Design of experiments approach for the development of a validated method to determine the exenatide content in poly(lactide-co-glycolide) microspheres.

Due to the lack of pharmacopeia guidelines for injectable microspheres based on poly (D, L-lactide-co-glycolide) (PLGA), an internal method validation is a critical prerequisite for quality assurance. One of the essential issues of developing peptide-based drugs loaded PLGA microspheres is the precise determination of the amount of peptide drug entrapped in the microspheres. The aim of this study is the development and optimization of a method for measuring the drug content loading of PLGA microspheres using exenatide as a model peptide drug. Exenatide-loaded PLGA microspheres were prepared by a double emulsion solvent evaporation method. The extraction method to determine exenatide content in microspheres was optimized using Design of Experiments (DoE) approach. After the initial screening of six factors, using Fractional Factorial design (FFD), four of them, including type of organic solvent, buffer/organic solvent ratio (v/v), shaking time and pH, exhibited significant effects on the response, namely the exenatide loading, and a Box-Behnken design (BBD) was subsequently applied to obtain its optimum level. The optimum level for organic solvent volume, buffer/organic solvent ratio, shaking time, and pH were 4 ml, 1, 5.6 hrs, and pH 6, respectively. The exenatide content in microspheres under these conditions was 6.4 ± 0.0 (%w/w), whereas a value of 6.1% was predicted by the derived equation. This excellent agreement between the actual and the predicted value demonstrates that the fitted model can thus be used to determine the exenatide content.

Synthesis and Preliminary Biological Assessment of Carborane-Loaded Theranostic Nanoparticles to Target Prostate-Specific Membrane Antigen.

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 89Zr 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. [89Zr]DFB(25) NPs and [89Zr]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.

A cell-free ROS-responsive hydrogel/oriented poly(lactide-co-glycolide) hybrid scaffold for reducing inflammation and restoring full-thickness cartilage defectsin vivo.

The modulation of inflammation in tissue microenvironment takes an important role in cartilage repair and regeneration. In this study, a novel hybrid scaffold was designed and fabricated by filling a reactive oxygen species (ROS)-scavenging hydrogel (RS Gel) into a radially oriented poly(lactide-co-glycolide) (PLGA) scaffold. The radially oriented PLGA scaffolds were fabricated through a temperature gradient-guided phase separation and freeze-drying method. The RS Gel was formed by crosslinking the mixture of ROS-responsive hyperbranched polymers and biocompatible methacrylated hyaluronic acid (HA-MA). The hybrid scaffolds exhibited a proper compressive modulus, good ROS-scavenging capability, and cell compatibility.In vivotests showed that the hybrid scaffolds significantly regulated inflammation and promoted regeneration of hyaline cartilage after they were implanted into full-thickness cartilage defects in rabbits for 12 w. In comparison with the PLGA scaffolds, the neo-cartilage in the hybrid scaffolds group possessed more deposition of glycosaminoglycans and collagen type II, and were well integrated with the surrounding tissue.

Effect and Biocompatibility of a Cross-Linked Hyaluronic Acid and Polylactide-co-glycolide Microcapsule Vehicle in Intratympanic Drug Delivery for Treating Acute Acoustic Trauma.

The treatment of acute hearing loss is clinically challenging due to the low efficacy of drug delivery into the inner ear. Local intratympanic administration of dexamethasone (D) and insulin-like growth factor 1 (IGF1) has been proposed for treatment, but they do not persist in the middle ear because they are typically delivered in fluid form. We developed a dual-vehicle drug delivery system consisting of cross-linked hyaluronic acid and polylactide-co-glycolide microcapsules. The effect and biocompatibility of the dual vehicle in delivering D and IGF1 were evaluated using an animal model of acute acoustic trauma. The dual vehicle persisted 10.9 times longer (8.7 days) in the middle ear compared with the control (standard-of-care vehicle, 0.8 days). The dual vehicle was able to sustain drug release over up to 1 to 2 months when indocyanine green was loaded as the drug. One-third of the animals experienced an inflammatory adverse reaction. However, it was transient with no sequelae, which was validated by micro CT findings, endoscopic examination, and histological assessment. Hearing restoration after acoustic trauma was satisfactory in both groups, which was further supported by comparable numbers of viable hair cells. Overall, the use of a dual vehicle for intratympanic D and IGF1 delivery may maximize the effect of drug delivery to the target organ because the residence time of the vehicle is prolonged.

