Types Of Payloads Research Articles

Brain Nucleic Acid Delivery and Genome Editing via Focused Ultrasound-Mediated Blood-Brain Barrier Opening and Long-Circulating Nanoparticles.

We introduce a two-pronged strategy comprising focused ultrasound (FUS)-mediated blood-brain barrier (BBB) opening and long-circulating biodegradable nanoparticles (NPs) for systemic delivery of nucleic acids to the brain. Biodegradable poly(β-amino ester) polymer-based NPs were engineered to stably package various types of nucleic acid payloads and enable prolonged systemic circulation while retaining excellent serum stability. FUS was applied to a predetermined coordinate within the brain to transiently open the BBB, thereby allowing the systemically administered long-circulating NPs to traverse the BBB and accumulate in the FUS-treated brain region, where plasmid DNA or mRNA payloads produced reporter proteins in astrocytes and neurons. In contrast, poorly circulating and/or serum-unstable NPs, including the lipid NP analogous to a platform used in clinic, were unable to provide efficient nucleic acid delivery to the brain regardless of the BBB-opening FUS. The marriage of FUS-mediated BBB opening and the long-circulating NPs engineered to copackage mRNA encoding CRISPR-associated protein 9 and single-guide RNA resulted in genome editing in astrocytes and neurons precisely in the FUS-treated brain region. The combined delivery strategy provides a versatile means to achieve efficient and site-specific therapeutic nucleic acid delivery to and genome editing in the brain via a systemic route.

CORBES: Radiation belt survey with international small satellite constellation

The COnstellation of Radiation BElt Survey program (CORBES) is designed to deploy small satellites into a highly elliptic orbit for multi-point exploration of the Earth’s radiation belts. Its scientific objective is to achieve unprecedented high-time-resolution dynamics measurements within the regions of Earth’s outer radiation belts. The CORBES program initiative comprises satellites equipped with three types of payloads: the Magnetometer (MAG), the Search Coil Wave Detector (SCWD), and the High Energy Electron Detector (HEED). The energy interval of HEED is suggested as 0.1–4 MeV, logarithmically divided into 12 channels. To ensure extensive coverage of the outer radiation belts, a highly eccentric and inclined orbit is suggested, featuring a perigee of 280 km, an apogee of 7 Earth-Radius (Re), and an inclination of approximately 11°, resulting in an orbital period of approximately 13.5 h. Within a single orbital period, it takes roughly 10 h to traverse the outer radiation belts (3 Re to 7Re). All satellites are expected to operate within the same orbit, maintaining a spin-stabilized with sun-pointing spinning axis, and a spinning speed of approximately 8 RPM. Each satellite’s mass should not exceed 30 kg. For telecommand, either S-band or X-band will be utilized, while X-band is designated for data downlink. The satellites are scheduled for launch by one or two rockets, with the equipped upper stage placing them into the target orbit, and the attached dispenser releasing them individually according to the required separation sequence. Key aspects of the program include cross-calibration, radiation shielding, assembly integration and testing (AIT). Prior to launch, the cross-calibration is optional for the payloads. The payloads will be tested in the same environment to calibrate the technical specifications. Post-launch, in orbit cross-calibration becomes necessary to maintain data consistency and comparability. Specifically for HEED, this involves selecting electrons with the same energy range during the magnetospheric quiet period (Kp < 3), and comparing the observation results of different HEEDs under the same L,B conditions. A similar method applies to MAG and SCWD comparing observations during selected quiet period. Given that the satellites will operate within radiation belts characterized by high-energy protons at low altitudes and electrons at high altitudes, all on-board electronic components must meet fundamental requirements, including shielding geometry structure design, and thickness calculation to mitigate the Total Ionizing Dose Effect (TID) to a level of 200 krad [Si] over a one-year mission cycle. Lastly, system-level AIT before launch could be performed.

