The effect of gamma and microwave radiation sterilization on periodontological grafts for microbiological evaluation.

Periodontological grafts are materials used in dentistry to regenerate lost gingival soft tissues or bone parts. In the case of direct contact with blood, the possibility of disease transmission from the source to the patient is high. This source can be an animal or a human. Therefore, the sterilization of grafts before implanting to the patient is of significant importance. The purpose of this study was to evaluate gamma radiation and microwave sterilization processes from microbiological and sterility perspectives and to compare the effectiveness of these two sterilization methods. Grafts were irradiated with 2, 4, 5, 10, 25 and 50 kGy doses of gamma radiation. Another group of same materials was irradiated by microwave for 1, 2, 3 and 4 min at 24,500 MHz and 900 W. Gamma radiation and microwave sterilization methods were evaluated as successful at minimum doses as 5 kGy and 3 min, respectively. Both gamma and microwave sterilization successfu lly sterilized periodontological grafts coded as PBG1, HBG1, HL1, PDG1, MBG3, MDG2 and PDG3. Moreover, microwave sterilization can be used as an alternative novel method to gamma radiation sterilization.

Diagnostic and therapeutic evaluation of folate-targeted paclitaxel and vinorelbine encapsulating theranostic liposomes for non-small cell lung cancer.

NSCLC is the most common type of lung cancer. However, non-specific contrast agents, radiopharmaceuticals, and treatment methods are insufficient in early diagnosis and eradication of all tumor tissue. Therefore, the formulation of a novel, targeted, specific theranostic agents possess critical importance. In our previous study, paclitaxel and vinorelbine encapsulating, Tc-99m radiolabeled, folate targeted, nanosized liposomes were formulated and found promising due to characterization properties, high cellular uptake, and cytotoxicity. In this study, in vivo therapeutic and diagnostic efficacy of liposomal formulations were tested by biodistribution study, evaluation of tumor growth inhibition, and histopathologic examination after in vitro assays on LLC1 cells. Both actively and passively targeted liposomal formulations exhibited high cellular uptake, and co-drug encapsulating liposomes showed a greater cytotoxicity profiles than free drug combination in LLC1 cells. By the results of biodistribution studies performed in NSCLC tumor-bearing C57BL/6 mice, the uptake of radiolabeled, actively folate targeted, co-drug encapsulating liposomal formulation was found to be higher in tumor tissue when compared to non-actively targeted one. Also, more effective treatment was achieved by using folate-targeted, co-drug encapsulating liposomal formulation when compared to free drugs combination according to changes in tumor size of mice. Furthermore, liposomal formulations showed lower toxicity compared to free drug combinations in the toxicity study considering body weight. Moreover, according to the histopathological study, folate targeted, co-drug encapsulating liposomes not only inhibited the tumor growth effectively but also restricted the lung metastasis entirely.

Targeted Alpha Therapy and Nanocarrier Approach.

The rates of cancer incidence and mortality are increasing day by day. Although several conventional methods including surgery, chemotherapy, and radiotherapy (RT) exist for cancer treatment, they are insufficient in the eradication of all tumor tissues and have some side-effects such as narrow therapeutic index and serious side-effects to healthy tissues. Moreover, it may probably recur in time due to the survival and spreading of cancerous cells or any possible metastases. Targeted radionuclide therapy is a promising alternative. α particles are ideal for localized cell killing because of their high linear energy transfer and short ranges. However, upon emission of α particles, the daughter nuclides induce a recoil energy to lead decoupling from any chemical bond that may accumulate in normal tissues. Targeted α therapy can also be performed by targeted delivery systems apart from mAb, mAb fragments, peptides, and small molecules for selective tumor therapy. Targeted drug delivery systems have been developed to overcome the limitations of α therapy. Moreover, drug delivery systems are one of the most searched applications in cancer imaging and/or treatment due to their targeting ability to tumor or biocompatibility properties. The aim of this article is to summarize tumor therapy applications, targeted α RT approach, and to review the role of drug delivery systems in the delivery of α particles for cancer therapy and some instances of targeted α-emitting drug delivery systems from the literature.

Theranostic polymeric nanoparticles for NIR imaging and photodynamic therapy.