The kinetics and release behaviour of curcumin loaded pH-responsive PLGA/chitosan fibers with antitumor activity against HT-29 cells.

The bioavailability and clinical effect of curcumin (Cur) are greatly restricted due to its physicochemical instability and high hydrophobicity. To overcome the disadvantages, the nanofibers of poly(lactide-glycolide)/chitosan loaded with Cur (PLGA/CS/Cur) was developed here by electrospinning technique for controlled Cur delivery. The incorporated Cur was well-dispersed and maintained crystalline form in PLGA/CS fiber matrix by hydrogen bonding. The incorporation of Cur had no obvious influence on the fiber size and morphology but exerted impacts on thermal stability. At pH 7.4, the release followed Fickian diffusion mechanism; while at pH 2.0, the release followed the coexistence of diffusion and erosion mechanisms. In addition, the amount of Cur released at pH 2.0 was much higher than that at pH 7.4. As a result, the nanofibers demonstrated higher anticancer activity at acidic environment. Therefore, the PLGA/CS/Cur nanofibers may be served as a potential pH responsive vehicle for the controlled drug delivery.

Biological compatibility, thermal and in vitro simulated degradation for poly(p-dioxanone)/poly(lactide-co-glycolide)/poly(ethylene succinate-co-glycolide).

Bio-absorbable polymers are widely desired to be applied and used as biomaterials for surgery hemostatic and medical tissue engineering devices. Ring-opening copolymerization reaction was applied to synthesize poly(ethylene succinate-co-glycolide) (PES-b-PGA). Stannous octoate was used as a catalyst whereas poly(ethylene succinate) was used as a macro-initiator to react with glycolide. PES-b-PGA was then used as a compatibilizer to prepare the blend biomaterial of PPDO/PLGA/PES-b-PGA by melt blending poly(p-dioxanone) (PPDO) with poly(lactide-co-glycolide) (PLGA). This would enhance the interactions of the inter-molecular chains and intra-molecular segments thus improving the compatibility. To obtain the biomaterial of PPDO/PLGA/PES-b-PGA with a regulated and controlled degradation and/or hydrolysis period, various ratios of PPDO, PLGA, and PES-b-PGA was blended. Behaviors of the thermal and in vitro simulated degradation, biological compatibility, cytotoxicity and subcutaneous implantation of PPDO/PLGA/PES-b-PGA were investigated. The results show that the in vitro hydrolytic degradation cycle is consistent with the wound healing time and that the biomaterial has slight cytotoxicity and it will do good to the cell proliferation, with 1 grade of cytotoxicity and the relative growth rate being the range from 92.5% to 96.2%. The implantation of the biomaterial into the rabbits' ears will not adversely affect the wound healing and the tissues surrounding the implanted sites. Therefore, the biomaterial has good biocompatibility and potential applications in medical tissue engineering devices.

Glutamate-urea-based PSMA-targeted PLGA nanoparticles for prostate cancer delivery of docetaxel.

Targeted drug delivery is a tool to make treatment more specific, selective, and effective and to prevent unwanted complications. Prostate specific membrane antigen (PSMA) is a useful biomarker in order to monitor and control prostate cancer. Glutamate-Urea-R (Glu-Urea-R) is a PSMA enzyme inhibitor capable of binding to this surface marker of prostate cancer cell in an efficient and special manner. The aim of this project was to develop a docetaxel-loaded nanoparticle of poly (lactic-co-glycolic acid) polyethylene glycol which is cojugated to a urea-based anti-PSMA ligand named glutamate-urea-lysine (glu-urea-lys) for targeted delivery of docetaxel in prostate cancer. The obtained nanoparticles, prepared by nanoprecipitation method, were spheres with a particle size of around 150 nm and zeta potential of -7.08 mV. Uptake studies on the PC3 (as PSMA negative) and LNCaP (as PSMA positive) cells demonstrated that drug uptake was efficient by the PSMA positive cells. IC50 of targeted NPs on LNCaP cell line compared to non-targeted ones was reduced by more than 70% in three different incubation times of 24, 48, and 72 h. In conclusion, the nanoparticles are expected to specifically transport docetaxel to PSMA-positive prostate cancer cells and consequently, enhance the antitumor efficacy of docetaxel on these cells.