Development of Next Generation Antibody-Polymer-Drug Conjugates for Treatment of Multiple Myeloma

Background: Antibody-drug conjugates (ADCs) are an effective class of cancer therapeutics, but current ADCs face stability challenges, resulting in premature payload release and off-target toxicity. To overcome this, we developed a novel strategy using antibody-polymer-based drug conjugates (pADCs). Our pADCs have a number of advantages compared to currently FDA approved ADCs, including: 1) Increased drug payload without altering binding site numbers, ensuring maximum drug loading without affecting antigen and Fc binding; 2) Potential for synergistic immunotherapy and chemotherapy; 3) Improved pharmacokinetics and reduced immunogenicity with modification using water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer, providing significant stealth effect; and 4) Enhanced stability under physiological conditions, reducing premature payload release and off-target toxicity. Panobinostat, a pan-HDAC (histone deacetylase) inhibitor, enhances CD38 expression and improves pADC efficiency against MM cells. Our hypothesis is that our pADC system induces strong cytotoxicity, further enhanced by panobinostat-induced CD38 upregulation, leading to more efficient treatment outcomes. Methods:mAbs decorated with cyclooctyne (DBCO) moieties in the hinge region were prepared in two steps: mAbs were reduced with tris(2-carboxyethyl)phosphine (TCEP), then thiol groups were capped with DBCO-PEG4-Mal. Azide-functionalized semitelechelic (ST) polymer-drug conjugates (ST-P-drug-N3) were synthesized via RAFT polymerization. Antibody-polymer-drug conjugates were prepared by CLICK chemistry. MM.1S and RPMI 8226 cell lines (ATCC) were used as the MM cell model. The cell internalization was revealed by confocal imaging. Primary MM cells were collected from the aspirate of eight patients with primary plasma cell leukemia and isolated via Ficoll centrifugation. CD38 upregulation was done by incubating with 10 or 25 nM panobinostat for 24 h and the apoptosis detection employed Annexin V and Propidium Iodide staining followed by flow cytometry analysis. Results: A series of CLICK-able mAbs and semitelechelic polymer-drug conjugates were synthesized. Among them, we firstly prepared Epirubicin (EPI)-based pADCs, such as DARA-P-EPI, ISA-P-EPI and DRO-P-EPI (Fig.1A). Unlike naked mAbs, pADCs can induce EPI concentration-dependent cytotoxicity. Surface calreticulin (CRT) was assessed and demonstrated the induction of EPI-dependent immunogenic cell death on MM.1S cells (Fig.1B). The pADC mechanism of action involves binding to cell surface antigens, internalization via endosomes, and subsequent cleavage of drugs at lysosomes by cathepsin B. This minimizes premature drug release and reduces off-target toxicity (Fig.1C). Ex vivo studies on patient MM cells revealed that pADCs induced significantly higher apoptosis compared to naked mAbs and free EPI, highlighting their efficacy (Fig.1D). CD38-based pADC's efficacy was enhanced by pretreatment with panobinostat (Fig.1F), which increased CD38 expression (Fig.1E). When incubating with NK cells and pADC, the number of target cells decreased significantly indicating the pADC preserve the original mAb ADCC functionality. Notably, co-treatment of RPMI8226 cells with anti-CD38 and GDC0980, a PI3k/mTOR inhibitor, significantly improved cytotoxicity, suggesting DARA's potential for chemo sensitization (Fig.1G). Conclusion: pADC's innovative design offers a high likelihood of successful clinical development and holds significant promise for MM therapy. Moreover, the unique mechanism provides potential to effectively overcome mAb and multiple drug resistance. Its facile nature allows for easy incorporation of multiple types of payloads into the ADC, making its synthesis highly scalable .

Methodology of evaluating ATLAS computing resources in handling user analysis workflows

The distributed computing infrastructure of the ATLAS Experiment includes over 170 sites and executes up to 3 million computing jobs daily. PanDA (Production and Distributed Analysis) is the Workload Management System responsible for task and job execution; its key components are the broker and job scheduler that define the mapping of computing jobs to the resources. The optimization of this mapping is crucial for handling the expected computational payloads during the HL-LHC era. Considering the heterogeneity and the distributed structure of the Worldwide LHC Computing Grid (WLCG) infrastructure that provides computing resources for analyzing the data, there is a need for specific approaches for evaluating computing resources according to their ability to process different types of workflows. This evaluation can potentially enhance the efficiency of the Grid by optimally distributing different types of payloads in heterogeneous computing environments. To tackle this challenge, this research proposes a method for evaluating WLCG resources regarding their ability to process user analysis payloads. This evaluation is based on leveraging available information about job execution on PanDA queues within the ATLAS computing environment.

