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Purpose: The nervous system is vulnerable to radiation damage, and further optimization is required to increase the efficacy of radiation therapy while reducing harm to neurons. Given recent developments in heavy ion therapy, experimental models would be valuable to improve these therapies. We used the nematode Caenorhabditis elegans ( C. elegans ) to evaluate the effects of high-dose radiation on neuron development., Methods and Materials: In this study, we used confocal microscopy to assess dendritic growth of the PVD nociceptor after high-dose gamma-irradiation from a Cs-137 source., Results: Irradiation during an early larval stage (L2) delayed overall development but also independently impaired dendrite outgrowth in the PVD nociceptive neuron. Irradiation at L4 larval stage did not result in significant alterations in dendrite morphology., Conclusions: The nematode C. elegans can serve as a high-throughput model to study the effects of high-dose radiation on dendrite growth. We propose that C. elegans can be useful for studies of experimental radiation therapy modalities and dose rates for translational research., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

The purpose of this work was to investigate whether minibeam therapy with heavy ions might offer improvements of the therapeutic ratio for the treatment of human brain cancers. To assess neurotoxicity, we irradiated normal juvenile rats using 120 MeV lithium-7 ions at an absorbed integral dose of 20 Gy. Beams were configured either as a solid parallel circular beam or as an array of planar parallel minibeams having 300-micron width and 1-mm center-to-center spacing within a circular array. We followed animals for 6 months after treatment and utilized behavioral testing and immunohistochemical studies to investigate the resulting cognitive impairment and chronic pathologic changes. We found both solid-beam therapy and minibeam therapy to result in cognitive impairment compared with sham controls, with no apparent reduction in neurotoxicity using heavy ion minibeams instead of solid beams under the conditions of this study.

Proton minibeams (MBs) comprised of parallel planar beamlets were evaluated for their ability to spare healthy brain compared to proton broad beams (BBs). Juvenile mice were given partial brain irradiation of 10 or 30 Gy integral dose using 100 MeV protons configured either as BBs or arrays of 0.3-mm planar MBs spaced 1.0 mm apart on center. Neurologic toxicity was evaluated during an 8-month surveillance: no overt constitutional or neurologic dysfunction was noted for any study animals. Less acute epilation was observed in MB than BB mice. Persistent chronic inflammation was noted along the entire BB path in BB mice whereas inflammation was confined to just within the MB peak regions in MB mice. The potential neurologic sparing, possibly via reduced volume of chronic inflammation, offers a compelling rationale for clinical advancement of this proton technique.

Proton minibeam therapy (PMBT) is a form of spatially fractionated radiotherapy wherein broad beam radiation is replaced with segmented minibeams-either parallel, planar minibeam arrays generated by a multislit collimator or scanned pencil beams that converge laterally at depth to create a uniform dose layer at the tumor. By doing so, the spatial pattern of entrance dose is considerably modified while still maintaining tumor dose and efficacy. Recent studies using computational modeling, phantom experiments, in vitro and in vivo preclinical models, and early clinical feasibility assessments suggest that unique physical and biological attributes of PMBT can be exploited for future clinical benefit. We outline some of the guiding principle of PMBT in this concise overview of this emerging area of preclinical and clinical research inquiry.

Radiation therapy is a frequently used modality for the treatment of solid cancers. Although the mechanisms of cell kill are similar for all forms of radiation, the in vivo properties of photon and proton beams differ greatly and maybe exploited to optimize clinical outcomes. In particular, proton particles lose energy in a predictable manner as they pass through the body. This property is used clinically to control the depth at which the proton beam is terminated, and to limit radiation dose beyond the target region. This strategy can allow for substantial reductions in radiation dose to normal tissues located just beyond a tumor target. However, the degradation of proton energy in the body remains highly sensitive to tissue density. As a consequence, any changes in tissue density during the course of treatment may significantly alter proton dosimetry. Such changes may occur through alterations in body weight, respiration, or bowel filling/gas, and may result in unfavorable dose deposition. In this manuscript, we provide a detailed method for the delivery of proton therapy using both passive scatter and pencil beam scanning techniques for prostate cancer. Although the described procedure directly pertains to prostate cancer patients, the method may be adapted and applied for the treatment of virtually all solid tumors. Our aim is to equip readers with a better understanding of proton therapy delivery and outcomes in order to facilitate the appropriate integration of this modality during cancer therapy.