pH-Triggered Poly(ethylene glycol)-Poly(lactic acid/glycolic acid)/Croconaine Nanoparticles-Assisted Multiplexed Photoacoustic Imaging and Enhanced Photothermal Cancer Therapy.

The most advantageous and attractive property of photoacoustic imaging is its capability to visualize and differentiate multiple species according to their unique absorbance profiles simultaneously in a single mixture. We here report the pH-sensitive near-infrared (NIR) croconaine (Croc) dyes-loaded copolymeric PEG-PLGA nanoparticles (NPs) for in vivo multiplexed PA imaging and pH-responsive photothermal therapy (PTT) in an orthotopic xenograft model. PEG chains on the polymeric NPs shell were conjugated with iRGD in another set of NPs to realize efficient tumor targeting. The distribution and the intensity of two sets of iRGD-targeted and nontargeted NPs inside tumors are simultaneously imaged and monitored in vivo. Meanwhile, the utilization of iRGD-targeted PPC815 NPs as a pH-active photothermal agent with promising tumor-inhibition efficacy was demonstrated. As a result, this nanoplatform is capable of assisting multiwavelength unmixing of PA imaging as well as providing remarkable photothermal ablation for anticancer treatment.

In vitro evaluation of the modified forwarder knot used to end a continuous suture pattern in large-gauge suture.

OBJECTIVE: To evaluate the strength and size of forwarder end (FE) knots modified to end continuous suture lines compared with Aberdeen (AB), square (SQ), and surgeon's (SU) knots. STUDY DESIGN: In vitro mechanical study. STUDY POPULATION: Knotted suture. METHODS: Knots were tied with 2 USP (United States Pharmacopeia) polydioxanone, 2 USP, and 3 USP polyglactin 910 and tested on a universal testing machine under linear tension. Mode of failure and knot holding capacity (KHC) were recorded, and relative knot security (RKS) was calculated. Knot volume and weight were determined by digital micrometer and balance. Knot holding capacity, RKS, size, and weight between knot type, number of throws, and suture type and size were compared by using analysis of variance testing, with P < .05 considered significant. RESULTS: In all suture types and number of throws, FE knot KHC/RKS was 28% to 66.99% (1.2-1.6 fold) stronger compared with SQ/SU knots (P < .001). For 2 USP polydioxanone, FE knots had 10% (1.1 fold) higher KHC/RKS compared with AB knots (P < .042). However, in 2 and 3 USP polyglactin 910, FE knot KHC/RKS values were not different from those of AB knots (P > .080). Forwarder end/AB knots failed by suture breakage at the knot, whereas some SQ/SU knots unraveled. Forwarder end knots in 2 and 3 USP polyglactin 910 were 21.1% to 44.4% (1.2-1.4 fold) smaller compared with SQ/SU knots (P < .028). Forwarder end knots in 2 and 3 USP polyglactin 910 were 40% to 99% (1.4-2.0 fold) larger compared with AB knots (P < .001). CONCLUSION: Forwarder end knots provided increased KHC/RKS compared with SQ/SU knots. CLINICAL RELEVANCE: Forwarder end knots should be considered for closures when suture is placed under tension.

A combined-modification method of carboxymethyl ß-cyclodextrin and lignin for nano-hydroxyapatite to reinforce poly(lactide-co-glycolide) for bone materials.