Targeted Anticancer Agent with Original Mode of Action Prepared by Supramolecular Assembly of Antibody Oligonucleotide Conjugates and Cationic Nanoparticles.

Despite their clinical success, Antibody-Drug Conjugates (ADCs) are still limited to the delivery of a handful of cytotoxic small-molecule payloads. Adaptation of this successful format to the delivery of alternative types of cytotoxic payloads is of high interest in the search for novel anticancer treatments. Herein, we considered that the inherent toxicity of cationic nanoparticles (cNP), which limits their use as oligonucleotide delivery systems, could be turned into an opportunity to access a new family of toxic payloads. We complexed anti-HER2 antibody-oligonucleotide conjugates (AOC) with cytotoxic cationic polydiacetylenic micelles to obtain Antibody-Toxic-Nanoparticles Conjugates (ATNPs) and studied their physicochemical properties, as well as their bioactivity in both in vitro and in vivo HER2 models. After optimising their AOC/cNP ratio, the small (73 nm) HER2-targeting ATNPs were found to selectively kill antigen-positive SKBR-2 cells over antigen-negative MDA-MB-231 cells in serum-containing medium. Further in vivo anti-cancer activity was demonstrated in an SKBR-3 tumour xenograft model in BALB/c mice in which stable 60% tumour regression could be observed just after two injections of 45 pmol of ATNP. These results open interesting prospects in the use of such cationic nanoparticles as payloads for ADC-like strategies.

One-Pot Assembly of Dual-Site-Specific Antibody-Drug Conjugates via Glycan Remodeling and Affinity-Directed Traceless Conjugation.

The drug-to-antibody ratio (DAR) value and dual-drug combination greatly influence the therapeutic index of antibody-drug conjugates (ADCs). The reported approaches usually require multifunctional branched linkers, a combination of complicated technologies, or protein-protein ligation, which may incorporate multihydrophobic fragments or result in low coupling efficiency. Herein, we developed a facile and efficient one-pot method to assemble dual-site-specific ADCs with defined DARs at both the N-glycosylation site and K248 site, either with the same payloads or with two types of payloads. The constructed dual-site ADCs showed acceptable homogeneity, excellent buffer stability, and enhanced in vitro and in vivo efficiency.

Abstract 2016: Preclinical evaluation of uPARAP (MRC2) antibody-drug conjugates (ADCE-003,010,011) in osteosarcoma pdx models

Abstract Introduction: Antibody-drug Conjugates (ADCs) targeting differentially expressed tumor cell-surface antigens show robust clinical activity in several solid tumor cancers, but none is yet available for osteosarcoma. Due to the high unmet medical need in this indication, there is an urgent requirement to identify respective osteosarcoma cell-surface antigens and evaluate the antitumor activity of an ADC that can deliver tailored cytotoxic payloads to osteosarcoma tumors expressing these targets. Methods: We used an integrated proteomic and transcriptomic surfaceome profiling approach to identify cell-surface proteins that are highly expressed in osteosarcoma but minimally expressed on normal tissues. uPARAP (MRC2) was found to be enriched in osteosarcoma at both protein and mRNA levels. The cell-surface expression of uPARAP (MRC2) was further validated by IHC and flow cytometry with osteosarcoma cell lines, PDX models, and patient tumor tissue microarray. As a proof of concept, three MRC2 targeted ADCs with different Microtubulin- and alkylating agent types of payloads were tested in 8 osteosarcoma PDX models. uPARAP (MRC2) ADC, control ADC, or vehicle control was administered IV to mice harboring flank tumors at a dose of 3mg/kg, weekly X 3 (ADCE-003), 2mg/kg on Day 1 (ADCE-010), and 10mg/kg weekly X 2 (ADCE-011). EFS for treatment (T) and control (C) groups, minimum relative tumor volume (minRTV), and objective response measures were analyzed. Results: Western blotting confirmed the expression of uPARAP (MRC2) in 8 osteosarcoma cell lines and 8 PDX models. Flow cytometry further validated cell-surface localization and expression levels of uPARAP (MRC2) in 7 osteosarcoma cell lines. We then performed immunohistochemistry (IHC) staining using an osteosarcoma tissue microarray from 37 patients and 19 PDX models. uPARAP (MRC2) was expressed in 97% of the patient samples and 95% of the PDXs. 51% of the patient samples and 39% of the PDXs had an overall H-score of 100 or higher. Mice tolerated ADCs well with minimal toxicity. All 3 ADCs significantly prolonged EFS in 6/8 osteosarcoma models. Complete response (CR) or maintained CR were observed in 2 models in ADCE-010 and ADCE-011 groups, respectively. Conclusions: uPARAP (MRC2) is highly expressed in most osteosarcoma samples, which makes it a viable target for respective antigen targeting ADC therapies. Three uPARAP (MRC2) targeting ADCs showed antitumor activities in osteosarcoma preclinical models which warrant further investigation of uPARAP targeting ADC therapies for osteosarcoma. Citation Format: Yifei Wang, Wendong Zhang, Zhongting Zhang, Xiangjun Tian, Rossana Lazcano, Pooja Hingorani, Michael Roth, Jonathan Gill, Douglas Harrison, Zhaohui Xu, Jing Wang, Niels Behrendt, Christoffer F. Nielsen, Lars H. Engelholm, Richard Gorlick. Preclinical evaluation of uPARAP (MRC2) antibody-drug conjugates (ADCE-003,010,011) in osteosarcoma pdx models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2016.

