Increased Delivery Efficiency Research Articles

VANET-based Secure Information Exchange for Smart Charging

Smart inventions have led to smart grids, which have paved the way to smart charging means. This smart charging information about a vehicle needs to be properly maintained in order to use it to exchange information between charging stations and electric vehicles. In this work, we have introduced an efficient methodology for managing and disseminating energy from the charging station to the smart vehicle in an urban area where the number of electric vehicles is high. We have designed and implemented a novel concept involving mobile edge computing in VANET. Moreover, we have also used an effective mechanism for communicating the information on charging with the moving electric vehicles and servers. A local relay scheme is used for reducing redundant overheads, increase delivery efficiency of charging information. This scheme is implemented with delay wait model as the base. The output is recorded by means of simulation environment and based on the observations the proposed work is found to be optimal in maintaining, accessing and disseminating the charging information.

Polymeric Nanocarriers with Controlled Chain Flexibility Boost mRNA Delivery In Vivo through Enhanced Structural Fastening.

Messenger RNA (mRNA) shows high therapeutic potential, though effective delivery systems are still needed for boosting its application. Nanocarriers loading mRNA via polyion complexation with block catiomers into core-shell micellar structures are promising systems for enhancing mRNA delivery. Engineering the interaction between mRNA and catiomers through polymer design can promote the development of mRNA-loaded micelles (mRNA/m) with increased delivery efficiency. Particularly, the polycation chain rigidity may critically affect the mRNA-catiomer interplay to yield potent nanocarriers, yet its effect remains unknown. Herein, the influence of polycation stiffness on the performance of mRNA/m by developing block complementary catiomers having polycation segments with different flexibility, that is, poly(ethylene glycol)-poly(glycidylbutylamine) (PEG-PGBA) and PEG-poly(L-lysine) (PEG-PLL) is studied. PEG-PGBA allows more than 50-fold stronger binding to mRNA than the relatively more rigid PEG-PLL, resulting in mRNA/m with enhanced protection against enzymatic attack and polyanions. mRNA/m from PEG-PGBA significantly enhances mRNA in vivo bioavailability and increased protein translation, indicating the importance of controlling polycation flexibility for forming stable polyion complexes with mRNA toward improved delivery.

Polymerized Selenium Nanoparticles for Folate-Receptor-Targeted Delivery of Anti-Luc-siRNA: Potential for Gene Silencing.

The development of a biocompatible and nontoxic gene delivery vehicle remains a challenging task. Selenium nanoparticles (SeNPs) have the potential to increase delivery efficiency, to reduce side effects, and to improve therapeutic outcomes. In this study, chitosan (Ch) functionalized folate (FA)-targeted SeNPs were synthesized, characterized, and evaluated for their potential to bind, protect, and safely deliver Fluc-siRNA in vitro. SeNPs of less than 100 nm were successfully synthesised and further confirmed using UV-vis and Fourier transform infrared spectroscopy, transmission electron microscopy, and nanoparticle tracking analysis. Cell viability studies were conducted in vitro in selected cancer and non-cancer cell lines. Folate receptor (FOLR1) targeted and nontargeted luciferase gene silencing studies were assessed in the transformed Hela-tat-Luc cell line expressing the luciferase gene. Targeted and nontargeted SeNP nanocomplexes showed minimal toxicity in all cell lines at selected w/w ratios. Maximum gene silencing was achieved at optimum w/w ratios for both nanocomplexes, with Selenium-chitosan-folic acid (SeChFA) nanocomplexes showing slightly better transgene silencing, as supported by results from docking studies showing that SeChFA nanocomplexes interacted strongly with the folate receptor (FOLR1) with high binding energy of −4.4 kcal mol−1.

Improving Tumor Accumulation of Aptamers by Prolonged Blood Circulation.

