Impact of Nebulization on the Physicochemical Properties of Polymer-Lipid Hybrid Nanoparticles for Pulmonary Drug Delivery.

Nanoparticles (NPs) have shown significant potential for pulmonary administration of therapeutics for the treatment of chronic lung diseases in a localized and sustained manner. Nebulization is a suitable method of NP delivery, particularly in patients whose ability to breathe is impaired due to lung diseases. However, there are limited studies evaluating the physicochemical properties of NPs after they are passed through a nebulizer. High shear stress generated during nebulization could potentially affect the surface properties of NPs, resulting in the loss of encapsulated drugs and alteration in the release kinetics. Herein, we thoroughly examined the physicochemical properties as well as the therapeutic effectiveness of Infasurf lung surfactant (IFS)-coated PLGA NPs previously developed by us after passing through a commercial Aeroneb® vibrating-mesh nebulizer. Nebulization did not alter the size, surface charge, IFS coating and bi-phasic release pattern exhibited by the NPs. However, there was a temporary reduction in the initial release of encapsulated therapeutics in the nebulized compared to non-nebulized NPs. This underscores the importance of evaluating the drug release kinetics of NPs using the inhalation method of choice to ensure suitability for the intended medical application. The cellular uptake studies demonstrated that both nebulized and non-nebulized NPs were less readily taken up by alveolar macrophages compared to lung cancer cells, confirming the IFS coating retention. Overall, nebulization did not significantly compromise the physicochemical properties as well as therapeutic efficacy of the prepared nanotherapeutics.

Developing virtual and augmented reality applications for science, technology, engineering and math education.

The Rhode Island IDeA Network of Biomedical Research Excellence Molecular Informatics Core at the University of Rhode Island Information Technology Services Innovative Learning Technologies developed virtual and augmented reality applications to teach concepts in biomedical science, including pharmacology, medicinal chemistry, cell culture and nanotechnology. The apps were developed as full virtual reality/augmented reality and 3D gaming versions, which do not require virtual reality headsets. Development challenges included creating intuitive user interfaces, text-to-voice functionality, visualization of molecules and implementing complex science concepts. In-app quizzes are used to assess the user's understanding of topics, and user feedback was collected for several apps to improve the experience. The apps were positively reviewed by users and are being implemented into the curriculum at the University of Rhode Island.

Development and characterization of lung surfactant-coated polymer nanoparticles for pulmonary drug delivery.

Lung cancer is often diagnosed at an advanced stage where tumors are usually inoperable and first-line therapies are inefficient and have off-targeted adverse effects, resulting in poor patient survival. Here, we report the development of an inhalable poly lactic-co-glycolic acid polymer-based nanoparticle (PLGA-NP) formulation with a biomimetic Infasurf® lung surfactant (LS) coating, for localized and sustained lung cancer drug delivery. The nanoparticles (188 ± 7 nm) were stable in phosphate buffered saline, serum and Gamble's solution (simulated lung fluid), and demonstrated cytocompatibility up to 1000 µg/mL concentration and dose-dependent uptake by lung cancer cells. The LS coating significantly decreased nanoparticle (NP) uptake by NR8383 alveolar macrophages in vitro compared to uncoated NPs. The coating, however, did not impair NP uptake by A549 lung adenocarcinoma cells. The anti-cancer drug gemcitabine hydrochloride encapsulated in the PLGA core was released in a sustained manner while the paclitaxel loaded in the LS shell demonstrated a rapid or burst release profile over 21 days. The drug-loaded NPs significantly decreased cancer cell survival and colony formation in vitro compared to free drugs and single drug-loaded NPs. In vivo studies confirmed greater retention of LS-coated NPs in the lungs of C57BL/6 WT mice compared to uncoated NPs, at 24 h and 72 h following intranasal administration. The overall results confirm that LS coating is a unique strategy for cloaking polymeric NPs to potentially prevent their rapid lung clearance and facilitate prolonged pulmonary drug delivery.

Biodegradable and Inherently Fluorescent pH-Responsive Nanoparticles for Cancer Drug Delivery.