Near-Infrared (NIR) dyes forming some of the photosensitizer agents show imaging and therapy features by themselves. NIR dyes show photodynamic therapy by formation of reactive oxygen species and imaging by NIR Fluorescence light. Photodynamic therapy occurs from irradiation of laser or light to photosensitizer matters and following by the formation of reactive oxygen species diseased tissues or cells can be killed effectively. NIR dyes have advantages such as stability, high specificity and sensitivity when compared with the other photosensitizer and imaging agents. Drug delivery systems are getting attention for either diagnosis or therapy of almost all of the diseases. Theranostic nanoparticles comprise the substances which shows the imaging and treatment features together. Besides, the combination of active substance and the imaging agent can also be encapsulated in theranostic nanoparticles. Many researchs are performed to evaluate the efficacy of theranostic drug delivery systems particularly polymeric nanoparticles in order to enhance targeting properties, specificity and bioavailability. Polymeric nanoparticles give advantages because of easier degradation properties when compared with the others. Theranostic polymeric nanoparticles can be used for NIR imaging and photodynamic therapy of several diseases especially cancers.

ESR investigations of gamma irradiated medical devices.

Guided tissue regeneration (GTR) and guided bone regeneration (GBR) biomaterials have been employed in recent years for periodontal procedures. In the present study, widely used dental GTR/GBR biomaterials (grafts: G1, G2, G3 and membranes: M1, M2, M3, M4) were exposed to gamma irradiation at an absorbed dose range of 0-50kGy and the radiolytic intermediates that have been created in the samples upon irradiation were characterized in detail by Electron Spin Resonance (ESR) spectroscopy. We aimed to standardize the measurement conditions for practical applications of gamma radiation sterilization of GTR/GBR biomaterials. We investigated the characteristic features of free radicals in gamma irradiated GTR/GBR biomaterials and examined the stability of the induced radicals at room temperature and accelerated stability conditions with ESR spectroscopy including dose-response curves, microwave power studies, dosimetric features of the biomaterials, variations of the peak heights with temperature, and long term stabilities of the radical species. Long-term stability studies have shown that G1 is quite stable even in accelerated storage conditions. The signal intensities of graft-type GTR/GBR biomaterials stored in normal and stability conditions have decreased very rapidly even only a few days after gamma irradiation sterilization. Thus, those samples indicating relatively low stability features can be very good candidates for the radiosterilization process. The beta-tricalcium phosphate and PLGA containing G1 and M1 respectively have found to be the most gamma stable bone substitute biomaterials and be safely sterilized by gamma radiation. ESR spectroscopy is an appropriate technique in giving important detailed spectroscopic findings in the gamma radiation sterilization studies of GTR/GBR biomaterials.

Drug Delivery Systems for Imaging and Therapy of Parkinson's Disease.

BACKGROUND: Although a variety of therapeutic approaches are available for the treatment of Parkinson's disease, challenges limit effective therapy. Among these challenges are delivery of drugs through the blood brain barier to the target brain tissue and the side effects observed during long term administration of antiparkinsonian drugs. The use of drug delivery systems such as liposomes, niosomes, micelles, nanoparticles, nanocapsules, gold nanoparticles, microspheres, microcapsules, nanobubbles, microbubbles and dendrimers is being investigated for diagnosis and therapy. METHODS: This review focuses on formulation, development and advantages of nanosized drug delivery systems which can penetrate the central nervous system for the therapy and/or diagnosis of PD, and highlights future nanotechnological approaches. RESULTS: It is esential to deliver a sufficient amount of either therapeutic or radiocontrast agents to the brain in order to provide the best possible efficacy or imaging without undesired degradation of the agent. Current treatments focus on motor symptoms, but these treatments generally do not deal with modifying the course of Parkinson's disease. Beyond pharmacological therapy, the identification of abnormal proteins such as α -synuclein, parkin or leucine-rich repeat serine/threonine protein kinase 2 could represent promising alternative targets for molecular imaging and therapy of Parkinson's disease. CONCLUSION: Nanotechnology and nanosized drug delivery systems are being investigated intensely and could have potential effect for Parkinson's disease. The improvement of drug delivery systems could dramatically enhance the effectiveness of Parkinson's Disease therapy and reduce its side effects.