Lignin is the second most abundant natural biomacromolecule. A new surface-modification for nano-hydroxyapatite (n-HA) by carboxymethyl ß-cyclodextrin (CM-ß-CD) and lignin and its reinforce effect for poly(lactide-co-glycolide) (PLGA) were investigated by Fourier transformation infrared (FTIR), X-ray diffraction pattern (XRD), transmission electron microscopy (TEM), thermal gravimetric analysis (TGA), dispersion images, the tensile tests, scanning electron microscope (SEM), differential scanning calorimeter (DSC) and polarized optical microscopy (POM), compared to the singled-modification of CM-ß-CD or lignin. The results showed that the appropriate combined-modified n-HA displayed excellent synergistic effects for increasing the dispersion, yielding good interfacial bonding between n-HA with PLGA matrix. The tensile strength of the composite was still 14.53% higher than that of PLGA, for a n-HA addition amount of 15 wt%, which was significantly better than that for the singled-modified n-HA. Additionally, in vitro degradation behavior was evaluated by soaking in simulated body fluid (SBF), and their cell response was carried out by interaction tests with bone mesenchymal stem cells. The results indicated that the combined-modification method promoted good degradation behavior and apatite deposition, as well as excellent cell biocompatibility. This study may offer an important guidance to obtain PLGA-based composites reinforced by surface-modified n-HA as bone materials.

Extended Release of Doxorubicin-Loaded 3DNA Nanocarriers from In-Situ Forming, Self-Assembled Hydrogels.

Purpose: Cataracts are the leading cause of blindness worldwide, resulting in over 30 million surgeries each year. These cases are expected to double within the next 10 years. About 25% of all patients develop secondary cataracts or posterior capsule opacification (PCO) postsurgery. PCO is a vision impairment disorder that develops from myofibroblasts migration and contraction that deforms the capsule surrounding the lens. Currently, Nd:YAG laser therapy is used to treat PCO; however, laser is not available worldwide and adverse side effects may arise. Thus, there is a considerable unmet need for more efficacious and convenient preventive treatments for PCO. Our work focuses on engineering an innovative, prophylactic sustained release platform for DNA-based nanocarriers to further reduce the incidence of PCO. Methods: Novel, optically clear, self-assembled poly(d,l-lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-PEG) triblock copolymer hydrogels were used for the sustained release of the DNA-based nanocarriers (3DNA®) loaded with cytotoxic doxorubicin (DOX) and targeted with a monoclonal antibody called G8 (3DNA:DOX:G8), which is specific to cells responsible for PCO. Results: The 29 (w/v)% polymer hydrogels with the 3DNA nanocarriers presented over 80% of light transmittance, soft mechanical properties (<350 Pa), and sustained release for 1 month. Conclusions: In this work, we show for the first time that the hydrophobic PLGA-PEG-PLGA hydrogels can be used as platforms for sustained delivery of nucleic acid-based nanocarriers. This work demonstrates that polymeric formulations can be used for the extended delivery of ocular therapeutics and other macromolecules to treat a variety of ocular conditions.

Fixed-point "blasting" triggered by second near-infrared window light for augmented interventional photothermal therapy.

One of the major limitations of current cancer therapy is the inability to destroy tumors with high efficacy and minimal invasiveness. Herein, we developed a proof-of-concept fixed-point "blasting" strategy to destroy the "castle" of tumors and realized efficient interventional photothermal therapy. The "blasting" materials were composed of photothermal nanoparticles (ancient ink nanoparticles, AINP) and a low boiling point phase change agent (perfluoromethylcyclopentane, FMCP). An injectable in situ-forming thermal-responsive hydrogel composed of biodegradable and biocompatible polymers was employed as a carrier to load the AINP and FMCP. The obtained hydrogel system was a flowable aqueous solution at low or room temperature for facile injection; meanwhile, once administered, it rapidly transformed into a fixed gel at a body temperature of about 37 °C. This unique property could effectually fix the AINP and FMCP and thus restrict the destruction region inside the tumor. Subsequently, triggered by second window near-infrared light, the solid tumors were effectively destroyed by a mild photothermal effect and the subsequent gas mechanical damage. We envisage that this fixed-point "blasting" strategy will pave a new way for the next generation of cancer-interventional photothermal therapy.

Preparation and characterization of PLGA-PEG-PLGA polymeric nanoparticles for co-delivery of 5-Fluorouracil and Chrysin.