Conventional radiation therapy of brain tumors often produces cognitive deficits, particularly in children. We investigated the potential efficacy of merging Orthovoltage X-ray Minibeams (OXM). It segments the beam into an array of parallel, thin (~0.3 mm), planar beams, called minibeams, which are known from synchrotron x-ray experiments to spare tissues. Furthermore, the slight divergence of the OXM array make the individual minibeams gradually broaden, thus merging with their neighbors at a given tissue depth to produce a solid beam. In this way the proximal tissues, including the cerebral cortex, can be spared. Here we present experimental results with radiochromic films to characterize the method's dosimetry. Furthermore, we present our Monte Carlo simulation results for physical absorbed dose, and a first-order biologic model to predict tissue tolerance. In particular, a 220-kVp orthovoltage beam provides a 5-fold sharper lateral penumbra than a 6-MV x-ray beam. The method can be implemented in arc-scan, which may include volumetric-modulated arc therapy (VMAT). Finally, OXM's low beam energy makes it ideal for tumor-dose enhancement with contrast agents such as iodine or gold nanoparticles, and its low cost, portability, and small room-shielding requirements make it ideal for use in the low-and-middle-income countries.

Although modern radiation therapy delivers a localized distribution of ionizing energy that can be used to cure primary cancers for many patients, the inevitable radiation exposure to non-targeted normal tissue leads to a risk of a radiation-related new cancer. Modern therapies often produce a complex spectrum of secondary particles, both charged and uncharged, that must be considered both in their physical radiation transport throughout the patient and their potential to induce biological damage, which depends on the microscopic energy deposition from the cascade of primary, secondary, and downstream particles. This work summarizes the experimental data for relative biological effectiveness for particles associated with modern radiotherapy in light of their capacity to induce secondary malignancies in patients. A distinction is highlighted between the radiobiological experimental data and the coarser metrics used frequently in radiation protection. For critical assessment of the risks of secondary malignancies for patients undergoing radiation therapy, a detailed description of primary and secondary radiation fields is needed, though not routinely considered for individual patient treatments. Furthermore, not only the particle type, but also the microscopic dose and track structure, must be considered, which points to a demand for detailed physics models and high-performance computing strategies to model the risks.

Competing Interests: Conflicts of interest: The authors have no conflicts of interest to disclose.