The benefits of pramipexole selection in the treatment of Parkinson's disease.

Levodopa administration as a gold standard in Parkinson's disease (PD) treatment is very valuable, however, long-term administration may cause some motor complications such as abnormal unintended movements and shortening response to each dose (wearing off phenomenon). Dopamine agonists were developed to reduce duration of immobile off periods and dependence to levodopa for improving motor impairments (Clarke et al., Cochrane Libr 1:1-23, 2000). Pramipexole is one of these nonergot dopamine agonists with high relative in vitro specificity and full intrinsic activity at D2 subfamily of dopamine receptors, with a higher binding affinity to D3 than to D4 or D2 receptor subtypes (Piercey, Clin Neuropharmacol 21:141-151, 1998). It can be advantageously administered as monotherapy or adjunctive therapy to levodopa to decrease side effects and increase effectiveness in both early and advanced PD treatment.

Radiation sterilization of new drug delivery systems.

Radiation sterilization has now become a commonly used method for sterilization of several active ingredients in drugs or drug delivery systems containing these substances. In this context, many applications have been performed on the human products that are required to be sterile, as well as on pharmaceutical products prepared to be developed. The new drug delivery systems designed to deliver the medication to the target tissue or organ, such as microspheres, nanospheres, microemulsion, and liposomal systems, have been sterilized by gamma (γ) and beta (ß) rays, and more recently, by e-beam sterilization. In this review, the sterilization of new drug delivery systems was discussed other than conventional drug delivery systems by γ irradiation.

Liposome, gel and lipogelosome formulations containing sodium hyaluronate.

The moisture-imparting effect of sodium hyaluronate (Na-HA) was investigated in liposome, gel and lipogelosome topical formulations. Sixteen liposome formulations were prepared with or without Na-HA (45 kDa) using various ratios of dimyristoylphosphatidylcholine, 1,2-dimyristoyl-sn-glycero-3-phosphatidylglycerol, dipalmitoylphosphatidylcholine and phospholipon 100H. The liposomes were characterized in terms of their structure, composition, zeta potential, Na-HA-entrapment capacity and stability. In particular, scanning electron microscopy, polarized light microscopy, dynamic light scattering and atomic force microscopy were utilized to probe appearance, size and size distribution and lamellarity. The work was then extended to gels using the gelling agents poloxamer (PXM 188 or 407) and Carbopol or Ultrez 21 (U-21), yielding liposome-loaded gel formulations (i.e. lipogelosomes). The in vitro release kinetics of Na-HA from liposomes, lipogelosomes and commercial Na-HA reference formulations were studied via a flow-through cell method. Among the liposomal formulations tested, L6, comprising of Na-HA-loaded phospholipon 100H:stearylamine:cholesterol (7:1:2), displayed optimal traits. The mean particle size, zeta potential and entrapment capacity of L6 were determined as 1900 nm, -20.9 mV and 15.0%. The optimum lipogelosome, LG4, was obtained by incorporating liposome L6 into a U-21 gel at a ratio of 1:1 (w/w). In clinical trials, in-house formulations were applied twice daily to 15 female volunteers. The two-week benefits were assessed against a commercial product; and in all cases, changes of skin humidity, sebum content, pH and wrinkle depth were promising. In particular, the LG4 lipogelosome-based formulation had significantly improved skin hydration and compliance, as evidenced by a moisture content gain of 30.4%.

Gamma-irradiated liposome/noisome and lipogelosome/niogelosome formulations for the treatment of rheumatoid arthritis.

Treatment of rheumatoid arthritis by intraarticular administration of anti-inflammatory drugs encapsulated in drug delivery systems, such as liposomes/niosomes and lipogelosomes/niogelosomes, prolongs the residence time of the drugs in the joint. It was therefore anticipated that liposome/niosome entrapment would enhance the efficacy of drugs in the inflammatory sides. Liposomes are good candidates for the local delivery of therapeutic agents, such as diclofenac sodium (DFNa), for intraarticular delivery. Drugs for parenteral delivery must be sterile, and radiation sterilization is a method recognized by pharmacopoeias to achieve sterility of drugs. However, irradiation might also affect the performance of drug delivery systems. One of the most critical points is irradiation dose, because certain undesirable chemical and physical changes may accompany with the treatment, especially with the traditionally applied dose of 25 kGy. The present study aims to determine the effects of gamma irradiation on DFNa-loaded liposomes/niosomes and lipogelosomes/niogelosomes for the treatment of rheumatoid arthritis.