Developing cancer targeted medicine depends on increasing delivery efficiency and tumor site accumulation of theranostic agents. To accomplish this, we report a modification of PTK7 receptor-specific aptamer Sgc8 with the small molecule Evans Blue (EB), thus implementing an albumin binding hitchhike strategy for prolonged blood circulation. The EB molecule could insert into the hydrophobic region of serum albumin and form an aptamer/albumin complex. This complex showed superior physiological stability, facilitating longer blood half-life, and maintaining its targeting capacity. Successful conjugation of EB-aptamers was confirmed by a series of characterization methods. Targeting performance was tested on a xenografted mouse tumor model. Taking advantage of the long circulating aptamer/HSA complex, improved accumulation, and delivery efficiency to the tumor site were achieved. Through ex vivo quantification of the EB-Sgc8 aptamers' biodistribution, the mechanism of improved targeting performance was illuminated. Therefore, the increased aptamers tumor delivery efficiency and accumulation indicate that prolonging blood circulation is a promising strategy to improve aptamers' targeted delivery performance in the future clinical translation.

Folate Receptor-Targeted Albumin Nanoparticles Based on Microfluidic Technology to Deliver Cabazitaxel.

Microfluidic technology (MF) has improved the formulation of nanoparticles (NPs) by achieving uniform particle size distribution, controllable particle size, and consistency. Moreover, because liquid mixing can be precisely controlled in the pores of the microfluidic chip, maintaining high mixing efficiency, MF exerts higher of NP encapsulation efficiency (EE) than conventional methods. MF-NPs-cabazitaxel (CTX) particles (MF-NPs-CTX) were first prepared by encapsulating CTX according to MF. Folate (FA)- Polyethylene glycol (PEG)-NPs-CTX particles (FA-PEG-NPs-CTX) were formulated by connecting FA to MF-NPs-CTX to endow NPs with targeted delivery capability. Accordingly, the mean particle size of FA-PEG-NPs-CTX increased by approximately 25 nm, as compared with MF-NPs-CTX. Upon morphological observation of FA-PEG-NPs-CTX and MF-NPs-CTX by transmission electron microscopy (TEM), all NPs were spherical and particle size distribution was uniform. Moreover, the increased delivery efficiency of CTX in vitro and its strong tumor inhibition in vivo indicated that FA-PEG-NPs-CTX had a powerful tumor-suppressive effect both in vitro and in vivo. In vivo imaging and pharmacokinetic data confirmed that FA-PEG-NPs-CTX had good drug delivery efficiency. Taken together, FA-PEG-NPs-CTX particles prepared using MF showed high efficient and targeted drug delivery and may have a considerable driving effect on the clinical application of targeting albumin NPs.

Ultrasound-microbubbles-mediated microRNA-449a inhibits lung cancer cell growth via the regulation of Notch1.

BackgroundThe application of gene-loaded microbubbles (MBs) combined with ultrasound that results in increased delivery efficiency may be an excellent method of gene delivery. This study aimed to discuss the effects of ultrasound-MB-mediated microRNA (miR)-449a on lung cancer (LC) development by targeting Notch1.MethodsInitially, miR-449a expression in LC tissues, paracancerous tissues, LC cell lines, and lung epithelial cells was detected and its association with LC patients’ clinical characteristics was analyzed. The gain-of-function studies were performed to probe the roles of miR-449a and ultrasound-MB-mediated miR-449a in LC progression. Then, RT-qPCR combined with Western blot analysis was applied to verify the levels of miR-449a, Notch1, proliferation- and apoptosis-related proteins. Moreover, xenograft tumors in nude mice were also applied for in vivo experiments.ResultsPoorly expressed miR-449a was observed in LC, and its expression was associated with clinical staging, differentiation and lymph node metastasis of LC patients. Overexpression of miR-449a suppressed LC cell proliferation and promoted G2/M arrest and apoptosis. Ultrasound-MB-mediated miR-449a strengthened inhibitory effects of miR-449a on cell growth and resistance to apoptosis. miR-449a inhibited H1299 cell activity by targeting Notch1.ConclusionOur data supported that miR-449a overexpression inhibited LC cell growth, and ultrasound-MB-mediated miR-449a reinforced the repressive effects of miR-449a on LC progression. This investigation may offer new insight for LC treatment.