Purpose: Commissioning beam data for proton spot scanning beams are compared for the first two Varian ProBeam sites in the United States, at the Maryland Proton Treatment Center (MPTC) and Scripps Proton Therapy Center (SPTC). In addition, the extent to which beams can be matched between gantry rooms at MPTC is investigated., Method: Beam data for the two sites were acquired with independent dosimetry systems and compared. Integrated depth dose curves (IDDs) were acquired with Bragg peak ion chambers in a 3D water tank for pencil beams at both sites. Spot profiles were acquired at different distances from the isocenter at a gantry angle of 0° as well as a function of gantry angles. Absolute dose calibration was compared between SPTC and the gantries at MPTC. Dosimetric verification of test plans, output as a function of gantry angle, monitor unit (MU) linearity, end effects, dose rate dependence, and plan reproducibility were compared for different gantries at MPTC., Results: The IDDs for the two sites were similar, except in the plateau region, where the SPTC data were on average 4.5% higher for lower energies. This increase in the plateau region decreased as energy increased, with no marked difference for energies higher than 180 MeV. Range in water coincided for all energies within 0.5 mm. The sigmas of the spot profiles in air were within 10% agreement at isocenter. This difference increased as detector distance from the isocenter increased. Absolute doses for the gantries measured at both sites were within 1% agreement. Test plans, output as function of gantry angle, MU linearity, end effects, dose rate dependence, and plan reproducibility were all within tolerances given by TG142., Conclusion: Beam data for the two sites and between different gantry rooms were well matched., (© 2017 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Purpose: This work proposes a theoretical framework that enables comparative risk predictions for second cancer incidence after particle beam therapy for different ion species for individual patients, accounting for differences in relative biological effectiveness (RBE) for the competing processes of tumor initiation and cell inactivation. Our working hypothesis was that use of carbon-ion therapy instead of proton therapy would show a difference in the predicted risk of second cancer incidence in the breast for a sample of Hodgkin lymphoma (HL) patients., Methods and Materials: We generated biologic treatment plans and calculated relative predicted risks of second cancer in the breast by using two proposed methods: a full model derived from the linear quadratic model and a simpler linear-no-threshold model., Results: For our reference calculation, we found the predicted risk of breast cancer incidence for carbon-ion plans-to-proton plan ratio, , to be 0.75 ± 0.07 but not significantly smaller than 1 (P=.180)., Conclusions: Our findings suggest that second cancer risks are, on average, comparable between proton therapy and carbon-ion therapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Monte Carlo (MC) methods are acknowledged as the most accurate technique to calculate dose distributions. However, due its lengthy calculation times, they are difficult to utilize in the clinic or for large retrospective studies. Track-repeating algorithms, based on MC-generated particle track data in water, accelerate dose calculations substantially, while essentially preserving the accuracy of MC. In this study, we present the validation of an efficient dose calculation algorithm for intensity modulated proton therapy, the fast dose calculator (FDC), based on a track-repeating technique. We validated the FDC algorithm for 23 patients, which included 7 brain, 6 head-and-neck, 5 lung, 1 spine, 1 pelvis and 3 prostate cases. For validation, we compared FDC-generated dose distributions with those from a full-fledged Monte Carlo based on GEANT4 (G4). We compared dose-volume-histograms, 3D-gamma-indices and analyzed a series of dosimetric indices. More than 99% of the voxels in the voxelized phantoms describing the patients have a gamma-index smaller than unity for the 2%/2 mm criteria. In addition the difference relative to the prescribed dose between the dosimetric indices calculated with FDC and G4 is less than 1%. FDC reduces the calculation times from 5 ms per proton to around 5 μs.

One of the fundamental attributes of proton therapy and carbon ion therapy is the ability of these charged particles to spare tissue distal to the targeted tumor. This significantly reduces normal tissue toxicity and has the potential to translate to a wider therapeutic index. Although, in general, particle therapy also reduces dose to the proximal tissues, particularly in the vicinity of the target, dose to the skin and to other very superficial tissues tends to be higher than that of megavoltage x-rays. The methods presented here, namely, "interleaved carbon minibeams" and "radiosurgery with arrays of proton and light ion minibeams," both utilize beams segmented into arrays of parallel "minibeams" of about 0.3 mm incident-beam size. These minibeam arrays spare tissues, as demonstrated by synchrotron x-ray experiments. An additional feature of particle minibeams is their gradual broadening due to multiple Coulomb scattering as they penetrate tissues. In the case of interleaved carbon minibeams, which do not broaden much, two arrays of planar carbon minibeams that remain parallel at target depth, are aimed at the target from 90° angles and made to "interleave" at the target to produce a solid radiation field within the target. As a result, the surrounding tissues are exposed only to individual carbon minibeam arrays and are therefore spared. The method was used in four-directional geometry at the NASA Space Radiation Laboratory to ablate a 6.5-mm target in a rabbit brain at a single exposure with 40 Gy physical absorbed dose. Contrast-enhanced magnetic resonance imaging and histology 6-month later showed very focal target necrosis with nearly no damage to the surrounding brain. As for minibeams of protons and light ions, for which the minibeam broadening is substantial, measurements at MD Anderson Cancer Center in Houston, TX, USA; and Monte Carlo simulations showed that the broadening minibeams will merge with their neighbors at a certain tissue depth to produce a solid beam to treat the target. The resulting sparing of proximal normal tissue allows radiosurgical ablative treatments with smaller impact on the skin and shallow tissues. This report describes these two methods and discusses their potential clinical applications.

