies have been developed that enable the association of a variety of drugs to these nanocarriers, ranging from classical small drug to large DNA fragments. The in vitro cell culture studies and the in vivo experiments have evidenced the potential of these nanocarriers for overcoming important mucosal barriers, such as the intestinal, nasal and ocular barriers. Hopefully, this will soon represent a strategy for making cheaper and faster, more efficacious medicines.
High molecular weight (Mw) chitosan (CS) solutions have already been proposed as vehicles for nasal immunization. The aim of the present work was to investigate the potential utility of low Mw CS in the form of nanoparticles as new long-term nasal vaccine delivery vehicles. For this purpose, CS of low Mws (23 and 38 kDa) was obtained previously by a depolymerization process of the commercially available CS (70 kDa). Tetanus toxoid (TT), used as a model antigen, was entrapped within CS nanoparticles by an ionic cross-linking technique. TT-loaded nanoparticles were first characterized for their size, electrical charge, loading efficiency and in vitro release of antigenically active toxoid. The nanoparticles were then administered intranasally to conscious mice in order to study their feasibility as vaccine carriers. CS nanoparticles were also labeled with FITC-BSA and their interaction with the rat nasal mucosa examined by confocal laser scanning microcopy (CLSM). Irrespective of the CS Mw, the nanoparticles were in the 350 nm size range, and exhibited a positive electrical charge (+40 mV) and associated TT quite efficiently (loading efficiency: 50-60%). In vitro release studies showed an initial burst followed by an extended release of antigenically active toxoid. Following intranasal administration, TT-loaded nanoparticles elicited an increasing and long-lasting humoral immune response (IgG concentrations) as compared to the fluid vaccine. Similarly, the mucosal response (IgA levels) at 6 months post-administration of TT-loaded CS nanoparticles was significantly higher than that obtained for the fluid vaccine. The CLSM images indicated that CS nanoparticles can cross the nasal epithelia and, hence, transport the associated antigen. Interestingly, the ability of these nanoparticles to provide improved access to the associated antigen to the immune system was not significantly affected by the CS Mw. Indeed, high and long-lasting responses could be obtained using low Mw CS molecules. Furthermore, the response was not influenced by the CS dose (70-200 microg), achieving a significant response for a very low CS dose. In conclusion, nanoparticles made of low Mw CS are promising carriers for nasal vaccine delivery.
Taxol is a marketed product for the treatment of ovarian, breast, non-small cell lung cancer and AIDS-related Kaposi's Sarcoma. It is thus far one of the most effective anticancer drugs available on the market. However, paclitaxel is only sparingly soluble in water and therefore, intravenous administration depends on the use of the non-ionic surfactant Cremophor EL (polyethoxylated castor oil) to achieve a clinically relevant concentrated solution. Unfortunately, Cremophor EL increases toxicity and leads to hypersensitivity reactions in certain individuals. We have developed a well characterized novel lyophilized liposome-based paclitaxel (LEP-ETU) formulation that is sterile, stable and easy-to-use. The mean particle size of the liposomes is about 150 nm before and after lyophilization, and the drug entrapment efficiency is greater than 90%. Stability data indicated that the lyophilized LEP-ETU was physically and chemically stable for at least 12 months at 2-8 and 25 degrees C. Moreover, the formulation can be diluted to about 0.25mg/ml without drug precipitation or change in particle size. In vitro drug release study in phosphate-buffered saline (PBS, pH 7.4) showed that less than 6% of the entrapped paclitaxel was released after 120 h, indicating that the drug is highly stable in an entrapped form at physiologic temperature.
Nanocrystals (quantum dots) and other nanoparticles (gold colloids, magnetic bars, nanobars, dendrimers and nanoshells) have been receiving a lot of attention recently with their unique properties for potential use in drug discovery, bioengineering and therapeutics. In this review, structural, optical and biological assets of nanocrystals are summarized and their applications to drug discovery studies are discussed. Unique properties of these nanoparticles can offer new advancements in drug discovery.
