Peritumoral Microgel Reservoir for Long-Term Light-Controlled Triple-Synergistic Treatment of Osteosarcoma with Single Ultra-Low Dose.

Local minimally invasive injection of anticancer therapies is a compelling approach to maximize the utilization of drugs and reduce the systemic adverse drug effects. However, the clinical translation is still hampered by many challenges such as short residence time of therapeutic agents and the difficulty in achieving multi-modulation combination therapy. Herein, mesoporous silica-coated gold nanorods (AuNR@SiO2 ) core-shell nanoparticles are fabricated to facilitate drug loading while rendering them photothermally responsive. Subsequently, AuNR@SiO2 is anchored into a monodisperse photocrosslinkable gelatin (GelMA) microgel through one-step microfluidic technology. Chemotherapeutic drug doxorubicin (DOX) is loaded into AuNR@SiO2 and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is loaded in the microgel layer. The osteosarcoma targeting ligand alendronate is conjugated to AuNR@SiO2 to improve the tumor targeting. The microgel greatly improves the injectability since they can be dispersed in buffer and the injectability and degradability are adjustable by microfluidics during the fabrication. The drug release can, in turn, be modulated by multi-round light-trigger. Importantly, a single super low drug dose (1 mg kg-1 DOX with 5 mg kg-1 DMXAA) with peritumoral injection generates long-term therapeutic effect and significantly inhibited tumor growth in osteosarcoma bearing mice. Therefore, this nanocomposite@microgel system can act as a peritumoral reservoir for long-term effective osteosarcoma treatment.

PEGylated Tantalum Nanoparticles: A Metallic Photoacoustic Contrast Agent for Multiwavelength Imaging of Tumors.

Elemental tantalum is a well-known biomedical metal in clinics due to its extremely high biocompatibility, which is superior to that of other biomedical metallic materials. Hence, it is of significance to expand the scope of biomedical applications of tantalum. Herein, it is reported that tantalum nanoparticles (Ta NPs), upon surface modification with polyethylene glycol (PEG) molecules via a silane-coupling approach, are employed as a metallic photoacoustic (PA) contrast agent for multiwavelength imaging of tumors. By virtue of the broad optical absorbance from the visible to near-infrared region and high photothermal conversion efficiency (27.9%), PEGylated Ta NPs depict high multiwavelength contrast capability for enhancing PA imaging to satisfy the various demands (penetration depth, background noise, etc.) of clinical diagnosis as needed. Particularly, the PA intensity of the tumor region postinjection is greatly increased by 4.87, 7.47, and 6.87-fold than that of preinjection under 680, 808, and 970 nm laser irradiation, respectively. In addition, Ta NPs with negligible cytotoxicity are capable of eliminating undesirable reactive oxygen species, ensuring the safety for biomedical applications. This work introduces a silane-coupling strategy for the surface engineering of Ta NPs, and highlights the potential of Ta NPs as a biocompatible metallic contrast agent for multiwavelength photoacoustic image.

Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy.

T cells with high functional avidity can sense and respond to low levels of cognate Ag, a characteristic that is associated with more potent responses against tumors and many infections, including HIV. Although an important determinant of T cell efficacy, it has proven difficult to selectively induce T cells of high functional avidity through vaccination. Attempts to induce high-avidity T cells by low-dose in vivo vaccination failed because this strategy simply gave no response. Instead, selective induction of high-avidity T cells has required in vitro culturing of specific T cells with low Ag concentrations. In this study, we combined low vaccine Ag doses with a novel potent cationic liposomal adjuvant, cationic adjuvant formulation 09, consisting of dimethyldioctadecylammonium liposomes incorporating two immunomodulators (monomycolyl glycerol analog and polyinosinic-polycytidylic acid) that efficiently induces CD4 Th cells, as well as cross-primes CD8 CTL responses. We show that vaccination with low Ag dose selectively primes CD4 T cells of higher functional avidity, whereas CD8 T cell functional avidity was unrelated to vaccine dose in mice. Importantly, CD4 T cells of higher functional avidity induced by low-dose vaccinations showed higher cytokine release per cell and lower inhibitory receptor expression (PD-1, CTLA-4, and the apoptosis-inducing Fas death receptor) compared with their lower-avidity CD4 counterparts. Notably, increased functional CD4 T cell avidity improved antiviral efficacy of CD8 T cells. These data suggest that potent adjuvants, such as cationic adjuvant formulation 09, render low-dose vaccination a feasible and promising approach for generating high-avidity T cells through vaccination.

In situ fabrication of a tunable microlens.