Purpose: Despite several advantages of proton therapy over megavoltage x-ray therapy, its lack of proximal tissue sparing is a concern. The method presented here adds proximal tissue sparing to protons and light ions by turning their uniform incident beams into arrays of parallel, small, or thin (0.3-mm) pencil or planar minibeams, which are known to spare tissues. As these minibeams penetrate the tissues, they gradually broaden and merge with each other to produce a solid beam., Methods and Materials: Broadening of 0.3-mm-diameter, 109-MeV proton pencil minibeams was measured using a stack of radiochromic films with plastic spacers. Monte Carlo simulations were used to evaluate the broadening in water of minibeams of protons and several light ions and the dose from neutron generated by collimator., Results: A central parameter was tissue depth, where the beam full width at half maximum (FWHM) reached 0.7 mm, beyond which tissue sparing decreases. This depth was 22 mm for 109-MeV protons in a film stack. It was also found by simulations in water to be 23.5 mm for 109 MeV proton pencil minibeams and 26 mm for 116 MeV proton planar minibeams. For light ions, all with 10 cm range in water, that depth increased with particle size; specifically it was 51 mm for Li-7 ions. The ∼2.7% photon equivalent neutron skin dose from the collimator was reduced 7-fold by introducing a gap between the collimator and the skin., Conclusions: Proton minibeams can be implemented at existing particle therapy centers. Because they spare the shallow tissues, they could augment the efficacy of proton therapy and light particle therapy, particularly in treating tumors that benefit from sparing of proximal tissues such as pediatric brain tumors. They should also allow hypofractionated treatment of all tumors by allowing the use of higher incident doses with less concern about proximal tissue damage., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Proton therapy confers substantially lower predicted risk of second cancer compared with photon therapy. However, no previous studies have used an algorithmic approach to optimize beam angle or fluence-modulation for proton therapy to minimize those risks. The objectives of this study were to demonstrate the feasibility of risk-optimized proton therapy and to determine the combination of beam angles and fluence weights that minimizes the risk of second cancer in the bladder and rectum for a prostate cancer patient. We used 6 risk models to predict excess relative risk of second cancer. Treatment planning utilized a combination of a commercial treatment planning system and an in-house risk-optimization algorithm. When normal-tissue dose constraints were incorporated in treatment planning, the risk model that incorporated the effects of fractionation, initiation, inactivation, repopulation and promotion selected a combination of anterior and lateral beams, which lowered the relative risk by 21% for the bladder and 30% for the rectum compared to the lateral-opposed beam arrangement. Other results were found for other risk models.

Beam tracking with scanned carbon ion radiotherapy achieves highly conformal target dose by steering carbon pencil beams to follow moving tumors using real-time magnetic deflection and range modulation. The purpose of this study was to evaluate the robustness of target dose coverage from beam tracking in light of positional uncertainties of moving targets and beams. To accomplish this, we simulated beam tracking for moving targets in both water phantoms and a sample of lung cancer patients using a research treatment planning system. We modeled various deviations from perfect tracking that could arise due to uncertainty in organ motion and limited precision of a scanned ion beam tracking system. We also investigated the effects of interfractional changes in organ motion on target dose coverage by simulating a complete course of treatment using serial (weekly) 4DCTs from six lung cancer patients. For perfect tracking of moving targets, we found that target dose coverage was high ([Formula: see text] was 94.8% for phantoms and 94.3% for lung cancer patients, respectively) but sensitive to changes in the phase of respiration at the start of treatment and to the respiratory period. Phase delays in tracking the moving targets led to large degradation of target dose coverage (up to 22% drop for a 15° delay). Sensitivity to technical uncertainties in beam tracking delivery was minimal for a lung cancer case. However, interfractional changes in anatomy and organ motion led to large decreases in target dose coverage (target coverage dropped approximately 8% due to anatomy and motion changes after 1 week). Our findings provide a better understand of the importance of each of these uncertainties for beam tracking with scanned carbon ion therapy and can be used to inform the design of future scanned ion beam tracking systems.

