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Boron neutron capture therapy (BNCT) is an encouraging therapeutic modality for cancer treatment. Prostate-specific membrane antigen (PSMA) is a cell membrane protein that is abundantly overexpressed in prostate cancer and can be targeted with radioligand therapies to stimulate clinical responses in patients. In principle, a spatially targeted neutron beam together with specifically targeted PSMA ligands could enable prostate cancer-targeted BNCT. Thus, we developed and tested PSMA-targeted poly(lactide- co -glycolide)-block-poly(ethylene glycol) (PLGA- b -PEG) nanoparticles (NPs) loaded with carborane and tethered to the radiometal chelator deferoxamine B (DFB) for simultaneous positron emission tomography (PET) imaging and selective delivery of boron to prostate cancer. Monomeric PLGA- b -PEGs were covalently functionalized with either DFB or the PSMA ligand ACUPA. Different nanoparticle formulations were generated by nanoemulsification of the corresponding unmodified and DFB- or ACUPA-modified monomers in varying percent fractions. The nanoparticles were efficiently labeled with 89 Zr and were subjected to in vitro and in vivo evaluation. The optimized DFB(25)ACUPA(75) NPs exhibited strong in vitro binding to PSMA in direct binding and competition radioligand binding assays in PSMA(+) PC3-Pip cells. [ 89 Zr]DFB(25) NPs and [ 89 Zr]DFB(25)ACUPA(75) NPs were injected to mice with bilateral PSMA(-) PC3-Flu and PSMA(+) PC3-Pip dual xenografts. The NPs demonstrated twofold superior accumulation in PC3-Pip tumors to that of PC3-Flu tumors with a tumor/blood ratio of 25; however, no substantial effect of the ACUPA ligands was detected. Moreover, fast release of carborane from the NPs was observed, resulting in a low boron delivery to tumors in vivo . In summary, these data demonstrate the synthesis, characterization, and initial biological assessment of PSMA-targeted, carborane-loaded PLGA- b -PEG nanoparticles and establish the foundation for future efforts to enable their best use in vivo .

Cancer immunity is mediated by a delicate orchestration between the innate and adaptive immune system both systemically and within the tumor microenvironment. Although several adaptive immunity molecular targets have been proven clinically efficacious, stand-alone innate immunity targeting agents have not been successful in the clinic. Here, we report a nanoparticle optimized for systemic administration that combines immune agonists for TLR9, STING, and RIG-I with a melanoma-specific peptide to induce antitumor immunity. These immune agonistic nanoparticles (iaNPs) significantly enhance the activation of antigen-presenting cells to orchestrate the development and response of melanoma-sensitized T-cells. iaNP treatment not only suppressed tumor growth in an orthotopic solid tumor model, but also significantly reduced tumor burden in a metastatic animal model. This combination biomaterial-based approach to coordinate innate and adaptive anticancer immunity provides further insights into the benefits of stimulating multiple activation pathways to promote tumor regression, while also offering an important platform to effectively and safely deliver combination immunotherapies for cancer.

Micro and nanoscale drug carriers must navigate through a plethora of dynamic biological systems prior to reaching their tissue or disease targets. The biological obstacles to drug delivery come in many forms and include tissue barriers, mucus and bacterial biofilm hydrogels, the immune system, and cellular uptake and intracellular trafficking. The biointerface of drug carriers influences how these carriers navigate and overcome biological barriers for successful drug delivery. In this review, we examine how key material design parameters lead to dynamic biointerfaces and improved drug delivery across biological barriers. We provide a brief overview of approaches used to engineer key physicochemical properties of drug carriers, such as morphology, surface chemistry, and topography, as well as the development of dynamic responsive materials for barrier navigation. We then discuss essential biological barriers and how biointerface engineering can enable drug carriers to better navigate and overcome these barriers to drug delivery., Competing Interests: Declaration of Competing Interest M.M.S is a co-inventor of a filed patent (UKIPO, application number: 1914659.6) that concerns the use of polymers for drug delivery applications., (Copyright © 2020. Published by Elsevier B.V.)