Despite significant advances in cancer therapy, chemotherapeutic agents are still the main types of drugs used to treat cancer patients. 5-Fluorouracil (5-FU) is the first-line treatment in several types of human cancers, however, nonspecific function, low plasma half-life, and high doses toxicity are the important barrier to achieve efficient response in cancer patients. The use of polymeric nanoparticles (NPs) for tumor targeted delivery of 5-FU in combination with other potent anticancer agent is considered an important strategy to enhance the therapeutic efficacy of 5-FU. In this study, we proposed to use PLGA-PEG-PLGA NPs to co-encapsulate 5-FU and Chrysin, a natural compound known to enhance the therapeutic efficacy of chemotherapy. NPs were prepared by double emulsion method and characterized for size and drug encapsulation efficacy. The cell growth inhibitory effect of prepared NPs was assessed by MTT assay in HT29 human colon cancer cell line. The analysis of NPs by dynamic light scattering showed that the developed NPs have average size of 40 nm. The encapsulation efficiency of NPs was 81.3% and 97.5% for 5-FU and Chrysin, respectively. Furthermore, the NPs showed a remarkable uptake in HT29 cells. NPs loaded with both 5-FU and Chrysin (5-FU@Chrysin loaded NPs) were found to have significantly higher growth inhibitory effects compared with NPs loaded with each drug alone in HT29 cell line. The synergistic anticancer effects of 5-FU and Chrysin loaded in NPs were confirmed with the combination index (CI) being 0.35. CI for combination therapy with free 5-FU and Chrysin was found to be 0.73, indicating weaker synergistic anticancer effects of these two drugs in free forms as compared with 5-FU@Chrysin loaded NPs. These finding indicates that co-delivery of 5-FU and Chrysin with PLGA-PEG-PLGA copolymer can be used to improve the therapeutic and functional delivery efficacy of 5-FU and Chrysin in cancer.

Design, Formulation and in vivo Evaluation of Novel Honokiol-Loaded PEGylated PLGA Nanocapsules for Treatment of Breast Cancer.

BACKGROUND: Honokiol (HK) is a common herbal medicine extracted from magnolia plants. Low aqueous solubility and limited bioavailability of HK have hindered its clinical application, especially for cancer treatment. Nano-drug delivery system has the potential to enhance HK delivery and therefore, enhance its anti-cancer activity. PURPOSE: The study's aim is to design novel PEGylated-PLGA polymeric nanocapsules (NCs) for HK delivery to breast tumor-bearing mice after systemic administration. METHODS: Formulation of different HK-loaded NCs and their physio-chemical characterization were optimized through the use of different formulation variables. The antitumor activity of the HK-loaded NCs was investigated both in vitro using MCF-7 and EAC breast cancer cell lines and in vivo using solid Ehrlich carcinoma (SEC) breast cancer model. RESULTS: The optimum HK-loaded NCs were prepared from 15% PEG-PLGA diblock copolymer and exhibited the lowest nano size of 125 nm, smooth spherical morphology, highest drug loading of 94% and highest cellular uptake into breast cancer cells. HK-loaded PEGylated NCs can effectively inhibit the in vitro cell growth of breast cancer cells by 80.2% and 58.1% compared to 35% and 31% with free HK in the case of MCF-7 and EAC, respectively. HK-loaded NCs inhibited SEC tumor growth by 2.3 fold significantly higher than free HK, in vivo. CONCLUSION: The designed drug delivery system encapsulating HK exhibited a pronounced decrease in tumor growth biomarkers meanwhile proved its safety in animals. Therefore, 15% PEGylated HK-loaded NCs may act as a promising new approach for breast cancer treatment.

Gold nanorod-loaded (PLGA-PEG) nanocapsules as near-infrared controlled release model of anticancer therapeutics.