Motion mitigation strategies are needed to fully realize the theoretical advantages of scanned ion beam therapy for patients with moving tumors. The purpose of this study was to determine whether a new four-dimensional (4D) optimization approach for scanned-ion-beam tracking could reduce dose to avoidance volumes near a moving target while maintaining target dose coverage, compared to an existing 3D-optimized beam tracking approach. We tested these approaches computationally using a simple 4D geometrical phantom and a complex anatomic phantom, that is, a 4D computed tomogram of the thorax of a lung cancer patient. We also validated our findings using measurements of carbon-ion beams with a motorized film phantom. Relative to 3D-optimized beam tracking, 4D-optimized beam tracking reduced the maximum predicted dose to avoidance volumes by 53% in the simple phantom and by 13% in the thorax phantom. 4D-optimized beam tracking provided similar target dose homogeneity in the simple phantom (standard deviation of target dose was 0.4% versus 0.3%) and dramatically superior homogeneity in the thorax phantom (D5-D95 was 1.9% versus 38.7%). Measurements demonstrated that delivery of 4D-optimized beam tracking was technically feasible and confirmed a 42% decrease in maximum film exposure in the avoidance region compared with 3D-optimized beam tracking. In conclusion, we found that 4D-optimized beam tracking can reduce the maximum dose to avoidance volumes near a moving target while maintaining target dose coverage, compared with 3D-optimized beam tracking.

Background and Purpose: Scanned carbon beam therapy offers advantageous dose distributions and an increased biological effect. Treating moving targets is complex due to sensitivity to range changes and interplay. We propose a 4D treatment planning concept that considers motion during particle number optimization., Material and Methods: The target was subdivided into sectors, one for each motion phase of a 4D-CT. Each sector was non-rigidly transformed to its motion phase and there targeted by a dedicated raster field (RST). Therefore, the resulting 4D-RST compensated target motion and range changes. A 4D treatment control system (TCS) was needed for synchronized delivery to the measured patient motion. 4D-optimized plans were simulated for 9 NSCLC lung cancer patients and compared to static irradiation at end-exhale. A prototype TCS was implemented and successfully tested in a film experiment., Results: The 4D-optimized treatment plan resulted in only slightly lower dose coverage of the target compared to static optimization, with V 95% of 97.9% (median, range 96.5-99.4%) vs. 99.3% (98.5-99.8%), with negligible overdose. The conformity number was comparable at 88.2% (85.1-92.5%) vs. 85.2% (79.9-91.2%) for 4D and static, respectively., Conclusion: We implemented and tested a 4D treatment plan optimization method resulting in highly conformal dose delivery., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The purpose of this work was to investigate the potential of discrete Gaussian edge feathering of the higher energy electron fields for improving abutment dosimetry in the planning volume when using an electron multileaf collimator (eMLC) to deliver segmented-field electron conformal therapy (ECT)., Methods: A discrete (five-step) Gaussian edge spread function was used to match dose penumbras of differing beam energies (6-20 MeV) at a specified depth in a water phantom. Software was developed to define the leaf eMLC positions of an eMLC that most closely fit each electron field shape. The effect of 1D edge feathering of the higher energy field on dose homogeneity was computed and measured for segmented-field ECT treatment plans for three 2D PTVs in a water phantom, i.e., depth from the water surface to the distal PTV surface varied as a function of the x-axis (parallel to leaf motion) and remained constant along the y-axis (perpendicular to leaf motion). Additionally, the effect of 2D edge feathering was computed and measured for one radially symmetric, 3D PTV in a water phantom, i.e., depth from the water surface to the distal PTV surface varied as a function of both axes. For the 3D PTV, the feathering scheme was evaluated for 0.1-1.0-cm leaf widths. Dose calculations were performed using the pencil beam dose algorithm in the Pinnacle(3) treatment planning system. Dose verification measurements were made using a prototype eMLC (1-cm leaf width)., Results: 1D discrete Gaussian edge feathering reduced the standard deviation of dose in the 2D PTVs by 34, 34, and 39%. In the 3D PTV, the broad leaf width (1 cm) of the eMLC hindered the 2D application of the feathering solution to the 3D PTV, and the standard deviation of dose increased by 10%. However, 2D discrete Gaussian edge feathering with simulated eMLC leaf widths of 0.1-0.5 cm reduced the standard deviation of dose in the 3D PTV by 33-28%, respectively., Conclusions: A five-step discrete Gaussian edge spread function applied in 2D improves the abutment dosimetry but requires an eMLC leaf resolution better than 1 cm.