Analysis of Settling and RCS Response of Copper Coated Carbon and its Comparison with Aluminium Fibres

Background/Objectives: The present research focuses on comparative studies of two different type of chaff fibres for their effectiveness as electronics counter measure. Chaffs are electronic counter measures used in creating false radar signature to deceive tracking radar systems. Many types of chaff payloads are there in use, but the major one is aluminium fibres. These chaffs are designed to cover radar frequency range from 2-18 GHz. However, in future, tracking radars will operate in higher frequency range and will have improved algorithms to mitigate chaff noise of certain Radar Cross Section (RCS) threshold. Methods: The researcher used two different chaff fibres and their corresponding RCS are measured in anechoic chamber for their comparative study. Findings: It is observed that the RCS of the copper coated carbon (CuC) fiber is nearly equal to that of aluminium fiber but due their thinner diameter packing density of chaff fibres within a specified chaff cartridge volume has increased thus resulting in more number of dipole per chaff payload. Larger number of dipoles will help in improving dynamic RCS of chaff payload as it is directly proportional to the number of dipoles. Moreover, the terminal velocity of copper coated carbon fibres is lesser than that of aluminium fibres has improved the persistent time for CuCfiberwhich is a desirable parameter for the effective performance of chaff payload. Novelty: In order to increase dynamic RCS threshold one needs to increase chaff fiber density and chaff cloud suspension time. Both these can be achieved by the development of innovative thin CuCchaff fibres. In this paper, RCS of light weight and thin copper coated carbon chaff fibres were studied in comparison with traditional aluminium fibres and their advantages over aluminium fibres are reported. Keywords: Backscattered RCS; electrically conducting fiber; anechoic chamber; chaff; Settling Time

Novel development strategies and challenges for anti-Her2 antibody-drug conjugates.

Antibody-drug conjugates (ADCs) combining potent cytotoxicity of small-molecule drugs with the selectivity and excellent pharmacokinetic profile of monoclonal antibody (mAb) are promising therapeutic modalities for a diverse range of cancers. Owing to overexpression in a wide range of tumors, human epidermal growth factor receptor 2 (Her2) is one of the most utilized targeting antigens for ADCs to treat Her2-positive cancers. Owing to the high density of Her2 antigens on the tumor cells and high affinity and high internalization capacity of corresponding antibodies, 56 anti-Her2 ADCs which applied >10 different types of novel payloads had entered preclinical or clinical trials. Seven of 12 Food and Drug Administration (FDA)-approved ADCs including Polivy (2019), Padcev (2019), EnHertu (2019), Trodelvy (2020), Blenrep (2020), Zynlonta (2021), and Tivdak) (2021) have been approved by FDA in the past three years alone, indicating that the maturing of ADC technology brings more productive clinical outcomes. This review, focusing on the anti-Her2 ADCs in clinical trials or on the market, discusses the strategies to select antibody formats, the linkages between linker and mAb, and effective payloads with particular release and action mechanisms for a good clinical outcome.