The effects of gamma irradiation on diclofenac sodium, liposome and niosome ingredients for rheumatoid arthritis.

The use of gamma rays for the sterilization of pharmaceutical raw materials and dosage forms is an alternative method for sterilization. However, one of the major problems of the radiosterilization is the production of new radiolytic products during the irradiation process. Therefore, the principal problem in radiosterilization is to determine and to characterize these physical and chemical changes originating from high-energy radiation. Parenteral drug delivery systems were prepared and in vitro characterization, biodistribution and treatment studies were done in our previous studies. Drug delivery systems (liposomes, niosomes, lipogelosomes and niogelosomes) encapsulating diclofenac sodium (DFNa) were prepared for the treatment of rheumatoid arthritis (RA). This work complies information about the studies developed in order to find out if gamma radiation could be applied as a sterilization method to DFNa, and the raw materials as dimyristoyl phosphatidylcholine (DMPC), surfactant I [polyglyceryl-3-cethyl ether (SUR I)], dicethyl phosphate (DCP) and cholesterol (CHOL) that are used to prepare those systems. The raw materials were irradiated with different radiation doses (5, 10, 25 and 50 kGy) and physicochemical changes (organoleptic properties pH, UV and melting point), microbiological evaluation [sterility assurance level (SAL), sterility and pyrogen test] and electron spin resonance (ESR) characteristics were studied at normal (25 °C, 60% relative humidity) and accelerated (40 °C, 75% relative humidity) stability test conditions.

Nanosized multifunctional liposomes for tumor diagnosis and molecular imaging by SPECT/CT.

Among currently used cancer imaging methods, nuclear medicine modalities provide metabolic information, whereas modalities in radiology provide anatomical information. However, different modalities, having different acquisition times in separate machines, decrease the specificity and accuracy of images. To solve this problem, hybrid imaging modalities were developed as a new era, especially in the cancer imaging field. With widespread usage of hybrid imaging modalities, specific contrast agents are essentially needed to use in both modalities, such as single-photon emission computed tomography/computed tomography (SPECT/CT). Liposomes are one of the most desirable drug delivery systems, depending on their suitable properties. The aim of this study was to develop a liposomal contrast agent for the diagnosis and molecular imaging of tumor by SPECT/CT. Liposomes were prepared nanosized, coated with polyethylene glycol to obtain long blood circulation, and modified with monoclonal antibody 2C5 for specific tumor targeting. Although DTPA-PE and DTPA-PLL-NGPE (polychelating amphilic polymers; PAPs) were loaded onto liposomes for stable radiolabeling for SPECT imaging, iopromide was encapsulated into liposomes for CT imaging. Liposomes [(DPPC:PEG(2000)-PE:Chol:DTPA-PE), (PL 90G:PEG(2000)-PE:Chol:DTPA-PE), (DPPC:PEG(2000)-PE:Chol:PAPs), (PL 90G:PEG(2000)-PE:Chol:PAPs), (60:0.9:39:0.1% mol ratio)] were characterized in terms of entrapment efficiency, particle size, physical stability, and release kinetics. Additionally, in vitro cell-binding studies were carried out on two tumor cell lines (MCF-7 and EL 4) by counting radioactivity. Tumor-specific antibody-modified liposomes were found to be effective multimodal contrast agents by designating almost 3-8 fold more uptake than nonmodified ones in different tumor cell lines. These results could be considered as an important step in the development of tumor-targeted SPECT/CT contrast agents for cancer imaging.

Liposomes and their applications in molecular imaging.