PURPOSE: The development of two novel pH-only and pH- and thermo-responsive theranostic nanoparticle (NP) formulations to deliver an anticancer drug and track the accumulation and therapeutic efficacy of the formulations through inherent fluorescence. METHODS: A pH-responsive formulation was synthesized from biodegradable photoluminescent polymer (BPLP) and sodium bicarbonate (SBC) via an emulsion technique, while a thermoresponsive BPLP copolymer (TFP) and SBC were used to synthesize a dual-stimuli responsive formulation via free radical co-polymerization. Cisplatin was employed as a model drug and encapsulated during synthesis. Size, surface charge, morphology, pH-dependent fluorescence, lower critical solution temperature (LCST; TFP NPs only), cytocompatibility and in vitro uptake, drug release kinetics and anticancer efficacy were assessed. RESULTS: While all BPLP-SBC and TFP-SBC combinations produced spherical nanoparticles of a size between 200-300 nm, optimal polymer-SBC ratios were selected for further study. Of these, the optimal BPLP-SBC formulation was found to be cytocompatible against primary Type-1 alveolar epithelial cells (AT1) up to 100 µg/mL, and demonstrated sustained drug release over 14 days, dose-dependent uptake, and marked pH-dependent A549 cancer cell killing (72 vs. 24% cell viability, at pH 7.4 vs. 6.0). The optimal TFP-SBC formulation showed excellent cytocompatibility against AT1 cells up to 500 µg/mL, sustained release characteristics, dose-dependent uptake, pH-dependent (78% at pH 7.4 vs. 64% at pH 6.0 at 37°C) and marked temperature-dependent A549 cancer cell killing (64% at 37°C vs. 37% viability at pH 6.0, 41°C). CONCLUSIONS: In all, both formulations hold promise as inherently fluorescent, stimuli-responsive theranostic platforms for passively targeted anti-cancer therapy.

3D Bioprinted Implants for Cartilage Repair in Intervertebral Discs and Knee Menisci.

Cartilage defects pose a significant clinical challenge as they can lead to joint pain, swelling and stiffness, which reduces mobility and function thereby significantly affecting the quality of life of patients. More than 250,000 cartilage repair surgeries are performed in the United States every year. The current gold standard is the treatment of focal cartilage defects and bone damage with nonflexible metal or plastic prosthetics. However, these prosthetics are often made from hard and stiff materials that limits mobility and flexibility, and results in leaching of metal particles into the body, degeneration of adjacent soft bone tissues and possible failure of the implant with time. As a result, the patients may require revision surgeries to replace the worn implants or adjacent vertebrae. More recently, autograft - and allograft-based repair strategies have been studied, however these too are limited by donor site morbidity and the limited availability of tissues for surgery. There has been increasing interest in the past two decades in the area of cartilage tissue engineering where methods like 3D bioprinting may be implemented to generate functional constructs using a combination of cells, growth factors (GF) and biocompatible materials. 3D bioprinting allows for the modulation of mechanical properties of the developed constructs to maintain the required flexibility following implantation while also providing the stiffness needed to support body weight. In this review, we will provide a comprehensive overview of current advances in 3D bioprinting for cartilage tissue engineering for knee menisci and intervertebral disc repair. We will also discuss promising medical-grade materials and techniques that can be used for printing, and the future outlook of this emerging field.

Synthesis and characterization of a novel pH-responsive drug-releasing nanocomposite hydrogel for skin cancer therapy and wound healing.

Local skin cancer recurrence occurs in ∼12% of the patients post-surgery due to persistent growth of residual cancer cells. Wound infection is another significant complication following surgery. We report a novel in situ-forming nanocomposite hydrogel (NCH) containing PLGA-carboxymethyl chitosan nanoparticles (186 nm) for localized pH-responsive skin cancer therapy and wound healing. This injectable hydrogel, comprising of a citric acid-derived polymer backbone, gelled within 5 minutes, and demonstrated excellent swelling (283% of dry weight) and compressive strengths (∼5.34 MPa). Nanoparticle incorporation did not significantly affect hydrogel properties. The NCH effluents were cytocompatible with human dermal fibroblasts at 500 µg ml-1 concentration and demonstrated pH-dependent drug release and promising therapeutic efficacy against A431 and G361 skin cancer cells in vitro. Significant zones of inhibition were observed in S. aureus and E. coli cultures on NCH treatment, confirming its antibacterial properties. Our studies show that the pH-responsive NCH can be potentially used for adjuvant skin cancer treatment and wound healing.

Current State of Breast Cancer Diagnosis, Treatment, and Theranostics.