Development of a Balloon-Borne Acoustic Anemometer to Measure Winds for SENSOR Campaign

The Stratospheric Environmental respoNses to Solar stORms (SENSOR) campaign investigates the influence of solar storms on the stratosphere. This campaign employs a long-duration zero-pressure balloon as a platform to carry multiple types of payloads during a series of flight experiments in the mid-latitude stratosphere from 2019 to 2022. This article describes the development and testing of an acoustic anemometer for obtaining in situ wind measurements along the balloon trajectory. The anemometer is also equipped with temperature, pressure, and humidity sensors from a Temperature-Pressure-Humidity measurement module, inherited from a radiosonde developed for sounding balloons. The acoustic anemometer and other sensors were used in a flight experiment of the SENSOR campaign that took place in the Da chaidan District (95.37&#x00B0;E, 37.74&#x00B0;N) on 4 September 2019. Three-dimensional wind speed observations, which were obtained during level flight at an altitude of around 25 km, are presented. A preliminary analysis of the measurements yielded by the anemometer are also discussed. To our knowledge, this is the first time that wind measurements were obtained by an acoustic anemometer during level flight of the high-altitude balloon and were used to analyze Lagrangian spectrum in the inertial subrange over the Tibetan Plateau. In addition to wind speed measurements, temperature, pressure, and relative humidity measurements during ascent are compared to observations from a nearby radiosonde launched four hours earlier, and the results show very good agreement.

Responsive polymeric drug delivery systems for combination anticancer therapy: experimental design and computational insights

Combination therapy has been designed to overcome the setbacks of traditional chemotherapy in anticancer therapy. Since combination therapy comprises a combination of anticancer agents, the different pharmacokinetics and biodistribution properties of multiple drugs are the primary concern. Stimuli-responsive polymers can vary in structure with changes in environmental conditions. Therefore, the microenvironmental differences between tumor sites and normal tissues can be utilized to achieve controlled drug release within a specific time and location range. Thus, stimuli-responsive polymers have the ability to optimize combination drug administration. This present review addresses four different strategies for preparing a polymeric combination drug delivery system. Different types of payloads, including various chemo drugs, gene drugs, and photosensitizers, that have been explored in the experiment are crucial parts of the discussion in this review. In addition, the triggering conditions of stimuli-responsive polymers used in combination therapy in recent years are summarized. Moreover, due to the investigation of drug-carrier or drug-drug interactions at the molecular level, computational chemistry provides inspiration for the rational design of novel drug delivery systems. Thus, a series of simulations to calculate the thermodynamic and kinetic properties of drug carriers are also introduced. The challenges and perspectives of nanocarrier-based combination therapy have also been discussed.

Design of the Payload Subsystem of Chang’E-5 Lunar Explorer

To achieve the scientific and engineering goals for situ exploration of the sampling area, The payload subsystem of Chang'E-5 explorer is equipped with four types of scientific payloads: the panoramic camera, descending camera, lunar regolith penetrating radar, lunar mineral spectrometer. It is also equipped with the national flag of China exhibition system, the panoramic camera pan-tilt table, and payload data processor as engineering and supporting payloads. This paper introduces the scientific and engineering goals, system composition, function and performance, system design, and operating achievements of the Chang'E-5 payload subsystem.

One-Pot Preparation of Peptide-Doped Metal-Amino Acid Framework for General Encapsulation and Targeted Delivery.

Metal-organic frameworks (MOFs), especially those made by biological molecules (bio-MOFs), have been proved to be prospective candidates for biomedical applications. However, a simple and universal bio-MOF to load different substances for precise targeting is still lacking. In this work, we propose a facile one-pot method to prepare a peptide-doped bio-MOF for general encapsulation and targeted delivery. This bio-MOF is constructed by 9-fluorenylmethyloxycarbonyl-modified histidine (Fmoc-His) as a bridging linker that coordinates with Zn2+ ions, denoted as ZFH. The Fmoc-His-Asp-Gly-Arg peptide (Fmoc-HDGR) can be easily doped into the ZFH structure with different ratios to modulate the targeting ability of ZFH-DGR. Containing both hydrophobic Fmoc and hydrophilic His moieties, this framework is compatible with encapsulating various types of payloads, including hydrophobic chemotherapeutic, hydrophilic protein, and positively/negatively charged inorganic nanoparticles. It has also been proved to be highly biocompatible and stable in circulation, exhibit the capabilities to target ανβ3 integrin overexpressed on tumor cells, and trigger drug release in a low pH microenvironment at the tumor site. As a proof of concept, Doxorubicin (Dox)-loaded ZFH-DGR (ZFH-DGR/Dox) demonstrated high cell selectivity between liver hepatocellular carcinoma (HepG2) cells and normal liver (L02) cells, which express high and low ανβ3 integrin, respectively. This selectivity endows ZFH-DGR/Dox precise treatment and low toxicity in Heps-bearing liver cancer mice. This work develops a de novo approach to construct a peptide-doped bio-MOF system for universal load, precise delivery, and peptide drug combination therapy in the future.