Oral administration is a pillar of the pharmaceutical industry and yet it remains challenging to administer hydrophilic therapeutics by the oral route. Smart and controlled oral drug delivery could bypass the physiological barriers that limit the oral delivery of these therapeutics. Micro- and nanoscale technologies, with an unprecedented ability to create, control, and measure micro- or nanoenvironments, have found tremendous applications in biology and medicine. In particular, significant advances have been made in using these technologies for oral drug delivery. In this review, we briefly describe biological barriers to oral drug delivery and micro and nanoscale fabrication technologies. Micro and nanoscale drug carriers fabricated using these technologies, including bioadhesives, microparticles, micropatches, and nanoparticles, are described. Other applications of micro and nanoscale technologies are discussed, including fabrication of devices and tissue engineering models to precisely control or assess oral drug delivery in vivo and in vitro, respectively. Strategies to advance translation of micro and nanotechnologies into clinical trials for oral drug delivery are mentioned. Finally, challenges and future prospects on further integration of micro and nanoscale technologies with oral drug delivery systems are highlighted., (Copyright © 2020. Published by Elsevier B.V.)

Characterization of intestinal absorption of nanoparticles is critical in the design of noninvasive anticancer, protein-based, and gene nanoparticle-based therapeutics. Here we demonstrate a general approach for the characterization of the intestinal absorption of nanoparticles and for understanding the mechanisms active in their processing within healthy intestinal cells. It is generally accepted that the cellular processing represents a major drawback of current nanoparticle-based therapeutic systems. In particular, endolysosomal trafficking causes degradation of therapeutic molecules such as proteins, lipids, acid-sensitive anticancer drugs, and genes. To date, investigations into nanoparticle processing within intestinal cells have studied mass transport through Caco-2 cells or everted rat intestinal sac models. We developed an approach to visualize directly the mechanisms of nanoparticle processing within intestinal tissue. These results clearly identify a mechanism by which healthy intestinal cells process nanoparticles and point to the possible use of this approach in the design of noninvasive nanoparticle-based therapies., From the Clinical Editor: Advances in nanomedicine have resulted in the development of new therapies for various diseases. Intestinal route of administration remains the easiest and most natural. The authors here designed experiments to explore and characterize the process of nanoparticle transport across the intestinal tissue. In so doing, further insights were gained for future drug design., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Cell-encapsulating devices can play an important role in advancing the types of tissue available for transplantation and further improving transplant success rates. To have an effective device, encapsulated cells must remain viable, respond to external stimulus, and be protected from immune responses, and the device itself must elicit a minimal foreign body response. To address these challenges, we developed a micro- and a nanoporous thin-film cell encapsulation device from polycaprolactone (PCL), a material previously used in FDA-approved biomedical devices. The thin-film device construct allows long-term bioluminescent transfer imaging, which can be used for monitoring cell viability and device tracking. The ability to tune the microporous and nanoporous membrane allows selective protection from immune cell invasion and cytokine-mediated cell death in vitro, all while maintaining typical cell function, as demonstrated by encapsulated cells' insulin production in response to glucose stimulation. To demonstrate the ability to track, visualize, and monitor the viability of cells encapsulated in implanted thin-film devices, we encapsulated and implanted luciferase-positive MIN6 cells in allogeneic mouse models for up to 90 days. Lack of foreign body response in combination with rapid neovascularization around the device shows promise in using this technology for cell encapsulation. These devices can help elucidate the metrics required for cell encapsulation success and direct future immune-isolation therapies.