Breast cancer is one of the leading causes of cancer-related morbidity and mortality in women worldwide. Early diagnosis and effective treatment of all types of cancers are crucial for a positive prognosis. Patients with small tumor sizes at the time of their diagnosis have a significantly higher survival rate and a significantly reduced probability of the cancer being fatal. Therefore, many novel technologies are being developed for early detection of primary tumors, as well as distant metastases and recurrent disease, for effective breast cancer management. Theranostics has emerged as a new paradigm for the simultaneous diagnosis, imaging, and treatment of cancers. It has the potential to provide timely and improved patient care via personalized therapy. In nanotheranostics, cell-specific targeting moieties, imaging agents, and therapeutic agents can be embedded within a single formulation for effective treatment. In this review, we will highlight the different diagnosis techniques and treatment strategies for breast cancer management and explore recent advances in breast cancer theranostics. Our main focus will be to summarize recent trends and technologies in breast cancer diagnosis and treatment as reported in recent research papers and patents and discuss future perspectives for effective breast cancer therapy.

Fabrication of PNIPAm-based thermoresponsive hydrogel microwell arrays for tumor spheroid formation.

Complex three-dimensional (3D) cell cultures are being increasingly implemented in biomedical research as they provide important insights into complex cancer biology, and cell-cell and cell-matrix interactions in the tumor microenvironment. However, most methods used today for 3D cell culture are limited by high cost, the need for specialized skills, low throughput and the use of unnatural culture environments. We report the development of a unique biomimetic hydrogel microwell array platform for the generation and stress-free isolation of cancer spheroids. The poly N-isopropylacrylamide-based hydrogel microwell array (PHMA) has thermoresponsive properties allowing for the attachment and growth of cell aggregates/ spheroids at 37 °C, and their easy isolation at room temperature (RT). The reversible phase transition of the microwell arrays at 35 °C was confirmed visually and by differential scanning calorimetry. Swelling/ shrinking studies and EVOS imaging established that the microwell arrays are hydrophilic and swollen at temperatures <35 °C, while they shrink and are hydrophobic at temperatures >35 °C. Spheroid development within the PHMA was optimized for seeding density, incubation time and cell viability. Spheroids of A549, HeLa and MG-63 cancer cell lines, and human lung fibroblast (HLF) cell line generated within the PHMAs had relatively spherical morphology with hypoxic cores. Finally, using MG-63 cell spheroids as representative models, a proof-of-concept drug response study using doxorubicin hydrochloride was conducted. Overall, we demonstrate that the PHMAs are an innovative alternative to currently used 3D cell culture techniques, for the high-throughput generation of cell spheroids for disease modeling and drug screening applications.

Emerging drug delivery strategies for idiopathic pulmonary fibrosis treatment.

Idiopathic pulmonary fibrosis (IPF) is a debilitating and fatal condition that causes severe scarring of the lungs. While the pathogenesis of IPF continues to be extensively studied and several factors have been considered, an exact cause has yet to be established. With inadequate treatment options and no cure available, overall disease prognosis is still poor. Existing oral therapies, pirfenidone and nintedanib, may attempt to improve the patients' quality of life by mitigating symptoms and slowing disease progression, however chronic doses and systemic deliveries of these drugs can lead to severe side effects. The lack of effective treatment options calls for further investigation of restorative as well as additional palliative therapies for IPF. Nanoparticle-based sustained drug delivery strategies can be utilized to ensure targeted delivery for site-specific treatment as well as long-acting therapy, improving overall patient compliance. This review provides an update on promising strategies for the delivery of anti-fibrotic agents, along with an overview of key therapeutic targets as well as relevant emerging therapies currently being evaluated for IPF treatment.

Porous Polymeric Microspheres With Controllable Pore Diameters for Tissue Engineered Lung Tumor Model Development.