Design of a hybrid refractive-diffractive telescope for observations in UV

Telescopes are one of the common types of satellite payloads. They are used both for Earth and astronomical observations. By using space telescopes it is possible to eliminate the negative effect of the atmosphere on image quality. Additionally, observations in some spectral ranges can be performed only from space due to absorption of certain wavelengths in the atmosphere. One such range is UV below 300 nm, which is of particular interest when it comes to the investigation of hot objects. Reflective telescopes are commonly used in this spectral range, although many classical designs are limited in their useful field of view to values below 1°. In this paper a hybrid refractive-diffractive telescope design working in a 200 nm – 300 nm spectral range with a field of view 10°×10° is proposed. Its performance is compared to purely refractive and reflective systems and significant improvement in the imaging quality of the system and decrease of its size is shown. The choice of the diffractive element type is explained. Parameters of the systems are based on the requirements for a proposed Polish mission UVSat which aims to enable long-term observations of a large number of stars exhibiting UV variance.

UUVs support to naval operations

The article analyzes the environmental conditions present in the Black Sea basin and, in this view, the opportunity of employment of unmanned underwater platforms, especially in the contested littoral area. The introductory part of the article is presented up to date UUVs platforms in use with their capabilities and limitations. Then, the paper identifies the shortfalls and opportunities to engage unmanned platforms to operate independently or paired with other undersea, surface, unmanned aerial platforms, or fixed arrays. The closing section analyzes the types of payloads, missions, and capabilities of actual vehicles, and some ways ahead are underlined, especially regarding future sensors, weapons, navigation, and underwater communications capabilities.

Wavelength-Selective Light-Controlled Stepwise Photolysis from Single Gold Nanoparticles.

Light-controlled sequential photolysis from a single nanoparticle is a challenge for controlled release. A wavelength-selective sequential photolysis from single gold nanoparticles is reported for the first time. In particular, it is also demonstrated that such nanoparticle can be used to sequentially release two payloads in living cells. In principle, this system can be extended to sequential release of multiple different types of payloads by rational design of diverse photocleavable linkers. It is expected that this work can provide a new tool for better orderly controlling cellular events that request high spatiotemporal manners.

Nanobottles for Controlled Release and Drug Delivery.

Nanobottles refer to colloidal particles with a hollow interior and a single opening in the wall. These unique features make them ideal carriers for the loading, encapsulation, release, and delivery of various types of theranostic agents in an array of biomedical applications. The hollow interior gives them a high loading capacity while the opening enables quick loading and controlled release of the payload(s). More significantly, on-demand release can be readily achieved by adding a stimuli-responsive material as the inner matrix or cork stopper. This progress report begins with an introduction to the general structures and properties of nanobottles, followed by a brief discussion on the methods developed for their fabrication. The use of nanobottles for loading different types of payloads is then showcased, including small-molecule drugs, biomacromolecules, imaging contrast agents, and functional nanoparticles. The strategies explored for controlling the release by varying the size of the opening and/or integrating with a stimuli-responsive material are also highlighted. This paper concludes with some perspectives on future directions for this class of nanomaterials in terms of fabrication, functionalization, and application.

Polydopamine Coating of Glucan Particles Increases Uptake into Peyer's Patches.