Asthma and COPD are chronic inflammatory conditions that affect hundreds of millions of patients worldwide. New therapeutics are desperately needed, especially those that target the underlying causes and prevent disease progression. Although asthma and COPD have distinct etiologies, both are associated with reduced airflow caused by excess infiltration of inflammatory cells into healthy lung tissues. As selectin-mediated adhesion of leukocytes to the vascular endothelium is a key early event in the initiation of the inflammatory response, selectin inhibition is thought to be a good target for therapeutic intervention. Three known selectins are expressed in distinct subsets of cells: P-selectin is presented on the surface of activated platelets and endothelial cells, L-selectin is constitutively expressed on leukocytes, and E-selectin synthesis is upregulated in activated endothelial cells. They mediate cell-cell adhesion in the shear flow of the bloodstream via specialized interactions with clusters of oligosaccharides presented on cell surface glycopeptide ligands. The role of selectin-ligand interactions in the inflammatory response has been demonstrated in various animal models, prompting considerable attention from the pharmaceutical industry.Drug discovery efforts have yielded many different classes of selectin inhibitors, including soluble protein ligands, antibodies, oligosaccharides and small molecules. Although many selectin inhibitors have shown activity in preclinical models, clinical progress of selectin-directed therapies has been slow. Early approaches employed carbohydrate-based inhibitors to mimic the natural ligand sialyl Lewis X; however, these compounds proved challenging to develop. Cytel's CY 1503, a complex oligosaccharide, progressed to phase II/III trials for reperfusion injury, but further development was halted when it failed to demonstrate clinical efficacy. Two protein-based selectin inhibitors have reached phase II development. These included Wyeth's recombinant soluble P-selectin ligand, TSI (PSGL-1), which was discontinued after disappointing results in myocardial infarction trials and Protein Design Labs' humanized anti-L-selectin monoclonal antibody, which is currently in development for trauma. Bimosiamose, discovered by Encysive Pharmaceutical and presently being developed by Revotar Biopharmaceuticals, is an 863 g/mol molecular weight dimer with minimal carbohydrate content and is, to date, the leading selectin inhibitor in clinical development. This compound has shown promise in a phase IIa 'proof of concept' trial in patients with asthma, reducing airway recruitment of eosinophils after intravenous administration. Further clinical development of an inhaled formulation is underway. Despite a significant need for new therapeutics, selectin inhibitors have not yet been explored for the treatment of COPD. Bimosiamose represents an important proof of principle, and hopefully continued success will spark renewed interest in selectin-directed therapeutics for respiratory diseases.
Nanotechnology can be defined as the science and engineering involved in the design, synthesis, characterization, and application of materials and devices whose smallest functional organization in at least one dimension is on the nanometer scale or one billionth of a meter. At these scales, consideration of individual molecules and interacting groups of molecules in relation to the bulk macroscopic properties of the material or device becomes important, since it is control over the fundamental molecular structure that allows control over the macroscopic chemical and physical properties. Applications to medicine and physiology imply materials and devices designed to interact with the body at subcellular (i.e., molecular) scales with a high degree of specificity. This can potentially translate into targeted cellular and tissue-specific clinical applications designed to achieve maximal therapeutic affects with minimal side effects. In this review the main scientific and technical aspects of nanotechnology are introduced and some of its potential clinical applications are discussed.
Liposomes composed of HePC:EPC:SA 10:10:0.1 (molar ratio) (1) and EPC:SA 10:0.1 (molar ratio) (2) were prepared and were used for incorporating the doxorubicin-PAMAM complex (3:1 molar ratio) (3). The doxorubicin-PAMAM complex was attached to liposomes and the incorporation efficiency was 91 and 95% for 1 and 2, respectively. The incorporation efficiency for doxorubicin into PAMAM was almost 97% while doxorubicin to PAMAM molar ratio was 3.56+/-0.04. The release rate of doxorubicin as doxorubicin-PAMAM complex from liposomes 1 and 2 and from the complex 3, was studied using buffers and 50% RPMI cell culture medium at 37 and 25 degrees C. The low release rate of doxorubicin as well as the high incorporation efficiency of doxorubicin-PAMAM complex into liposomes are considered as beneficial factors concerning the activity of doxorubicin. The cytotoxic activity of the liposomal formulation 1 incorporating doxorubicin-PAMAM complex, based on doxorubicin activity, was compared to that of 2 incorporating doxorubicin-PAMAM complex and to that of 3. The results showed that complex 1 was the most active formulation against all cancer cell lines compared to that of 2 and 3. Liposomal formulations composed of lipids and of a drug-dendrimer complex could be characterized as modulatory liposomal controlled release system (MLCRS), and could provide benefits to the delivery of drugs and modulate their release.
The biological application of nanoparticles is a rapidly developing area of nanotechnology that raises new possibilities in the diagnosis and treatment of human cancers. In cancer diagnostics, fluorescent nanoparticles can be used for multiplex simultaneous profiling of tumour biomarkers and for detection of multiple genes and matrix RNA with fluorescent in-situ hybridisation. In breast cancer, three crucial biomarkers can be detected and accurately quantified in single tumour sections by use of nanoparticles conjugated to antibodies. In the near future, the use of conjugated nanoparticles will allow at least ten cancer-related proteins to be detected on tiny tumour sections, providing a new method of analysing the proteome of an individual tumour. Supermagnetic nanoparticles have exciting possibilities as contrast agents for cancer detection in vivo, and for monitoring the response to treatment. Several chemotherapy agents are available as nanoparticle formulations, and have at least equivalent efficacy and fewer toxic effects compared with conventional formulations. Ultimately, the use of nanoparticles will allow simultaneous tumour targeting and drug delivery in a unique manner. In this review, we give an overview of the use of clinically applicable nanoparticles in oncology, with particular focus on the diagnosis and treatment of breast cancer.