Complex cell cultures are more representative of in vivo conditions than conventionally used monolayer cultures, and are hence being investigated for predictive screening of therapeutic agents. Poly lactide co-glycolide (PLGA) polymer is frequently used in the development of porous substrates for complex cell culture. Substrates or scaffolds with highly interconnected, micrometric pores have been shown to positively impact tissue model formation by enhancing cell attachment and infiltration. We report a novel alginate microsphere (AMS)-based controlled pore formation method for the development of porous, biodegradable PLGA microspheres (PPMS), for tissue engineered lung tumor model development. The AMS porogen, non-porous PLGA microspheres (PLGAMS) and PPMS had spherical morphology (mean diameters: 10.3 ± 4, 79 ± 21.8, and 103 ± 30 µm, respectively). The PPMS had relatively uniform pores and a porosity of 45.5%. Degradation studies show that PPMS effectively maintained their structural integrity with time whereas PLGAMS showed shrunken morphology. The optimized cell seeding density on PPMS was 25 × 103 cells/mg of particles/well. Collagen coating on PPMS significantly enhanced the attachment and proliferation of co-cultures of A549 lung adenocarcinoma and MRC-5 lung fibroblast cells. Preliminary proof-of-concept drug screening studies using mono- and combination anti-cancer therapies demonstrated that the tissue-engineered lung tumor model had a significantly higher resistance to the tested drugs than the monolayer co-cultures. These studies indicate that the PPMS with controllable pore diameters may be a suitable platform for the development of complex tumor cultures for early in vitro drug screening applications.

Ultrasound-Enhanced Chemiluminescence for Bioimaging.

Tissue imaging has emerged as an important aspect of theragnosis. It is essential not only to evaluate the degree of the disease and thus provide appropriate treatments, but also to monitor the delivery of administered drugs and the subsequent recovery of target tissues. Several techniques including magnetic resonance imaging (MRI), computational tomography (CT), acoustic tomography (AT), biofluorescence (BF) and chemiluminescence (CL), have been developed to reconstruct three-dimensional images of tissues. While imaging has been achieved with adequate spatial resolution for shallow depths, challenges still remain for imaging deep tissues. Energy loss is usually observed when using a magnetic field or traditional ultrasound (US), which leads to a need for more powerful energy input. This may subsequently result in tissue damage. CT requires exposure to radiation and a high dose of contrast agent to be administered for imaging. The BF technique, meanwhile, is affected by strong scattering of light and autofluorescence of tissues. The CL is a more selective and sensitive method as stable luminophores are produced from physiochemical reactions, e.g. with reactive oxygen species. Development of near infrared-emitting luminophores also bring potential for application of CL in deep tissues and whole animal studies. However, traditional CL imaging requires an enhancer to increase the intensity of low-level light emissions, while reducing the scattering of emitted light through turbid tissue environment. There has been interest in the use of focused ultrasound (FUS), which can allow acoustic waves to propagate within tissues and modulate chemiluminescence signals. While light scattering is decreased, the spatial resolution is increased with the assistance of US. In this review, chemiluminescence detection in deep tissues with assistance of FUS will be highlighted to discuss its potential in deep tissue imaging.

Thermo-responsive Fluorescent Nanoparticles for Multimodal Imaging and Treatment of Cancers.

Theranostic systems capable of delivering imaging and therapeutic agents at a specific target are the focus of intense research efforts in drug delivery. To overcome non-degradability and toxicity concerns of conventional theranostic systems, we formulated a novel thermo-responsive fluorescent polymer (TFP) and conjugated it on the surface of iron oxide magnetic nanoparticles (MNPs) for imaging and therapeutic applications in solid tumors. METHODS: TFP-MNPs were synthesized by copolymerizing poly(N-isopropylacrylamide), allylamine and a biodegradable photoluminescent polymer, and conjugating it on MNPs via a free radical polymerization reaction. Physicochemical properties of the nanoparticles were characterized using Fourier transform infrared spectroscopy, dynamic light scattering, and vibrational sample magnetometry. Nanoparticle cytocompatibility, cellular uptake and cytotoxicity were evaluated using in vitro cell assays. Finally, in vivo imaging and therapeutic efficacy studies were performed in subcutaneous tumor xenograft mouse models. RESULTS: TFP-MNPs of ~135 nm diameter and -31 mV ζ potential maintained colloidal stability and superparamagnetic properties. The TFP shell was thermo-responsive, fluorescent, degradable, and released doxorubicin in response to temperature changes. In vitro cell studies showed that TFP-MNPs were compatible to human dermal fibroblasts and prostate epithelial cells. These nanoparticles were also taken up by prostate and skin cancer cells in a dose-dependent manner and exhibited enhanced killing of tumor cells at 41°C. Preliminary in vivo studies showed theranostic capabilities of the nanoparticles with bright fluorescence, MRI signal, and therapeutic efficacy under magnetic targeting after systemic administration in tumor bearing mice. CONCLUSION: These results indicate the potential of TFP-MNPs as multifunctional theranostic nanoparticles for various biological applications, including solid cancer management.