Calculating Total Delivery Times from Service Time Distribution

This study aims to improve the efficiency of last-mile delivery by quantifying service time and estimating delivery time based on service time distribution. We present a method to increase delivery efficiency

MicroRNA Biogenesis is Enhanced by Liposome-Encapsulated Pin1 Inhibitor in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is in an urgent need of new, effective therapies to reduce morbidity and mortality. We have previously demonstrated that peptidyl-prolyl cis/trans isomerase Pin1 is a potential target for HCC therapy, due to its pivotal role in HCC development through regulating miRNA biogenesis, and discovered the small molecule API-1 as a novel and specific Pin1 inhibitor. Despite its significant anti-HCC activity, the low water solubility and in vivo bioavailability of API-1 limit its clinical application. To address these issues, we herein developed a liposomal formulation of API-1 to improve API-1 delivery and enhance its anti-HCC efficacy.Methods: We designed and developed a nanoscale liposomal formulation of API-1, named as API-LP. Subsequently, the mean diameter, polydispersity, zeta potential, encapsulation efficiency and thermal properties of the optimization API-LP were characterized. The enhanced anti-HCC activity and the molecular mechanism of API-LP were investigated both in vitro and in vivo. Finally, the safety and pharmacokinetic property of API-LP were evaluated systematically.Results: API-LP had good formulation characteristics and exhibited an enhanced in vitro activity of suppressing proliferation and migration of HCC cells when compared with free API-1. The mechanism study showed that API-LP upregulated miRNA biogenesis via inhibiting Pin1 activity followed by restoring the nucleus-to-cytoplasm export of XPO5. Because of the increased delivery efficiency, API-LP displayed a stronger ability to promote miRNA biogenesis than free API-1. Importantly, API-LP displayed higher systemic exposure than free API-1 in mice without apparent toxicity, resulting in an enhanced tumor inhibition in xenograft mice.Conclusion: The development and assessment of API-LP provide an attractive and safe anti-HCC agent, highlighting the miRNA-based treatment for human cancers.

A hybrid planning strategy for stereotactic body radiation therapy of early stage non-small-cell lung cancer.

Currently dynamic conformal arcs (DCA) and volumetric modulated arc therapy (VMAT) are two popular planning techniques to treat lung stereotactic body radiation therapy (SBRT) patients. Of the two, DCA has advantages in terms of multi‐leaf collimator (MLC) motion, positioning error, and delivery efficiency. However, VMAT is often the choice when critical organ sparing becomes important. We developed a hybrid strategy to incorporate DCA component into VMAT planning, results were compared with DCA and VMAT plans. Four planning techniques were retrospectively simulated for 10 lung SBRT patients: DCA, Hybrid‐DCA (2/3 of the doses from DCA beams), Hybrid‐VMAT (2/3 of the doses from VMAT beams) and VMAT. Plan complexity was accessed by modulation complexity score (MCS). Conformity index (CI) for the planning target volume (PTV), V 20 and V 5 for the lung, V 30 for the chestwall, and maximum dose to all other critical organs were calculated. Plans were compared with regard to these metrics and measured agreement between the planned and delivered doses. DCA technique did not result in acceptable plan quality due to target location for five patients. Hybrid‐DCA produced one unacceptable plan, and Hybrid‐VMAT and VMAT produced no unacceptable plans. The CI improved with increasing VMAT usage, as did the dose sparing to critical structures. Compared to the VMAT technique, a total MU reduction of 14%, 25% and 37% were found for Hybrid‐VMAT, Hybrid‐DCA and DCA techniques for 54 Gy patient group, and 9%, 23% and 34% for 50 Gy patient group, suggesting improvement in delivery efficiency with increasing DCA usage. No significant variations of plan complexity were observed between Hybrid‐DCA and Hybrid‐VMAT (P = 0.46 from Mann–Whitney U‐test), but significant differences were found among DCA, Hybrid and VMAT (P < 0.05). Better agreements between the planned and delivered doses were found with more DCA contributions. By adding DCA components to VMAT planning, hybrid technique offers comparable dosimetry to full VMAT, while increasing delivery efficiency and minimizing MLC complexity.

Different Nanoformulations Alter the Tissue Distribution of Paclitaxel, Which Aligns with Reported Distinct Efficacy and Safety Profiles.