Despite of high in vitro anticancer efficacy of many chemotherapeutics, their in vivo use is limited due to lack of biocompatibility and tumor targeting. Near-infrared (NIR) photothermally induced phase transition of PLGA-PEG regime was utilized for developing highly efficient photoresponsive drug delivery systems. Co-encapsulation of plasmonic gold nanorods (GNRs), as NIR-trigger, with the novel and highly efficient anticancer drug N'-(2-Methoxybenzylidene)-3-methyl-1-phenyl-H-Thieno[2,3-c]Pyrazole-5-Carbohyd-razide (MTPC) produced NIR-responsive biodegradable polymeric (PLGA-b-PEG) nanocapsules. This remotely controllable drug release significantly enhanced both biodistribution and pharmacokinetics of the hydrophobic drug. Intravenous (IV) injection of the prepared nanocapsules (MTPC/GNRs@PLGA-PEG) to tumor-bearing mice followed by extracorporeal exposure of the tumor to NIR light resulted in highly selective drug accumulation at the tumor sites. In vivo biodistribution and pharmacokinetics utilizing iodine-131 drug-radiolabelling technique revealed a maximum target to non-target ratio (T/NT) of 5.8, 4 h post-injection with maximum drug level in the tumor (6.3 ± 0.6% of the injected dose). Graphical abstract.

An anticancer agent-loaded PLGA nanomedicine with glutathione-response and targeted delivery for the treatment of lung cancer.

Stimuli response or controlled release is a new research hotspot in nanomedicine; however, there is scarce research on organic nanomedicines with stimuli responses, which limits their practical biological applications. In addition, homoharringtonine (HHT) has been used as an effective anticancer agent, but reducing its toxicity and side effects is an urgent problem to be solved. Herein, an EGFR (epidermal growth factor receptor) aptamer-modified HHT-loaded PLGA-SS-PEG nanomedicine was developed. The nanomaterial possesses spherical morphology and admirable biocompatibility. After targeted endocytosis in tumour cells via the selective recognition between EGFR and its aptamer, the PLGA nanomedicine is triggered by a high GSH level and releases its cargo in lung cancer cells. The in vitro and in vivo results reveal that the PLGA nanomedicine not only inhibited the proliferation and promoted the apoptosis of lung cancer cells, but also possessed better therapeutic efficacy and less toxic side effects compared with the free anticancer agent. Consequently, this study provides a novel approach to construct a biodegradable nanomedicine with targeted recognition and stimuli response. Moreover, it inhibited the proliferation of lung cancer cells with high efficiency and low toxicity. Importantly, the PLGA nanomedicine demonstrates encouraging potential as a multifunctional nano-system applicable for cancer therapy.

Preparation and Characterization of PLGA-PEG-PLGA Nanoparticles Containing Salidroside and Tamoxifen for Breast Cancer Therapy.

Nanoparticles (NPs) containing the hydrophilic drug salidroside (Sal) and the hydrophobic drug tamoxifen (Tam) were prepared using a triblock copolymer poly(lactic-co-glycolic acid) (PLGA)-poly(ethylene glycol) (PEG)-PLGA to achieve synergism in the treatment of breast cancer. The double emulsion (w/o/w) method was used to prepare Sal-Tam NPs with an average particle size of 275.3 ± 44.0 nm, a polydispersity index of 0.302 ± 0.102, and a zeta potential of - 6.98 ± 2.99. The entrapment efficiency of the hydrophilic and hydrophobic components was 32.63% ± 0.73% and 49.18% ± 3.04%, respectively. On differential scanning calorimetry, the NPs showed the amorphous nature of both Sal and Tam. The sustained release of Sal and Tam from the NPs was significantly prolonged under physiological conditions (pH 7.4). The CCK-8 assay using the 4T1 cell line revealed a 1.7-fold decrease in the IC50 value for Sal-Tam NPs when compared with free Tam. The in vivo anti-tumor effect was assessed in BALB/c mice, and the results demonstrated that these NPs decreased the tumor volume compared with saline and showed high anti-tumor activity. A pharmacokinetic study showed significant enhancement of the bioavailability of Tam in Sal-Tam NPs compared with free Tam in suspension. The intracellular and mitochondrial anti-oxidative effect of Sal was thought to be attributed to the promising anti-tumor effect of drug co-delivery. This study confirmed that the use of Sal-Tam NPs may be a promising approach in breast cancer therapy.

A Retrospective Review of Vaginal Cuff Dehiscence: Comparing Absorbable and Nonabsorbable Sutures.