Two methods of preparing polymer nanoparticles containing (a) insulin and (b) insulin-like growth factor-1 were compared and the influence of process parameters on size and release characteristics was determined. Poly(lactide-glycolide)co-polymer (50:50) was used in both methods. Method one used a salting-out process; while method two used a solvent evaporation/double emulsion procedure forming a w/o/w secondary emulsion. Particles were separated by centrifugation and dried under vacuum. Particle size was analysed by scanning electron microscopy and protein release by dissolution and high pressure liquid chromatography. Method one produced particles of diameter 0.3-0.8 microm, whereas method two gave larger particles of 0.76-1.05 microm and in both procedures reducing pH also decreased particle size. Optimal emulsifying speed was below 4 000 rpm and scanning electron micrographs showed smooth spherical particles. Release characteristics of insulin and IGF-1 in method one and two were similar releasing 60% in 10 days but in method one release was diminished to 8% over a similar time period. Method one proved successful in producing spheres of the required size range but hampered protein loading by denaturation resulting in a low release rate. Method two provided an acceptable release rate but produced particles with diameters of about one micron.

Objective: To evaluate the competency of second-year pharmacy students to compound capsules from a prescription 12 months after completing a compounding course., Methods: Students who completed the compounding course were given the same prescription they had been given 12 months earlier to compound metoprolol capsules. No warning of the second exercise was given and they were expected to prepare capsules and package and label the finished product. Performance was evaluated in an identical manner for both exercises based on the level of professional competency of a score of 80% or above., Results: Eighty-seven percent fewer students achieved a score of 90% or more on the second exercise and 81% fewer students demonstrated the required competency., Conclusions: Differences in scores on the first and second exercises indicate that pharmacy students' level of competency and retention of knowledge with respect to compounding capsules is not adequately retained after a 12-month hiatus.

Purpose: To evaluate the permeability enhancing effects of octylglucoside (OG) for molecules with poor absorption such as insulin by in vitro cell models., Methods: Transepithelial electrical resistance (TEER) was monitored to ensure monolayer integrity. Permeability was ascertained using paracellular markers. Markers and insulin were dissolved in Hanks balanced salt solution and placed on the apical side of the cells in Transwell(c) plates and allowed to diffuse under sink conditions., Results: The effect of OG on the permeability of molecules across both monolayers was concentration and time dependent. Enhanced transport of the three molecules was observed across both monolayers treated with OG as compared to untreated monolayers. The effects of OG were reversible at low concentrations but there was permanent damage to cells at higher concentrations. Absorption enhancement was greater across T-84 monolayers compared to Caco-2 monolayers., Conclusions: The results indicate OG has potential as a permeability enhancer for poorly absorbed drugs with no significant damage to monolayers at low concentrations. Immediate attenuation in TEER upon exposure to OG indicates that permeability enhancing effects were likely to be associated with modulation of tight junctions suggesting the involvement of paracellular transport.

Dodecylmaltoside (DDM), an alkylglycoside showing tissue-permeability-enhancing properties, has been successful in improving nasal and ocular transport of poorly absorbed drugs. It was hypothesized that optimization of DDM concentration would improve the transport of insulin across epithelial monolayers without causing cell damage. Samples of markers and insulin were collected over a 6-h period and transepithelial electrical resistance was measured at concurrent time points to ascertain the effect of DDM on tight junctions. Samples were analyzed for lucifer yellow and insulin using reversed-phase high-performance liquid chromatography and for (3)[H]-mannitol by scintillation counting. A significant increase in the transport of markers and insulin was recorded in DDM-treated cells compared with controls. DDM enhanced the transport of markers and insulin in a concentration-dependent manner. Decreased transepithelial electrical resistance values confirmed that enhanced transport is caused by loosening of tight junctions. Cell recovery was >95% in 8 h indicating the potential of DDM as a penetration enhancer for clinical administration of insulin and other poorly absorbed drugs without causing cell damage., (Copyright 2004 Wiley-Liss, Inc.)