Previous studies have shown that different paclitaxel formulations produce distinct anticancer efficacy and safety profiles in animals and humans. This study aimed to investigate the distinct pharmacokinetics and tissue distribution of various nanoformulations of paclitaxel, which may translate into potential differences in safety and efficacy. Four nanoparticle formulations ( nab-paclitaxel, mouse albumin nab-paclitaxel [m -nab-paclitaxel], micellar paclitaxel, and polymeric nanoparticle paclitaxel) as well as solvent-based paclitaxel were intravenously administered to mice. Seventeen blood and tissue samples were collected at different time points. The total paclitaxel concentration in each tissue specimen was measured with liquid chromatography-tandem mass spectrometry. Compared with solvent-based paclitaxel, all four nanoformulations demonstrated decreased paclitaxel exposure in plasma. All nanoformulations were associated with paclitaxel blood-cell accumulation in mice; however, m- nab-paclitaxel was associated with the lowest accumulation. Five minutes after dosing, the total paclitaxel in the tissues and blood was approximately 44% to 57% of the administered dose of all paclitaxel formulations. Paclitaxel was primarily distributed to liver, muscle, intestine, kidney, skin, and bone. Compared with solvent-based paclitaxel, the different nanocarriers altered the distribution of paclitaxel in all tissues with distinct paclitaxel concentration-time profiles. nab-paclitaxel was associated with increased delivery efficiency of paclitaxel in the pancreas compared with the other formulations, consistent with the demonstrated efficacy of nab-paclitaxel in pancreatic cancer. All the nanoformulations led to high penetration in the lungs and fat pad, which potentially points to efficacy in lung and breast cancers. Micellar paclitaxel and polymeric nanoparticle paclitaxel were associated with high paclitaxel accumulation in the heart; thus, the risk of cardiovascular toxicity with these formulations may warrant further investigation. The solvent-based formulation was associated with the poorest paclitaxel penetration in all tissues and the lowest tissue-to-plasma ratio. The different nanocarriers of paclitaxel were associated with distinct pharmacokinetics and tissue distribution, which largely align with the observed efficacy and toxicity profiles in clinical trials.

Lipid Polymer Hybrid Nanomaterials for mRNA Delivery.

In the past decade, messenger RNA (mRNA) has been extensively explored in a wide variety of biomedical applications. However, efficient delivery of mRNA is still one of the key challenges for its broad applications in the clinic. Recently, lipid polymer hybrid nanoparticles (LPNs) are evolving as a promising class of biomaterials for RNA delivery, which integrate the physicochemical properties of both lipids and polymers. We previously developed an N1,N3,N5-tris(2-aminoethyl)benzene-1,3,5-tricarboxamide (TT) derived lipid-like nanomaterial (TT3-LLN) which was capable of effectively delivering multiple types of mRNA. In order to further improve the delivery efficiency of TT3-LLN, in this study, we focused on studying the effects of incorporating different polymers on establishing LPNs and aimed to develop an optimized lipid polymer hybrid nanomaterial for efficient mRNA delivery. We incorporated a series of biodegradable and biocompatible polymer materials into the formulation of TT3-LLNs to develop LPNs. mRNA delivery efficiency of different LPNs were evaluated and a systematic orthogonal optimization was further carried out. Our data indicate that PLGA4 (MW 24,000-38,000 g/mol) dramatically increased delivery efficiency of TT3-LLNs in comparison to other polymers. Further optimization identified PLGA4-7 LPNs (PLGA:mRNA=9:1, mass ratio; TT3:DOPE:Cholesterol:DMG-PEG2000=25:25:45:0.75, molar ratio) as a lead formulation, which displayed significantly enhanced delivery of two types of mRNA in three different human cell lines as compared with TT3-LLNs. Results from this study potentially provide new insights into developing LPNs for mRNA based therapeutics.

A Prospective 4π Radiation Therapy Clinical Study in Recurrent High-Grade Glioma Patients