STUDY OBJECTIVE: To compare the rate of spontaneous and complete vaginal cuff dehiscence (VCD) using absorbable versus nonabsorbable sutures for vaginal cuff closure. DESIGN: Retrospective comparative cohort design. SETTING: Freestanding ambulatory surgery center in suburban Maryland. PATIENTS: Women age >18 years old who underwent hysterectomy for benign conditions between October 2013 and April 2018. INTERVENTION: Laparoscopic retroperitoneal hysterectomy was performed by 2 gynecologic surgical specialists. Transvaginal cuff closure was performed using either absorbable Vicryl (polyglactin 910) sutures (n = 881) or nonabsorbable Ethibond (polyester) sutures (n = 574). The nonabsorbable sutures were surgically removed after 90 days. MEASUREMENTS AND MAIN RESULTS: No statistically significant differences in age, race, weight, body mass index, parity, uterine weight, or number of comorbidities were noted between the nonabsorbable and absorbable suture groups. Spontaneous vaginal cuff dehiscence (VCD) occurred in 3 patients (0.52%) in the nonabsorbable group and in 12 patients (1.4%) in the absorbable group (p = .183). Eleven of the 12 cases of VCD in the absorbable group were precipitated by intercourse and occurred within 90 days of surgery. CONCLUSION: Our data suggest that use of a nonabsorbable suture may be an effective approach to prevent spontaneous VCD, but the benefits should be weighed against the inherent risk associated with a second procedure to remove sutures.

PDGFBB-modified stem cells from apical papilla and thermosensitive hydrogel scaffolds induced bone regeneration.

Bone defects caused by cancer surgery or trauma have a strong negative impact on human health. Treatment with cell and material-based complexes provides an alternative strategy for the regeneration of damaged bone tissue. The good physical properties and suitable biodegradability of a thermosensitive hydrogel has been shown to act as a valuable scaffold. Platelet derived growth factor BB (PDGFBB) is mainly secreted by platelets and promotes the migration and angiogenesis of mesenchymal stem cells (MSCs). Although PDGFBB is known to indirectly enhance bone repair in vivo, the effects of PDGFBB on stem cells from apical papilla (SCAPs) require further investigation. In our study, the proliferation of cells was investigated by the cell counting kit-8 and live/dead staining methods. The results indicated that PDGFBB promoted the proliferation of SCAPs. Real-time polymerase chain reaction and Western blot experiments were used to detect osteogenic genes and proteins. Moreover, calvarial defects were created in Sprague-Dawley rats and different complexes implanted. The results shown by micro-CT and hematoxylin and eosin analysis demonstrated that the hydrogel combined with lentiviral supernatant-green fluorescent protein-PDGFBB significantly improved new bone formation and mineralization compared with the other three groups. In summary, our research showed that a thermosensitive hydrogel can be used as a scaffold for 3D cell culture, and PDGFBB gene-modified SCAPs can improve bone formation in calvarial defects.

Indocyanine Green J Aggregates in Polymersomes for Near-Infrared Photoacoustic Imaging.

Clinical translation of photoacoustic imaging (PAI) has been limited by the lack of near-infrared (NIR) contrast agents with low toxicity required for regulatory approval. Herein, J aggregates of indocyanine green (ICG) with strong NIR absorbance were encapsulated at high loadings within small 77 nm polymersomes (nanocapsules) composed of poly(lactide-co-glycolide-b-poly(ethylene glycol)) (PLGA-b-PEG) bilayers, thus enabling PAI of of breast and ovarian cancer cells with high specificity and a sensitivity at the level of ∼100 total cells. All of the major components of the polymersomes are FDA approved and used in the clinic. During formation of polymersomes with a water-in-oil-in-water double emulsion process, loss of ICG from the ICG J aggregates was minimized by coating them with a layer of branched polyethylenimine and by providing excess "sacrificial" ICG to adsorb at the oil-water interfaces. The encapsulated J aggregates were protected against dissociation by the polymersome shell for 24 h in 100% fetal bovine serum, after which the polymersomes biodegraded and the J aggregates dissociated to ICG monomers.