Staphylococcus aureus internalized by bone cells and shielded from the immune system provides a reservoir of bacteria in recurring osteomyelitis. Its targeting by the antibiotic therapy may thus be more relevant for treating chronic bone infection than eliminating only the pathogens colonizing the bone matrix. Assessed was the combined osteogenic and antibacterial effect of clindamycin-loaded calcium phosphate nanoparticles of different monophasic compositions on co-cultures comprising osteoblasts infected with S. aureus. Antibiotic-carrying particles were internalized by osteoblasts and minimized the concentration of intracellular bacteria. In vitro treatments of the infected cells, however, could not prevent cell necrosis due to the formation of toxic byproducts of the degradation of the bacterium. Antibiotic-loaded particles had a positive morphological effect on osteoblasts per se, without reducing their viability, alongside stimulating the upregulation of expression of different bone growth markers in infected osteoblasts to a higher degree than achieved during the treatment with antibiotic only., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Understanding and modulating the cellular response to implanted biomaterials is crucial for the field of tissue engineering and regenerative medicine. Since cells typically reside in an extracellular matrix containing nanoscale architecture, identifying synthetic nanostructures that induce desirable cellular behaviors could greatly impact the field. Using nanoimprint lithography, nanostructured patterns were generated on thin film polymeric materials. The ability of these surfaces to influence protein adsorption, fibroblast proliferation and morphology, and fibrotic markers was investigated. Nanostructured features with aspect ratios greater than five allowed for less protein adsorption, resulting in decreased fibroblast proliferation and rounded cellular morphology. These nanofeatures also induced significantly lower gene expression of collagen 1α2, collagen 3α1, and growth factors such as connective tissue growth factor, integrin linked kinase, transforming growth factor β1 (TGF-β1), and epidermal growth factor, key factors associated with a fibrotic response. The results demonstrate that select nanostructured surfaces could be used to modulate the fibrotic behavior in cells and have the potential to be used as antifibrotic architecture for medical implants or tissue engineering scaffolds.

Development of a material for simultaneous sustained and localized delivery of antibiotics and induction of spontaneous regeneration of hard tissues affected by osteomyelitis stands for an important clinical need. In this work, a comparative analysis of the bacterial and osteoblastic cell response to two different nanoparticulate carriers of clindamycin, an antibiotic commonly prescribed in the treatment of bone infection, one composed of calcium phosphate and the other comprising poly-(D,L-lactide-co-glycolide)-coated calcium phosphate, was carried out. Three different non-cytotoxic phases of calcium phosphate, exhibiting dissolution and drug release profiles in the range of one week to two months to one year, respectively, were included in the analysis: monetite, amorphous calcium phosphate and hydroxyapatite. Spherical morphologies and narrow size distribution of both types of nanopowders were confirmed in transmission and scanning electron microscopic analyses. The antibiotic-containing powders exhibited sustained drug release contingent upon the degradation rate of the carrier. Assessment of the antibacterial performance of the antibiotic-encapsulated powders against Staphylococcus aureus, the most common pathogen isolated from infected bone, yielded satisfactory results both in broths and on blood agar plates for all the analyzed powders. In contrast, no cytotoxic behavior was detected upon the incubation of the antibiotic powders with the osteoblastic MC3T3-E1 cell line for up to three weeks. The cells were shown to engage in a close contact with the antibiotic-containing particles, irrespective of their internal or surface phase composition, polymeric or mineral. At the same time, both types of particles upregulated the expression of osteogenic markers osteocalcin, osteopontin, Runx2 and protocollagen type I, suggesting their ability to promote osteogenesis and enhance remineralization of the infected site in addition to eliminating the bacterial source of infection., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Developed in this study is a multifunctional material for simultaneous osseoinduction and drug delivery, potentially applicable in the treatment of osteomyelitis. It is composed of agglomerates of nanoparticles of calcium phosphate (CAP) with different monophasic contents. The drug-loading capacity and the release kinetics were investigated on two model drug compounds with different chemical structures, sizes, and adsorption propensities: bovine serum albumin and fluorescein. Loading of CAP powders with small molecule drugs was achieved by physisorption and desiccation-induced agglomeration of nanoparticulate subunits into microscopic blocks. The material dissolution rate and the drug release rate depended on the nature of the CAP phase, decreasing from monocalcium phosphate to monetite to amorphous CAP and calcium pyrophosphate to hydroxyapatite. The sustained release of the two model drugs was shown to be directly relatable to the degradation rate of CAP carriers. It was demonstrated that the degradation rate of the carrier and the drug release kinetics could be made tunable within the time scale of 1-2 h for the most soluble CAP phase, monocalcium phosphate, to 1-2 years for the least soluble one, hydroxyapatite. From the standpoint of antibiotic therapy for osteomyelitis, typically lasting for 6 weeks, the most prospective CAP powder was amorphous CAP with its release time scale for a small organic molecule, the same category to which antibiotics belong, of 1-2 months under the conditions applied in our experiments. By combining these different CAP phases in various proportions, drug release profiles could be tailored to the therapeutic occasion., (Copyright © 2012 Wiley Periodicals, Inc.)