To evaluate the feasibility, safety, dosimetric benefits, delivery efficiency, and patient comfort in the clinical implementation of 4π radiation therapy. Eleven patients with recurrent high-grade glioma were recruited for the trial. 4π plans integrating beam orientation and fluence-map optimization were created using an in-house column-generation algorithm. The collision-free beam solution space throughout the 4π steradian was determined using a computer-aided-design model of the Varian TrueBeam system and a human subject. Twenty beams were optimized for each case and imported into Eclipse for intensity modulated radiation therapy planning. Beam orientations with neighboring couch kicks were merged for increased delivery efficiency, generating plans with an average of 16 beam orientations. Volumetric modulated arc therapy (VMAT) plans with 3-4 arcs were also generated for each case, and the plan achieving superior dosimetric quality was selected for treatment. Patient comfort was surveyed after every fraction. Multiple 2-dimensional X-ray images were obtained to measure intrafractional motion. Of 11 patients, 9 were treated with 4π. Mean and maximum organ at risk doses were equal or significantly lower (P<.05) with 4π than with VMAT. Particularly substantial dose reduction of 2.92Gy in the average accumulated brainstem maximum dose enabled treatments that would otherwise not satisfy safe dose constraints with VMAT. One patient was not treated because neither plan met the dosimetric criteria. The other was treated with VMAT owing to comparable dosimetry resulting from a planning target volume located in a separate co-plane superior to organs at risk. Treatments were well tolerated, with an average patient comfort score of 8.6/10. Intrafractional motion was <1.5mm for all delivered fractions, and the average delivery time was 34.1minutes. The feasibility, safety, dosimetric benefits, delivery efficiency, and patient comfort of 4π radiation therapy have been clinically demonstrated with a prospective clinical trial. The results elucidate the potential and challenges of wider clinical implementations.

15. Evaluation of a dedicated brain metastases treatment planning optimization for radiosurgery: A new treatment paradigm?

Introduction To investigate the feasibility of a novel dedicated treatment planning solution, to automatically target multiple brain metastases with a single isocenter and multiple inversely-optimized dynamic conformal arcs (DCA), and to benchmark it against the well-established multiple isocenter DCA (MIDCA) and volumetric modulated arc therapy (VMAT) approaches. Methods Ten previously treated patients were randomly selected, each representing a variable number of lesions ranging between 1 to 8. The original MIDCA treatments were replanned with both VMAT and the novel brain metastases tool. The plans were compared by means of Paddick conformity (CI) and gradient index (GI), and the volumes receiving 10 Gy (V10) and 12 Gy (V12). Results The brain metastases software tool generated plans with similar CI (0.65 ± 0.08) as both established treatment techniques while improving the gradient (mean GI = 3.9 ± 1.4). The normal tissue exposure in terms of V10 (48.5 ± 35.9 cc) and V12 (36.3 ± 27.1 cc) compared similarly to the MIDCA technique and surpassed VMAT plans. Conclusions The automated brain metastases planning algorithm software is an optimization of DCA radiosurgery by increasing delivery efficiency to the level of VMAT approaches. Improving dose gradients and normal tissue sparing over VMAT, revives DCA as the paradigm for linac-based stereotactic radiosurgery of multiple brain metastases.

Acceptability of collection and delivery points from consumers’ perspective: A qualitative case study of Christchurch city

The growth in global online retail sales during the last decade has led to an enormous increase in the number of parcels to be delivered. Although vehicle kilometres travelled associated with shopping trips might decrease as a result of online shopping, an increased number of failed home deliveries might out-weigh this reduction, worsening urban transport problems caused by high car dependency. In many European countries, such as France, UK and the Netherlands, Collection and Delivery Points (CDPs) have been implemented and observed to increase delivery efficiency by reducing the number of failed home deliveries.Similar to the worldwide trend of online shopping, a major proportion of New Zealanders also shop online. However, CDPs were only recently introduced in limited locations within three of New Zealand’s biggest cities, i.e. Auckland, Wellington and Christchurch. Thus, little is understood about New Zealanders’ acceptance of CDPs and their online shopping behaviour. This study aimed to address these issues by means of focus groups, using Christchurch as a case study. The results show that the factors influencing the Christchurch’s residents’ acceptance of CDPs, can be categorised into several themes, such as CDP network density, parking availability at CDPs, spatial location of CDPs, proximity to consumers’ home or office, safe and secure operation, and hours of operation of CDPs. Such knowledge is important for policy makers to help formulate policies that can lead to more sustainable urban environments, and for the companies that want to establish successful CDP networks in Christchurch.