In this work, I present the application of single-molecule imaging to systems biology and discuss the relevant technical issues within this context. Imaging single molecules has made it possible to visualize individual molecules at work in living cells. This continuously improving technique allows the measurement of non-invasively quantitative parameters of intracellular reactions, such as the number of molecules, reaction rate constants and diffusion coefficients with spatial distributions and temporal fluctuations. This detailed information about unitary intracellular reactions is essential for constructing quantitative models of reaction networks that provide a systems-level understanding of the mechanisms by which various cellular behaviors are emerging.
Peptides and proteins remain poorly bioavailable upon oral administration. One of the most promising strategies to improve their oral delivery relies on their association with colloidal carriers, e.g. polymeric nanoparticles, stable in gastrointestinal tract, protective for encapsulated substances and able to modulate physicochemical characteristics, drug release and biological behavior. The mechanisms of transport of these nanoparticles across intestinal mucosa are reviewed. In particular, the influence of size and surface properties on their non-specific uptake or their targeted uptake by enterocytes and/or M cells is discussed. Enhancement of their uptake by appropriate cells, i.e. M cells by (i) modeling surface properties to optimize access to and transport by M cells (ii) identifying surface markers specific to human M cell allowing targeting to M cells and nanoparticles transcytosis is illustrated. Encouraging results upon in vivo testing are reported but low bioavailability and lack of control on absorbed dose slow down products development. Vaccines are certainly the most promising applications for orally delivered nanoparticles.
Treatment of brain cancer remains a challenge despite recent improvements in surgery and multimodal adjuvant therapy. Drug therapies of brain cancer have been particularly inefficient, due to the blood-brain barrier and the non-specificity of the potentially toxic drugs. The nanoparticle has emerged as a potential vector for brain delivery, able to overcome the problems of current strategies. Moreover, multi-functionality can be engineered into a single nanoplatform so that it can provide tumor-specific detection, treatment, and follow-up monitoring. Such multitasking is not possible with conventional technologies. This review describes recent advances in nanoparticle-based detection and therapy of brain cancer. The advantages of nanoparticle-based delivery and the types of nanoparticle systems under investigation are described, as well as their applications.
Noncoronary atherosclerotic vascular disease, including symptomatic lower extremity peripheral arterial disease (PAD), promises to extract a steadily rising medical and economic toll over the coming decades. Although drug-eluting stents have led to substantial advances in the management of coronary atherosclerosis, endovascular treatment of noncoronary, peripheral arterial lesions continues to yield high restenosis rates and early clinical failures. In this report, we review recent developments in microfabrication and nanotechnology strategies that offer new opportunities for improving stent-based technology for the treatment of more extensive and complex lesions. In this regard, stents with microfabricated reservoirs for controlled temporal and spatial drug release have already been successfully applied to coronary lesions. Microfabricated needles to pierce lesions and deliver therapeutics deep within the vascular wall represent an additional microscale approach. At the nanoscale, investigators have primarily sought to alter the strut surface texture or coat the stent to enhance inductive or conductive schemes for endothelialization and host artery integration. Nanotechnology research that identifies promising strategies to limit restenosis through targeted drug delivery after angioplasty and stenting is also reviewed.
Last September, a firestorm was ignited over drug-eluting stents when data were released showing an increase in the risk of late stent thrombosis. In response, the FDA held an open meeting of its Circulatory System Devices Panel in December. Dr. Miriam Shuchman reports on the panel's conclusions.
Nanotechnology involves the design, synthesis, and characterization of materials and devices that have a functional organization in at least one dimension on the nanometer (ie, one billionth of a meter) scale. One area in which nanotechnology may have a significant clinical impact in neuroscience is the selective transport and delivery of drugs and other small molecules across the blood brain barrier that cannot cross otherwise. Using a variety of nanoparticles composed of different chemical compositions, different groups are exploring proof-of-concept approaches for the delivery of different antineoplastic drugs, oligonucleotides, genes, and magnetic resonance imaging contrast agents. This review discusses some of the main technical challenges associated with the development of nanotechnologies for delivery across the blood brain barrier and summarizes ongoing work.