We demonstrate an optofluidic variable-focus microlens formed by a solid polydimethylsiloxane (PDMS) meniscus channel wall and a tunable liquid lens body. A novel method for in situ fabrication of the meniscus channel wall is developed by introducing liquid PDMS prepolymer into a microchannel followed by curing. Three-light manipulation techniques including tunable optical focusing, collimating, and diverging are realized by varying the refractive index (RI) of liquid lens body. Also, we present an absorption measurement of methylene blue (MB) with a collimated probing light, achieving a detection limit of 0.25 µM by using a 5-mm-long detection cell.

Pharmaceutical electrospinning and 3D printing scaffold design for bone regeneration.

Bone regenerative engineering provides a great platform for bone tissue regeneration covering cells, growth factors and other dynamic forces for fabricating scaffolds. Diversified biomaterials and their fabrication methods have emerged for fabricating patient specific bioactive scaffolds with controlled microstructures for bridging complex bone defects. The goal of this review is to summarize the points of scaffold design as well as applications for bone regeneration based on both electrospinning and 3D bioprinting. It first briefly introduces biological characteristics of bone regeneration and summarizes the applications of different types of material and the considerations for bone regeneration including polymers, ceramics, metals and composites. We then discuss electrospinning nanofibrous scaffold applied for the bone regenerative engineering with various properties, components and structures. Meanwhile, diverse design in the 3D bioprinting scaffolds for osteogenesis especially in the role of drug and bioactive factors delivery are assembled. Finally, we discuss challenges and future prospects in the development of electrospinning and 3D bioprinting for osteogenesis and prominent strategies and directions in future.

Targeted concurrent and sequential delivery of chemotherapeutic and antiangiogenic agents to the brain by using drug-loaded nanofibrous membranes.

Glioblastoma is the most frequent and devastating primary brain tumor. Surgery followed by radiotherapy with concomitant and adjuvant chemotherapy is the standard of care for patients with glioblastoma. Chemotherapy is ineffective, because of the low therapeutic levels of pharmaceuticals in tumor tissues and the well-known tumor-cell resistance to chemotherapy. Therefore, we developed bilayered poly(d,l)-lactide-co-glycolide nanofibrous membranes that enabled the sequential and sustained release of chemotherapeutic and antiangiogenic agents by employing an electrospinning technique. The release characteristics of embedded drugs were determined by employing an in vitro elution technique and high-performance liquid chromatography. The experimental results showed that the fabricated nanofibers showed a sequential drug-eluting behavior, with the release of high drug levels of chemotherapeutic carmustine, irinotecan, and cisplatin from day 3, followed by the release of high concentrations of the antiangiogenic combretastatin from day 21. Biodegradable multidrug-eluting nanofibrous membranes were then dispersed into the cerebral cavity of rats by craniectomy, and the in vivo release characteristics of the pharmaceuticals from the membranes were investigated. The results suggested that the nanofibrous membranes released high concentrations of pharmaceuticals for more than 8 weeks in the cerebral parenchyma of rats. The result of histological analysis demonstrated developmental atrophy of brains with no inflammation. Biodegradable nanofibrous membranes can be manufactured for long-term sequential transport of different chemotherapeutic and anti-angiogenic agents in the brain, which can potentially improve the treatment of glioblastoma multiforme and prevent toxic effects due to systemic administration.

Advanced interstitial chemotherapy combined with targeted treatment of malignant glioma in rats by using drug-loaded nanofibrous membranes.

Glioblastoma multiforme (GBM), the most prevalent and malignant form of a primary brain tumour, is resistant to chemotherapy. In this study, we concurrently loaded three chemotherapeutic agents [bis-chloroethylnitrosourea, irinotecan, and cisplatin; BIC] into 50:50 poly[(d,l)-lactide-co-glycolide] (PLGA) nanofibres and an antiangiogenic agent (combretastatin) into 75:25 PLGA nanofibres [BIC and combretastatin (BICC)/PLGA]. The BICC/PLGA nanofibrous membranes were surgically implanted onto the brain surfaces of healthy rats for conducting pharmacodynamic studies and onto C6 glioma-bearing rats for estimating the therapeutic efficacy.The chemotherapeutic agents were rapidly released from the 50:50 PLGA nanofibres after implantation, followed by the release of combretastatin (approximately 2 weeks later) from the 75:25 PLGA nanofibres. All drug concentrations remained higher in brain tissues than in the blood for more than 8 weeks. The experimental results, including attenuated malignancy, retarded tumour growth, and prolonged survival in tumour-bearing rats, demonstrated the efficacy of the BICC/PLGA nanofibrous membranes. Furthermore, the efficacy of BIC/PLGA and BICC/PLGA nanofibrous membranes was compared. The BICC/PLGA nanofibrous membranes more efficiently retarded the tumour growth and attenuated the malignancy of C6 glioma-bearing rats. Moreover, the addition of combretastatin did not significantly change the drug release behaviour of the BIC/PLGA nanofibrous membranes. The present advanced and novel interstitial chemotherapy and targeted treatment provide a potential strategy and regimen for treating GBM.