Characterizing the Impact of the Highly Endosmolytic Cell‐Penetrating Peptide, dfTAT, on Human Cells

One of the biggest challenges of delivering molecules into live cells is maintaining cellular homeostasis after delivery. In many reported delivery systems, cell viability decreases as a function of increased delivery efficiency. In our lab, we have generated a highly endosmolytic cell‐penetrating peptide, dfTAT, that aids the delivery of macromolecules into live cells without impacting cell viability or transcriptome regulation. dfTAT enters the cell by endocytosis, and is subsequently released from late endosomes to enter the cytosol. With its highly efficient endosomal release, dfTAT would be expected to be toxic to cells as a result of the predicted release of calcium and hydrolytic enzymes into the cytosol. However, because dfTAT‐mediated delivery does not elicit the same toxic responses as other delivery systems, it is of interest to investigate what is happening to the cell post‐release. One hypothesis is that other cellular processes mask certain physiological changes occurring to the cell. These processes may include repair of damaged late endosomal membranes or autophagy‐dependent degradation of damaged vesicles. Preliminary experiments have indicated that dfTAT‐mediated late endosomal disruption triggers a galectin‐3 response, a hallmark signal of autophagy induction. Based on this initial finding, it is of interest to identify what these cellular response mechanisms are, and what additional proteins may be involved in these processes. Another important aspect of characterizing a cell's response to dfTAT is to quantify how many endosomes are experiencing leakage, as well as elucidating the kinetics of how damaged endosomes are processed by the cell. Overall, the relevance of this work goes beyond intracellular delivery, in that the highly endosmolytic efficiency of dfTAT can be exploited to learn about membrane damage that occurs in other biological systems. In addition, further elucidating the proteomic profile, as well as kinetics, of a cell's response to endosomal membrane damage can be applied to understanding the fundamental biology of a cell.

Formulation of hydrophobic peptides for skin delivery via coated microneedles

Microneedles (MNs) have been investigated as a minimally-invasive delivery technology for a range of active pharmaceutical ingredients (APIs). Various formulations and methods for coating the surface of MNs with therapeutics have been proposed and exemplified, predominantly for hydrophilic drugs and particulates. The development of effective MN delivery formulations for hydrophobic drugs is more challenging with dosing restrictions and the use of organic solvents impacting on both the bioactivity and the kinetics of drug release. In this study we propose a novel formulation that is suitable for MN coating of hydrophobic auto-antigen peptides currently being investigated for antigen specific immunotherapy (ASI) of type 1 diabetes. The formulation, comprising three co-solvents (water, 2-methyl-2-butanol and acetic acid) and polyvinylalcohol 2000 (PVA2000) can dissolve both hydrophilic and hydrophobic peptide auto-antigens at relatively high, and clinically relevant, concentrations (25mg/ml or 12.5mg/ml). The drug:excipient ratio is restricted to 10:1 w/w to maximise dose whilst ensuring that the dry-coated payload does not significantly impact on MN skin penetration performance. The coating formulation and process does not adversely affect the biological activity of the peptide. The delivery efficiency of the coated peptide into skin is influenced by a number of parameters. Electropolishing the metal MN surface increases delivery efficiency from 2.0±1.0% to 59.9±6.7%. An increased mass of peptide formulation per needle, from 0.37μg to 2μg peptide dose, resulted in a thicker coating and a 20% reduction in the efficiency of skin delivery. Other important performance parameters for coated MNs include the role of excipients in assisting dissolution from the MNs, the intrinsic hydrophobicity of the peptide and the species of skin model used in laboratory studies. This study therefore both exemplifies the potential of a novel formulation for coating hydrophobic and hydrophilic peptides onto MN devices and provides new insight into the factors that influence delivery efficiency from coated MNs. Importantly, the results provide guidance for identifying critical attributes of the formulation, coating process and delivery device, that confer reproducible and effective delivery from coated MNs, and thus contribute to the requirements of the regulators appraising these devices.