Glucan particles (GPs) are hollow, porous 3-4 μm microspheres derived from the cell walls of Baker's yeast (Saccharomyces cerevisiae). The β-1,3-D glucan outer shell of GPs provides for receptor-mediated uptake by phagocytic cells expressing β-glucan receptors. GPs have been used for efficient encapsulation of different types of payloads (DNA, siRNA, proteins, antigens, small molecules), and these payloads have been delivered in vivo by a variety of routes including oral delivery. It is known that GPs are transported across the intestinal epithelium by Peyer's patch M-cells and accumulate in a subset of CD11c+Langerin-positive dendritic cells (DC) in the subepithelial dome (SED). An increase in GP uptake in the intestinal epithelium is needed to improve our efforts to develop GPs for oral delivery of therapeutics and vaccines. In this Article, we report that polydopamine coating of GPs (PDA-GPs) increases transepithelial uptake. Synthesis of PDA-GPs was optimized to allow for encapsulation of payloads inside the hollow cavity of GPs. PDA-GPs and GP controls were orally administered to mice, and PDA-GPs showed a 42% increased uptake in SED phagocytes. PDA-GP uptake by SED phagocytes in control and M-cell-depleted mice demonstrated both M-cell-dependent and -independent mechanisms. In future studies, we will evaluate PDA-GPs for oral vaccine delivery and the use of PDA-functional groups for secondary surface derivatization to generate particles with ligands targeting other intestinal epithelium cell-surface receptors.

Ultrasonic Generation of Pulsatile and Sequential Therapeutic Delivery Profiles from Calcium-Crosslinked Alginate Hydrogels.

Control over of biological processes can potentially be therapeutically regulated through localized biomolecular deliveries. While implantable hydrogels can provide localized therapeutic deliveries, they do not traditionally provide the temporally complex therapeutic delivery profiles required to regulate complex biological processes. Ionically crosslinked alginate hydrogels have been shown to release encapsulated payloads in response to a remotely applied ultrasonic stimulus, thus potentially enabling more temporally complex therapeutic delivery profiles. However, thorough characterizations of how different types of therapeutic payloads are retained and ultrasonically released need to be performed. Additionally, the impact of potentially disruptive ultrasonic stimulations on hydrogel structure and temperature need to be characterized to better understand what range of ultrasonic signals can be used to trigger release. To perform these characterizations, calcium-crosslinked alginate hydrogels were loaded with various model macromolecules (dextrans), chemotherapeutics, and protein signaling factors and exposed to a variety of single-pulse and multi-pulse ultrasonic signals at various amplitudes and durations. In response to single-pulsed ultrasonic exposures, quantifications of molecular release, degree of gel erosion, and increase in hydrogel temperature revealed that the ultrasonic stimulations required for statistically significant therapeutic deliveries often eroded and heated the gels to unacceptable levels. However, multi-pulse ultrasonic exposures were shown to achieve significant amounts of therapeutic release while keeping gel erosion and temperature increase at modest levels. Finally, experiments were performed demonstrating that ultrasonic stimulation could be used to generate drug release profiles shown to have potential therapeutic benefits (e.g., pulsatile and sequential anticancer delivery profiles). This work underscores the potential of using ultrasonically responsive polymeric hydrogels for providing on-demand control over more complex therapeutic deliver profiles and enhancing drug delivery strategies in cancer therapies and beyond.

Engineered Mesenchymal Stem Cell/Nanomedicine Spheroid as an Active Drug Delivery Platform for Combinational Glioblastoma Therapy.

Mesenchymal stem cell (MSC) has been increasingly applied to cancer therapy because of its tumor-tropic capability. However, short retention at target tissue and limited payload option hinder the progress of MSC-based cancer therapy. Herein, we proposed a hybrid spheroid/nanomedicine system, comprising MSC spheroid entrapping drug-loaded nanocomposite, to address these limitations. Spheroid formulation enhanced MSC's tumor tropism and facilitated loading of different types of therapeutic payloads. This system acted as an active drug delivery platform seeking and specifically targeting glioblastoma cells. It enabled effective delivery of combinational protein and chemotherapeutic drugs by engineered MSC and nanocomposite, respectively. In an in vivo migration model, the hybrid spheroid showed higher nanocomposite retention in the tumor tissue compared with the single MSC approach, leading to enhanced tumor inhibition in a heterotopic glioblastoma murine model. Taken together, this system integrates the merits of cell- and nanoparticle- mediated drug delivery with the tumor-homing characteristics of MSC to advance targeted combinational cancer therapy.