Ultrasound-mediated cavitation enhances the delivery of an EGFR-targeting liposomal formulation designed for chemo-radionuclide therapy.

Nanomedicines allow active targeting of cancer for diagnostic and therapeutic applications through incorporation of multiple functional components. Frequently, however, clinical translation is hindered by poor intratumoural delivery and distribution. The application of physical stimuli to promote tumour uptake is a viable route to overcome this limitation. In this study, ultrasound-mediated cavitation of microbubbles was investigated as a mean of enhancing the delivery of a liposome designed for chemo-radionuclide therapy targeted to EGFR overexpressing cancer. Method: Liposomes (111In-EGF-LP-Dox) were prepared by encapsulation of doxorubicin (Dox) and surface functionalisation with Indium-111 tagged epidermal growth factor. Human breast cancer cell lines with high and low EGFR expression (MDA-MB-468 and MCF7 respectively) were used to study selectivity of liposomal uptake, subcellular localisation of drug payload, cytotoxicity and DNA damage. Liposome extravasation following ultrasound-induced cavitation of microbubbles (SonoVue®) was studied using a tissue-mimicking phantom. In vivo stability, pharmacokinetic profile and biodistribution were evaluated following intravenous administration of 111In-labelled, EGF-functionalised liposomes to mice bearing subcutaneous MDA-MB-468 xenografts. Finally, the influence of ultrasound-mediated cavitation on the delivery of liposomes into tumours was studied. Results: Liposomes were loaded efficiently with Dox, surface decorated with 111In-EGF and showed selective uptake in MDA-MB-468 cells compared to MCF7. Following binding to EGFR, Dox was released into the intracellular space and 111In-EGF shuttled to the cell nucleus. DNA damage and cell kill were higher in MDA-MB-468 than MCF7 cells. Moreover, Dox and 111In were shown to have an additive cytotoxic effect in MDA-MB-468 cells. US-mediated cavitation increased the extravasation of liposomes in an in vitro gel phantom model. In vivo, the application of ultrasound with microbubbles increased tumour uptake by 66% (p<0.05) despite poor vascularisation of MDA-MB-468 xenografts (as shown by DCE-MRI). Conclusion:111In-EGF-LP-Dox designed for concurrent chemo-radionuclide therapy showed specificity for and cytotoxicity towards EGFR-overexpressing cancer cells. Delivery to tumours was enhanced by the use of ultrasound-mediated cavitation indicating that this approach has the potential to deliver cytotoxic levels of therapeutic radionuclide to solid tumours.

Applications of alginate microspheres in therapeutics delivery and cell culture: Past, present and future.

Polymers are the backbone of pharmaceutical drug delivery. There are several polymers with varying properties available today for use in different pharmaceutical applications. Alginate is widely used in biomedical research due to its attractive features such as biocompatibility, biodegradability, inertness, low cost, and ease of production and formulation. Encapsulation of therapeutic agents in alginate/alginate complex microspheres protects them from environmental stresses, including the acidic environment in the gastro-intestinal tract (GIT) and enzymatic degradation, and allows targeted and sustained delivery of the agents. Microencapsulation is playing an increasingly important role in drug delivery as evidenced by the recent surge in research articles on the use of alginate in the delivery of small molecules, cells, bacteria, proteins, vaccines, and for tissue engineering applications. Formulation of these alginate microspheres (AMS) are commonly achieved by conventional external gelation method using various instrumental manipulation such as vortexing, homogenization, ultrasonication or spray drying, and each method affects the overall particle characteristics. In this review, an inclusive summary of the currently available methods for the formulation of AMS, its recent use in the encapsulation and delivery of therapeutics, and future outlook will be discussed.

Scaffold-based lung tumor culture on porous PLGA microparticle substrates.