Optimal RTO Timer for Best Transmission Efficiency of DTN Protocol in Deep-Space Vehicle Communications

The delay/disruption-tolerant network (DTN) was proposed as an end-to-end networking architecture for file delivery service in a stressed communication environment. A typical application of DTN technology is for reliable data delivery in deep-space vehicle communications. The main protocol of DTN, i.e., bundle protocol (BP), utilizes a store-and-forward mechanism and a custody transfer option for transmission reliability. However, little work has been done on the performance evaluation of DTN's BP in deep-space communications. In this paper, we present a study of the retransmission timeout (RTO) timer setting for the use of BP for reliable file (or data) transmission over a relay-based deep-space vehicle communication infrastructure characterized by extremely long latency, lossy data links, and highly asymmetric channel rates. Unlike most studies proposed for terrestrial Internet for which the RTO timer is set equal to or longer than the round-trip time (RTT), we propose to set the RTO timer shorter than the RTT and expect that it will increase delivery efficiency per unit of time. We intend to find an RTO timer setting for maximum data delivery performance of BP, which is considered to be an optimal RTO timer, for deep-space missions. For the first time, analytical models are built for delivery performance involving the RTO timer. Using the built models, we tune the RTO timer toward the highest data delivery performance. The models are validated by running text file transfer experiments using a PC-based testbed and tuning the RTO timer toward the best performance of BP. A performance comparison between the optimal RTO timer proposed in this study and the existing commonly used RTO timers is also presented.

Computerized triplet beam orientation optimization for MRI-guided Co-60 radiotherapy.

Magnetic resonance imaging (MRI)-guided Co-60 provides daily and intrafractional MRI soft tissue imaging for improved target and critical organ tracking. To increase delivery efficiency, the system uses three Co-60 sources at 120° apart, allowing up to 600 cGy combined dose rate at isocenter. Despite the potential tripling in output, creating a delivery plan that uses all three sources is considerably unintuitive. Here, the authors computerize the triplet orientation optimization using column generation, an approach that was demonstrated effective in integrated beam orientation and fluence optimization for noncoplanar therapies. To achieve a better plan quality without increasing the treatment time, the authors then solve a fluence map optimization (FMO) problem while regularizing the fluence maps to reduce the number of deliverable MLC segments. Three patients-one prostate, one lung, and one head and neck boost plan (H&NBoost)-were evaluated in this study. For each patient, the beamlet doses were calculated using Monte Carlo, under a 0.35 T magnetic field, for 180 equally spaced coplanar beams grouped into 60 triplets. The beamlet size is 1.05 × 0.5 cm determined by the MLC leaf thickness and step size. The triplets were selected using the column generation algorithm. The FMO problem was formulated using an L2-norm dose fidelity term and an L1-norm anisotropic total variation regularization term, which allows controlling the number of MLC segments, and hence the treatment time, with minimal degradation to the dose. The authors' Fluence Regularization and Optimized Selection of Triplets (FROST) plans were compared against the clinical treatment plans (CLNs) produced by an experienced dosimetrist. PTV homogeneity, max dose, mean dose, D95, D98, and D99 were evaluated. OAR max and mean doses, as well as R50, defined as the ratio of the 50% isodose volume over the planning target volume were investigated. The mean PTV D95, D98, and D99 differ by +0.04%, +0.07%, and +0.25% of the prescription dose between planning methods. The mean PTV homogeneity was virtually same with values at 0.8788 (FROST) and 0.8812 (CLN). R50 decreased by 0.67 comparing FROST to CLN. On average, FROST reduced Dmax and Dmean of OARs by 7.30% and 6.08% of the prescription dose, respectively. The manual CLN planning processes required numerous trial and error runs. The FROST plans on the other hand required minimal human intervention. Efficient delivery of MRI-guided Co-60 therapy needs the output of multiple sources yet suffers from unintuitive and laborious manual beam selection processes. Computerized triplet orientation optimization improves both planning efficiency and plan dosimetry. The novel fluence map regularization provides additional controls over the number of MLC segments and treatment time.

SU‐F‐T‐637: Single‐Isocenter Versus Multiple‐Isocenter VMAT SRS for Unusual Multiple Metastasis Case with Two Widely Separated Lesions