Hemostasis is a major problem in surgical procedures and after major trauma. There are few effective methods to stop bleeding without causing secondary damage. We used a self-assembling peptide that establishes a nanofiber barrier to achieve complete hemostasis immediately when applied directly to a wound in the brain, spinal cord, femoral artery, liver, or skin of mammals. This novel therapy stops bleeding without the use of pressure, cauterization, vasoconstriction, coagulation, or cross-linked adhesives. The self-assembling solution is nontoxic and nonimmunogenic, and the breakdown products are amino acids, which are tissue building blocks that can be used to repair the site of injury. Here we report the first use of nanotechnology to achieve complete hemostasis in less than 15 seconds, which could fundamentally change how much blood is needed during surgery of the future.
The concept of polymeric nanoparticles for the design of new drug delivery systems emerged a few years ago, and recent rapid advances in nanotechnology have offered a wealth of new opportunities for diagnosis and therapy of various diseases. Recent progress has made possible the engineering of nanoparticles to allow the site-specific delivery of drugs and to improve the pharmacokinetic profile of numerous compounds with biomedical applications such as peptide and protein drugs. Biologically active peptides and their analogues are becoming an increasingly important class of drugs. Their use for human and animal treatment is problematic, however, because some of these drugs are generally ineffective when taken orally and thus have been administered chiefly by the parenteral route. This review covers some of the historical and recent advances of nanotechnology and concludes that polymeric nanoparticles show great promise as a tool for the development of peptide drug delivery systems.
Current advances in nanotechnology have led to the development of the new field of nanomedicine, which includes many applications of nanomaterials and nanodevices for diagnostic and therapeutic purposes. The same unique physical and chemical properties that make nanomaterials so attractive may be associated with their potentially calamitous effects on cells and tissues. Our recent study demonstrated that aspiration of single-walled carbon nanotubes elicited an unusual inflammatory response in the lungs of exposed mice with a very early switch from the acute inflammatory phase to fibrogenic events resulting in pulmonary deposition of collagen and elastin. This was accompanied by a characteristic change in the production and release of proinflammatory to anti-inflammatory profibrogenic cytokines, decline in pulmonary function, and enhanced susceptibility to infection. Chemically unmodified (nonfunctionalized) carbon nanotubes are not effectively recognized by macrophages. Functionalization of nanotubes results in their increased recognition by macrophages and is thus used for the delivery of nanoparticles to macrophages and other immune cells to improve the quality of diagnostic and imaging techniques as well as for enhancement of the therapeutic effectiveness of drugs. These observations on differences in recognition of nanoparticles by macrophages have important implications in the relationship between the potentially toxic health effects of nanomaterials and their applications in the field of nanomedicine.
The use of nanotechnology in drug delivery and imaging in vivo is a rapidly expanding field. The emphases of this review are on biophysical attributes of the drug delivery and imaging platforms as well as the biological aspects that enable targeting of these platforms to injured and diseased tissues and cells. The principles of passive and active targeting of nanosized carriers to inflamed and cancerous tissues with increased vascular leakiness, overexpression of specific epitopes, and cellular uptake of these nanoscale systems are discussed. Preparation methods-properties of nanoscale systems including liposomes, micelles, emulsions, nanoparticulates, and dendrimer nanocomposites, and clinical indications are outlined separately for drug delivery and imaging in vivo. Taken together, these relatively new and exciting data indicate that the future of nanomedicine is very promising, and that additional preclinical and clinical studies in relevant animal models and disease states, as well as long-term toxicity studies, should be conducted beyond the "proof-of-concept" stage. Large-scale manufacturing and costs of nanomedicines are also important issues to be addressed during development for clinical indications.
Jeffrey L.Anderson, Cynthia D.Adams, Elliott M.Antman, Charles R.Bridges, Robert M.Califf, Donald E.Casey, William E.Chavey, Francis M.Fesmire, Judith S.Hochman, Thomas N.Levin, A. MichaelLincoff, Eric D.Peterson, PierreTheroux, Nanette KassWenger, R. ScottWright, Sidney C.Smith, Alice K.Jacobs, Cynthia D.Adams, Jeffrey L.Anderson, Elliott M.Antman, Jonathan L.Halperin, Sharon A.Hunt, Harlan M.Krumholz, Frederick G.Kushner, Bruce W.Lytle, RickNishimura, Joseph P.Ornato, Richard L.Page, BarbaraRiegel. (2007) ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction. Journal of the American College of Cardiology 50, e1-e157
CrossRef
De las nanopartículas a los nanodispositivos
- D Clavijo
- G García
- DM Clavijo
- C Casadiego
- R Zamora
- JR Alarcón