Scaffold-based cancer cell culture techniques have been gaining prominence especially in the last two decades. These techniques can potentially overcome some of the limitations of current three-dimensional cell culture methods, such as uneven cell distribution, inadequate nutrient diffusion, and uncontrollable size of cell aggregates. Porous scaffolds can provide a convenient support for cell attachment, proliferation and migration, and also allows diffusion of oxygen, nutrients and waste. In this paper, a comparative study was done on porous poly (lactic-co-glycolic acid) (PLGA) microparticles prepared using three porogens-gelatin, sodium bicarbonate (SBC) or novel poly N-isopropylacrylamide [PNIPAAm] particles, as substrates for lung cancer cell culture. These fibronectin-coated, stable particles (19-42 µm) supported A549 cell attachment at an optimal cell seeding density of 250,000 cells/ mg of particles. PLGA-SBC porous particles had comparatively larger, more interconnected pores, and favored greater cell proliferation up to 9 days than their counterparts. This indicates that pore diameters and interconnectivity have direct implications on scaffold-based cell culture compared to substrates with minimally interconnected pores (PLGA-gelatin) or pores of uniform sizes (PLGA-PMPs). Therefore, PLGA-SBC-based tumor models were chosen for preliminary drug screening studies. The greater drug resistance observed in the lung cancer cells grown on porous particles compared to conventional cell monolayers agrees with previous literature, and indicates that the PLGA-SBC porous microparticle substrates are promising for in vitro tumor or tissue development.

111In-labelled polymeric nanoparticles incorporating a ruthenium-based radiosensitizer for EGFR-targeted combination therapy in oesophageal cancer cells.

Radiolabelled, drug-loaded nanoparticles may combine the theranostic properties of radionuclides, the controlled release of chemotherapy and cancer cell targeting. Here, we report the preparation of poly(lactic-co-glycolic acid) (PLGA) nanoparticles surface conjugated to DTPA-hEGF (DTPA = diethylenetriaminepentaacetic acid, hEGF = human epidermal growth factor) and encapsulating the ruthenium-based DNA replication inhibitor and radiosensitizer Ru(phen)2(tpphz)2+ (phen = 1,10-phenanthroline, tpphz = tetrapyridophenazine) Ru1. The functionalized PLGA surface incorporates the metal ion chelator DTPA for radiolabelling and the targeting ligand for EGF receptor (EGFR). Nanoparticles radiolabelled with 111In are taken up preferentially by EGFR-overexpressing oesophageal cancer cells, where they exhibit radiotoxicity through the generation of cellular DNA damage. Moreover, nanoparticle co-delivery of Ru1 alongside 111In results in decreased cell survival compared to single-agent formulations; an effect that occurs through DNA damage enhancement and an additive relationship between 111In and Ru1. Substantially decreased uptake and radiotoxicity of nanoparticles towards normal human fibroblasts and oesophageal cancer cells with normal EGFR levels is observed. This work demonstrates nanoparticle co-delivery of a therapeutic radionuclide plus a ruthenium-based radiosensitizer can achieve combinational and targeted therapeutic effects in cancer cells that overexpress EGFR.

Dual-Drug Containing Core-Shell Nanoparticles for Lung Cancer Therapy.

Late-stage diagnosis of lung cancer occurs ~95% of the time due to late manifestation of its symptoms, necessitating rigorous treatment following diagnosis. Existing treatment methods are limited by lack of specificity, systemic toxicity, temporary remission, and radio-resistance in lung cancer cells. In this research, we have developed a folate receptor-targeting multifunctional dual drug-loaded nanoparticle (MDNP) containing a poly(N-isopropylacrylamide)-carboxymethyl chitosan shell and poly lactic-co-glycolic acid (PLGA) core for enhancing localized chemo-radiotherapy to effectively treat lung cancers. The formulation provided controlled releases of the encapsulated therapeutic compounds, NU7441 - a potent radiosensitizer, and gemcitabine - an FDA approved chemotherapeutic drug for lung cancer chemo-radiotherapy. The MDNPs showed biphasic NU7441 release and pH-dependent release of gemcitabine. These nanoparticles also demonstrated good stability, excellent hemocompatibility, outstanding in vitro cytocompatibility with alveolar Type I cells, and dose-dependent caveolae-mediated in vitro uptake by lung cancer cells. In addition, they could be encapsulated with superparamagnetic iron oxide (SPIO) nanoparticles and visualized by MRI in vivo. Preliminary in vivo results demonstrated the low toxicity of these particles and their use in chemo-radiotherapy to effectively reduce lung tumors. These results indicate that MDNPs can potentially be used as nano-vehicles to provide simultaneous chemotherapy and radiation sensitization for lung cancer treatment.