A delivery system consisting of the lipophilic fluorescent dye coumarin-6 embedded into polymer nanoparticles in a suppository base was formulated. Particle diameters of 400-1100 nm were produced by a salting-out method and measured by laser diffraction. Nanoparticles reach the systemic circulation via fenestrated capillaries or remain within rectal membranes to release their contents. Dissolution over 168 hr was initially rapid followed by a steady decline, and tissue distribution showed coumarin-6 to be present in liver and lungs for a similar time period while in kidney, small intestines, and blood up to 96 hr. Microscopic observations showed nanoparticles to be present in blood up to 72 hr.

Sustained release nanospheres were prepared from the polymethacrylates Eudragit S(100) and E(100) containing a water insoluble dye by a salting-out method. Coumarin-6 was used as a model for insoluble analgesics to ascertain uptake and release properties dependent on polymer characteristics and pH. Morphology and particle size were characterized by scanning electron microscopy (SEM). Particles were smooth, spherical and uniform with diameters ranging from 0.6-0.8 micro m. Yield was 38% and 86% for E(100) and S(100), respectively, and encapsulation of coumarin-6 efficiency was 58% and 75%, respectively. Coumarin-6 was stable within the polymer matrix at temperatures from -20 degrees C to 45 degrees C for 4 months. Release was most efficient from S(100) polymers in phosphate buffer at pH 7.4 and 8.0 reaching a maximum; 5 hours prior to samples at pH 7.0 and 9.0. Release was biphasic and concentration as a function of the square root of time produced linear data suggesting a Higuchi type diffusion from a polymer matrix. Release from E(100) was 65% lower than that from S(100) and was not solely dependent upon the ionization of polymer but most likely due to a combination of factors including buffer ionization.

series of alkylglycosides has been evaluated on human cell lines to determine its ability to open cellular tight junctions. Alkylglycosides were applied to cell monolayers; the resulting change in resistance was determined by transepithelial electrical resistance measurements. Change in resistance across cell monolayers is an indication of tight junction activation, whereas subsequent increase in resistance signifies monolayer recovery. Of the 13 alkylglycosides tested, 4 caused irreversible solubilization of cell membranes, 5 allowed a partial recovery of the monolayer after a relatively rapid reduction in resistance, and 4 induced a decrease in resistance with more complete cell recovery. Alkylglycosides allowing extensive cell recovery after removal may indicate tight junctions' activity dominance over membrane fluidity. Repeated application of alkylglycosides for 6 hours lowered resistance across cells, which returned to near-normal values after a recovery period of 48 hours. A model dye was transported across the cell monolayer only in the presence of an alkylglycoside, although recovery of cells was incomplete. Activity of the alkylglycosides was unrelated to either the carbon chain length or to the carbohydrate moiety. A direct correlation was established between the concentration of applied alkylglycoside and reduction in resistance over a constant time period. Dodecylmaltoside and octylglucoside were found to be optimal in decreasing resistance at low concentrations and allowing significant recovery of cells. Therefore these 2 alkylglycosides may be useful in facilitating drug transport across biological membranes.

Oral delivery of proteins and peptides as therapeutic agents is problematic due to their low bioavailability. This study examined the effect of boronation on the transepithelial transport and metabolism of three glycine-phenylalanine dipeptides in Caco-2 and HCT-8 cell monolayers. The three dipeptides exhibited passive transport characteristics in the monolayer systems. However, metabolism of the boronated dipeptides did occur, but to a lesser extent than the non-boronated glycine-phenylalanine dipeptide. The same metabolic scheme was seen in both cell monolayer system, but greater metabolism was seen in the HCT-8 cell monolayers.

The interaction of low density lipoprotein (LDL) with two model dyes in the presence or absence of non-ionic surfactants has been studied. The water soluble dye, thymol blue, only weakly interacts with LDL to cause slight increases in particle size and the interaction can be reversed on column chromatography and dialysis. The oil-soluble dye sudan III reacts strongly with LDL to produce marked changes in particle size the complex formed being stable to dialysis and gel exclusion chromatography. These interactions are not affected by the presence of surfactants. The results indicate that even small quantities of lipophilic materials will easily partition into the particle, with or without the aid of surfactants and can have a marked effect on the measured size of the particle.