Molecular imaging is a relatively new discipline with a crucial role in diagnosis and treatment tracing of diseases through characterization and quantification of biological processes at cellular and sub-cellular levels of living organisms. These molecular targeted systems can be conjugated with contrast agents or radioligands to obtain specific molecular probes for the purpose of diagnosis of diseases more accurately by different imaging modalities. Nowadays, an interesting new approach to molecular imaging is the use of stealth nanosized drug delivery systems such as liposomes having convenient properties such as biodegradability, biocompatibility and non-toxicity and they can specifically be targeted to desired disease tissues by combining with specific targeting ligands and probes. The targeted liposomes as molecular probes in molecular imaging have been evaluated in this review. Therefore, the essential point is detection of molecular target of the disease which is different from normal conditions such as increase or decrease of a receptor, transporter, hormone, enzyme etc, or formation of a novel target. Transport of the diagnostic probe specifically to targeted cellular, sub-cellular or even to molecular entities can be performed by molecular imaging probes. This may lead to produce personalized medicine for imaging and/or therapy of diseases at earlier stages.

The use and importance of liposomes in positron emission tomography.

Among different imaging modalities, Positron Emission Tomography (PET) gained importance in routine hospital practice depending on ability to diagnose diseases in early stages and tracing of therapy by obtaining metabolic information. The combination of PET with Computed Tomography (CT) forms hybrid imaging modality that gives chance to obtain better images having higher resolution by fusing both functional and anatomical images in the same imaging modality at the same time. Therefore, better contrast agents are essentially needed. The advance in research about developing drug delivery systems as specific nanosized targeted systems gained an additional importance for obtaining better diagnosis and therapy of different diseases. Liposomes appear to be more attractive drug delivery systems in delivering either drugs or imaging ligands to target tissue or organ of diseases with higher accumulation by producing in nano-scale, long circulating by stealth effect and specific targeting by modifying with specific ligands or markers. The combination of positron emitting radionuclides with liposomes are commonly in research level nowadays and there is no commercially available liposome formulation for PET imaging. However by conjugating positron emitter radionuclide with liposomes can form promising diagnostic agents for improved diagnosis and following up treatments by increasing image signal/contrast in the target tissue in lower concentrations by specific targeting as the most important advantage of liposomes. More accurate and earlier diagnosis of several diseases can be obtained even in molecular level with the use of stable and effectively radiolabeled molecular target specific nano sized liposomes with longer half-lived positron emitting radionuclides.

Thrombus localization by using streptokinase containing vesicular systems.

Our research focused on the preparation of vesicular drug delivery systems, such as liposomes, noisomes, and sphingosomes, for achieving slow release of entrapped proteins in the circulation to increase half-life, to mask immunogenic properties, and to protect against loss of enzymatic activity. We prepared, characterized, and monitored the biodistribution of three types of vesicular systems (liposomes, niosomes, and sphingosomes) containing streptokinase. For biodistribution stuides, radiolabelled streptokinase dispersions were injected into the ear vein of female rabbits in the weight of 2.5-3 kg weight. Following the application, rabbits were sacrificed, then organs of these animals were removed and radioactivity of organs was measured by well-type gamma counter. The comparison of the biodistribution results of the free streptokinase with the streptokinase vesicles showed that incorporation of the enzyme into the vesicles changed the biodistribution of the drug and by the entrapment of the streptokinase in the vesicles, thrombus uptake and imaging quality were improved.

In vivo behaviour of vesicular urokinase.

Thromboembolic diseases including deep vein thrombus (DVT) are major causes of morbidity and mortality. Detection of DVT in low extremities is difficult. There are some accepted imaging techniques in clinic but most of them have several disadvantages limiting their effective use. Because of this, researchers are still performed to develop a rapid, specific means of detecting and/or imaging venous thrombi-based on the changing composition of the thrombus. Urokinase, fibrinolytic enzyme isolated form human urine, is a direct activator of plasminogen. In thrombus formation, plasminogen seems to be trapped in or absorbed onto fibrin matrix thus leading to a localised concentration of plasminogen. This suggests that radiolabelled urokinase would be a suitable compound for the detection of thrombi. The most important disadvantage of this enzyme is short plasma half life. To overcome this problem, it was decided to encapsulate the enzyme in drug delivery systems such as liposomes, niosomes or sphingosomes. In this study, we prepared, characterized and monitored the biodistribution of three types of vesicular systems containing urokinase. All types of prepared vesicles show in vitro an acceptable encapsulation, stability and release profile. Thrombus uptake was increased by encapsulation of urokinase into vesicles.