Nanoparticle facilitated inhalational delivery of erythropoietin receptor cDNA protects against hyperoxic lung injury.

Our goals were to develop and establish nanoparticle (NP)-facilitated inhalational gene delivery, and to validate its biomedical application by testing the hypothesis that targeted upregulation of pulmonary erythropoietin receptor (EpoR) expression protects against lung injury. Poly-lactic-co-glycolic acid (PLGA) NPs encapsulating various tracers were characterized and nebulizated into rat lungs. Widespread NP uptake and distribution within alveolar cells were visualized by magnetic resonance imaging, and fluorescent and electron microscopy. Inhalation of nebulized NPs bearing EpoR cDNA upregulated pulmonary EpoR expression and downstream signal transduction (ERK1/2 and STAT5 phosphorylation) in rats for up to 21 days, and attenuated hyperoxia-induced damage in lung tissue based on apoptosis, oxidative damage of DNA, protein and lipid, tissue edema, and alveolar morphology compared to vector-treated control animals. These results establish the feasibility and therapeutic efficacy of NP-facilitated cDNA delivery to the lung, and demonstrate that targeted pulmonary EpoR upregulation mitigates acute oxidative lung damage. FROM THE CLINICAL EDITOR: Acute lung injury often results in significant morbidity and mortality, and current therapeutic modalities have proven to be ineffective. In this article, the authors developed nanocarrier based gene therapy in an attempt to upregulate the expression of pulmonary erythropoietin receptor in an animal model. Inhalation delivery resulted in reduction of lung damage.

Polymeric nanoparticles for targeted radiosensitization of prostate cancer cells.

One of the many issues of using radiosensitizers in a clinical setting is timing daily radiation treatments to coincide with peak drug concentration in target tissue. To overcome this deficit, we have synthesized a novel nanoparticle (NP) system consisting of poly (lactic-co-glycolic acid) (PLGA) NPs conjugated with prostate cancer cell penetrating peptide-R11 and encapsulated with a potent radio-sensitizer 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one (NU7441) to allow prostate cancer-specific targeting and sustained delivery over 3 weeks. Preliminary characterization studies showed that the R11-conjugated NPs (R11-NU7441 NPs) had an average size of about 274 ± 80 nm and were stable for up to 5 days in deionized water and serum. The NPs were cytocompatible with immortalized prostate cells (PZ-HPV-7). Further, the particles showed a bi-phasic release of encapsulated NU7441 and were taken up by PC3 prostate cancer cells in a dose- and magnetic field-dependent manner while not being taken up in nonprostate cancer cell lines. In addition, R11-NU7441 NPs were effective radiation sensitizers of prostate cancer cell lines in vitro. These results thus demonstrate the potential of R11-conjugated PLGA NPs as novel platforms for targeted radiosensitization of prostate cancer cells.

Electrospun biodegradable elastic polyurethane scaffolds with dipyridamole release for small diameter vascular grafts.

Acellular biodegradable small diameter vascular grafts (SDVGs) require antithrombosis, intimal hyperplasia inhibition and rapid endothelialization to improve the graft patency. However, current antithrombosis and antiproliferation approaches often conflict with endothelial cell layer formation on SDVGs. To address this limitation, biodegradable elastic polyurethane urea (BPU) and the drug dipyridamole (DPA) were mixed and then electrospun into a biodegradable fibrous scaffold. The BPU would provide the appropriate mechanical support, while the DPA in the scaffold would offer biofunctions as required above. We found that the resulting scaffolds had tensile strengths and strains comparable with human coronary artery. The DPA in the scaffolds was continuously released up to 91 days in phosphate buffer solution at 37 °C, with a low burst release within the first 3 days. Compared to BPU alone, improved non-thrombogenicity of the DPA-loaded BPU scaffolds was evidenced with extended human blood clotting time, lower TAT complex concentration, lower hemolysis and reduced human platelet deposition. The scaffolds with a higher DPA content (5 and 10%) inhibited proliferation of human aortic smooth muscle cell significantly. Furthermore, the DPA-loaded scaffolds had no adverse effect on human aortic endothelial cell growth, yet it improved their proliferation. The attractive mechanical properties and biofunctions of the DPA-loaded BPU scaffold indicate its potential as an acellular biodegradable SDVG for vascular replacement.