Biodegradable vancomycin-eluting poly[(d,l)-lactide-co-glycolide] nanofibres for the treatment of postoperative central nervous system infection.

The incidence of postoperative central nervous system infection (PCNSI) is higher than 5%-7%. Successful management of PCNSI requires a combined therapy of surgical debridement and long-term antibiotic treatment. In this study, Duraform soaked in a prepared bacterial solution was placed on the brain surface of rats to induce PCNSI. Virgin poly[(d,l)-lactide-co-glycolide] (PLGA) nanofibrous membranes (vehicle-control group) and vancomycin-eluting PLGA membranes (vancomycin-nanofibres group) were implanted. The wound conditions were observed and serial brain MRI and pathology examinations were performed regularly. PCNSI was consistently induced in a single, simple step. In the vehicle-control group, most rats died within 1 week, and the survival rate was low (odds ratio = 0.0357, 95% confidence interval = 0.0057-0.2254). The wounds and affected cerebral tissues necrosed with purulence and increased in mass from the resulting PCNSI volumes. Initially, the mean PCNSI volumes showed no significant difference between the two groups. The PCNSI volume in the rats in the vancomycin-nanofibres group significantly decreased (P < 0.01), and the wound appearance was excellent. Pathologic examinations revealed that the necrosis and leukocyte infiltration area decreased considerably. The experimental results suggest that vancomycin-eluting PLGA nanofibres are favourable candidates for treating PCNSI after surgical debridement.

Sustained release of bactericidal concentrations of penicillin in the pleural space via an antibiotic-eluting pigtail catheter coated with electrospun nanofibers: results from in vivo and in vitro studies.

BACKGROUND: Inadequate intrapleural drug concentrations caused by poor penetration of systemic antibiotics into the pleural cavity is a major cause of treatment failure in empyema. Herein, we describe a novel antibiotic-eluting pigtail catheter coated with electrospun nanofibers used for the sustained release of bactericidal concentrations of penicillin in the pleural space. METHODS: Electrospun nanofibers prepared using polylactide-polyglycolide copolymer and penicillin G sodium dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol were used to coat the surface of an Fr6 pigtail catheter. The in vitro patterns of drug release were tested by placing the catheter in phosphate-buffered saline. In vivo studies were performed using rabbits treated with penicillin either intrapleurally (Group 1, 20 mg delivered through the catheter) or systemically (Group 2, intramuscular injection, 10 mg/kg). Penicillin concentrations in the serum and pleural fluid were then measured and compared. RESULTS: In vitro studies revealed a burst release of penicillin (10% of the total dose) occurring in the first 24 hours, followed by a sustained release in the subsequent 30 days. Intrapleural drug levels were significantly higher in Group 1 than in Group 2 (P<0.001). In the former, penicillin concentrations remained above the minimum inhibitory concentration breakpoint throughout the entire study period. In contrast, serum penicillin levels were significantly higher in Group 2 than in Group 1 (P<0.001). Notably, all Group 2 rabbits showed signs of systemic toxicity (paralytic ileus and weight loss). CONCLUSION: We conclude that our antibiotic-eluting catheter may serve as a novel therapeutic option to treat empyema.

[The changes of bacteria group on oral mucosa after radiotherapy of postoperative patients of oral carcinoma].

OBJECTIVE: To investigate the microbial contents presented on the surface of mucosa in the oral cavity of patients who accepted radiotherapy, and to provide the evidences of controlling post-radiotherapeutic infections. METHODS: 32 patients (19 males and 13 females) aged from 37 - 72 received radiotherapy after oral squamous cell carcinomas operation were selected. Samples of saliva were obtained from the radiated center and opposite mucosa before and after radiotherapy. The detective amount, detective ratio and constituent ratio were analysed by cultivation and identification. RESULTS: Streptococci, Candida albicans and Pseudomonas aeruginosa significantly increased on both sides of the oral mucosa while Neisseria and Actinobacillus decreased on radiated region after the radiotherapy. CONCLUSION: Radiotherapy has great effects on oral bacteria and pathogenic organism may play a role in post-radiotherapy infections. It is necessary to do bacteria culture and choose sensitive antibiotics regularly for post-radiotherapeutic patients.