Purpose:Single‐isocenter (SI) volumetric modulated arc therapy has been shown to be an effective and efficient approach to multiple metastasis radiosurgery. However, certain extreme cases raise the question of whether multiple‐isocenter (MI) approaches can still generate superior plans. In this study, we ask this question with respect to a clinical case with two very widely separated lesions.Methods:A patient with two widely separated (d = 12cm) tumors was treated with SI‐VMAT SRS using 10MV flattening filter free (FFF) beam with high‐definition multi‐leaf collimator (HD‐MLC, 2.5/5mm) in two non‐coplanar arcs using concentric rings to enforce steep gradient. Because of lesion positioning with respect to collimator angle selection, lesions were treated by 5mm leaves. We re‐planned the case with a congruent arc arrangement but separate isocenter for each lesion. In this manner, lesions were treated by 2.5mm leaves. Conformity index (CI), V50%, and mean brain dose were compared.Results:Neither conformity (CI_SI = 1.12, CI_MI = 1.08) nor V50% (V50%_SI =8.82cc, V50%_MI =8.81cc) were improved by utilizing a separate isocenter for each lesion. Mean brain dose was slightly reduced (dmean_SI = 118.4 cGy, dmean_MI = 88.7 cGy) by using multiple isocenters.Conclusion:For this case with a lesion at the apex of the brain and another distantly located at the base of skull, employing a separate isocenter for each target did not meaningfully improve plan quality. Single‐isocenter VMAT has been shown feasible and equivalent to multiple‐isocenter VMAT for multiple metastasis cases in general. In this extreme case, single‐ and multiple‐ isocenter VMAT were also equivalent. If rotational setup errors are appropriately corrected, the increased delivery efficiency of the single‐isocenter approach renders it preferable to the multiple isocenter approach.Dr's Thomas, Popple, and Fiveash have all received honoraria from Varian Medical Systems for discussing their experiences with stereotactic radiosurgery.

Advances of phenylboronic acid-containing materials in drug delivery

Phenylboronic acid (PBA) and its derivatives are a kind of synthetic chemicals which can recognize diols via reacting reversibly with them in aqueous solutions. Recently, based on the reversible covalent PBA/diol complexes, strategies to construct drug delivery system for diabetes treatments and cancer therapy have made enormous progress. Diabetis mellitus have greatly increased all over the world in recent decades. With the regular use of insulin in diabetes treatment, there is a high demand of insulin self-regulated release system responding to glucose concentration in vivo . Since the apparent p K a value of PBA and its derivatives is around 8.2–8.6, which is higher than human physiological pH 7.4, efficient glucose-responsiveness of PBA-based polymer materials could not be obtained at physiological pH and glucose level. Recently, studies to construct this insulin release system based on PBA polymer materials have made enormous progress, such as reducing the p K a of the PBA group, achieving “on-off” release of insulin according to the change of glucose concentration and so on. Similar to diabetes treatments, significant efforts have recently been made to develop drug delievery system based on PBA polymer materials in cancer therapy. Traditional chemotherapy has disadvantages such as poor permeability, short resident time, and toxic side effects. Therefore, the ideal drug delivery carrier should possess tumor targeting ability to prolong the retention time and enhance the aggregation of carriers in tumors. Inaddition, carriers should release drugs and degrade in response to intracellular triggers when inside the cancer cells, in order to increase delivery efficiency and reduce toxicity. The recognition ability of boronic acid to polyol residues in cell membranes enables PBA-functionalized nanocarriers to specific target to sialic acid groups, which are overexpressed on tumor cells. The high affinity and specificity of PBA to SA could significantly improve drug accumulation and retention in tumor, and increase the cellular uptake of carriers. Moreover, the reversible covalent PBA/diol complexes provide three modes of stimuli-responsive features of PBA polymer materials. Firstly, the reversible covalent of PBA with diols depends on the pH, and the PBA-diols bond will be weak at acidic pH such as within endosomes and lysosome. So this pH-responsiveness of PBA-modified carriers could be used to release drugs and genes accurately inside tumor tissues as well as cancer cells. Secondly, one diols complex with PBA could easily be replaced by another diols having better thermodynamic stability complex with PBA. Adenosine triphosphate (ATP) with a cis -diol moiety is abundant inside cells, and the PBA-sugar complex could be exchanged by more stable PBA-ATP formation. Finally, many types of tumor tissues and cancer cells have increased levels of reactive oxygen species (ROS), and PBA ester can react with these ROS such as H2O2, thus PBA ester can be used as the oxidation-responsive trigger during the drug delievery process. Herein, the responsiveness to stimuli of PBA polymer materials has been well studied, including glucose, pH, adenosine triphosphate (ATP), and H2O2 sensitive. This paper reviews recent research on drug delivery system for diabetes treatments and cancer therapy based on PBA polymer materials, and the possible development in the future is predicated.