Osteomyelitis has been traditionally treated by the combination of long-term antibiotic therapies and surgical removal of diseased tissue. The multifunctional material was developed in this study with the aim to improve this therapeutic approach by: (a) enabling locally delivered and sustained release of antibiotics at a tunable rate, so as to eliminate the need for repetitive administration of systemically distributed antibiotics; and (b) controllably dissolving itself, so as to promote natural remineralization of the portion of bone lost to disease. We report hereby on the effect of previously synthesized calcium phosphates (CAPs) with tunable solubilities and drug release timescales on bacterial and osteoblastic cell cultures. All CAP powders exhibited satisfying antibacterial performance against Staphylococcus aureus, the main causative agent of osteomyelitis. Still, owing to its highest drug adsorption efficiency, the most bacteriostatically effective phase was amorphous CAP with the minimal inhibitory concentration of less than 1 mg/mL. At the same time, the positive cell response and osteogenic effect of the antibiotic-loaded CAP particles was confirmed in vitro for all the sparsely soluble CAP phases. Adsorption of the antibiotic onto CAP particles reversed the deleterious effect that the pure antibiotic exerted on the osteogenic activity of the osteoblastic cells. The simultaneous osteogenic and antimicrobial performance of the material developed in this study, altogether with its ability to exhibit sustained drug release, may favor its consideration as a material base for alternative therapeutic approaches to prolonged antibiotic administration and surgical debridement typically prescribed in the treatment of osteomyelitis., (Copyright © 2012 Wiley Periodicals, Inc.)

Nanoprecipitation was utilized to synthesize biodegradable and surfactant-free nanoparticles loaded with quantum dots. This protocol also yielded nanoparticles coloaded with both quantum dots and hydrophobic drug (Coenzyme Q10) molecules. Importantly, even though surfactants were not utilized during the nanoprecipitation procedure, these loaded nanoparticles did not aggregate. Dialysis efficiently removed unencapsulated quantum dots from nanoparticle suspensions without altering the physical properties of the quantum-dot-loaded nanoparticles. The resultant purified, quantum-dot-loaded nanoparticles were biocompatible in differentiated PC12 cell cultures, which facilitated their use as nanoparticles in microscopy. In fact, confocal imaging studies showed that purified, quantum-dot-loaded nanoparticles were associated with PC12 cells after one day in vitro. These novel and multifunctional coloaded nanoparticles may prove advantageous in future simultaneous drug delivery and imaging applications.

The intent of this work was to synthesize and comprehensively characterize ubiquinone-loaded, surfactant-free biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles in vitro. Surfactant-free, empty and ubiquinone (CoQ10)-loaded biodegradable nanoparticles were synthesized by nanoprecipitation, and the physicochemical properties of these nanoparticles were analyzed with a variety of techniques. Nanoprecipitation consistently yielded individual, sub-200nm, surfactant-free empty and CoQ10-loaded nanoparticles, where the physical and drug encapsulation characteristics were controlled by varying the formulation parameters. CoQ10 release was sustained for 2 weeks but then plateaued before 100% CoQ10 release. A novel, nondestructive purification protocol involving transient sodium dodecyl sulfate (SDS) adsorption to nanoparticles followed by centrifugation and dialysis was developed to yield purified, surfactant-free, CoQ10-loaded nanoparticles. This protocol permitted removal of unencapsulated CoQ10, prevented centrifugation-induced nanoparticle aggregation and preserved the surfactant-free and drug encapsulation properties of the nanoparticles. These CoQ10-loaded nanoparticles are promising as sustained drug delivery devices due to their extended CoQ10 release. Importantly, a surfactant-free nanoprecipitation procedure is presented that in combination with a novel purification step enables the synthesis of individual and purified CoQ10-loaded nanoparticles.