Design and Preclinical Evaluation of Chitosan/Kaolin Nanocomposites with Enhanced Hemostatic Efficiency.

In the current study, hemostatic compositions including a combination of chitosan and kaolin have been developed. Chitosan is a marine polysaccharide derived from chitins, a structural component in the shells of crustaceans. Both chitosan and kaolin have the ability to mediate a quick and efficient hemostatic effect following immediate application to injury sites, and thus they have been widely exploited in manufacturing of hemostatic composites. By combining more than one hemostatic agent (i.e., chitosan and kaolin) that act via more than one mechanism, and by utilizing different nanotechnology-based approaches to enhance the surface areas, the capability of the dressing to control bleeding was improved, in terms of amount of blood loss and time to hemostasis. The nanotechnology-based approaches utilized to enhance the effective surface area of the hemostatic agents included the use of Pluronic nanoparticles, and deposition of chitosan micro- and nano-fibers onto the carrier. The developed composites effectively controlled bleeding and significantly improved hemostasis and survival rates in two animal models, rats and rabbits, compared to conventional dressings and QuikClot® Combat Gauze. The composites were well-tolerated as demonstrated by their in vivo biocompatibility and absence of clinical and biochemical changes in the laboratory animals after application of the dressings.

Nanoparticles integrating natural and synthetic polymers for in vivo insulin delivery.

The aims of the current study were to develop insulin-loaded nanoparticles comprised of various polymers at different compositions, and to evaluate their ability to lower blood glucose levels in diabetic rats following subcutaneous and oral administrations. Several combinations of natural and synthetic polymers have been utilized for preparation of nanoparticles including, chitosan, alginate, albumin and Pluronic. Nanosized (170 nm-800 nm) spherical particles of high encapsulation efficiency (15-52%) have been prepared. Composition and ratios between the integrated polymers played a pivotal role in determining size, zeta potential, and in vivo hypoglycemic activity of particles. After subcutaneous and oral administration in diabetic rats, some of the insulin-loaded nanoparticles were able to induce much higher hypoglycemic effect as compared to the unloaded free insulin. For instance, subcutaneous injection of nanoparticles comprised of chitosan combined with sodium tripolyphosphate, Pluronic or alginate/calcium chloride, resulted in comparable hypoglycemic effects to free insulin, at two-fold lower dose. Nanoparticles were well-tolerated after oral administration in rats, as evidenced by by measuring levels of alanine aminotransferase, aspartate aminotransferases, albumin, creatinine and urea. This study indicates that characteristics and delivery efficiency of nanomaterials can be controlled via utilizing several natural/synthetic polymers and by fine-tuning of combination ratio between polymers.

Development and in vivo evaluation of chitosan nanoparticles for the oral delivery of albumin.

Albumin is used as a plasma expander in critically ill patients and for several other clinical applications mainly via intravenous infusion. Oral administration of albumin can improve patient compliance although limited oral bioavailability of proteins is still a major challenge. Although nanomaterials have been extensively utilized for improving oral delivery of proteins, albumin has been utilized only as either a model drug or as a carrier for drug delivery. In the current study, for the first time, chitosan nanoparticles have been developed and extensively optimized to improve oral bioavailability of albumin as a therapeutic protein. Several characterizations have been performed for the albumin-loaded nanoparticles (e.g. drug encapsulation efficiency, DSC, FTIR, particle size, zeta potential, morphology, release kinetics, and enzymatic stability). Nanosized spherical particles were prepared and demonstrated high stability over three months either in a powdered form or as suspensions. Sustained release of albumin over time and high enzymatic stability as compared to the free albumin were observed. In vivo, higher serum concentrations of albumin in normal rabbits and cirrhotic rats were attained following oral and intraperitoneal administrations of the albumin-loaded nanoparticles as compared to the free albumin. The nanoparticles developed in the current study might provide efficient nanovehicles for oral administration of therapeutic albumin.

Poly(glycerol methacrylate)-based degradable nanoparticles for delivery of small interfering RNA.

Nucleic acids therapeutic efficiency is generally limited by their low stability and intracellular bioavailability, and by the toxicity of the carriers used to deliver them to the target sites. Aminated poly(glycerol methacrylate) polymers are biodegradable and pH-sensitive polymers that have been used previously to deliver antisense oligonucleotide and show high transfection efficiency. The purpose of this study is to compare the efficiency and toxicity of aminated linear poly(glycerol methacrylate) (ALT) biodegradable polymer to the most commonly used cationic degradable (i.e. chitosan) and non-degradable (i.e. polyethylenimine (PEI)) polymers for delivery of short interfering RNA (siRNA). ALT, PEI and chitosan polymers were able to form nanosized particles with siRNA. Size, size-distribution and zeta-potential were measured over a wide range of nitrogen-to-phosphate (N/P) ratios, and the stability of the formed nanoparticles in saline and upon freeze-drying was also assessed. No significant cytotoxicity at the range of the tested concentrations of ALT and chitosan nanoparticles was observed, whereas the non-degradable PEI showed significant toxicity in huh-7 hepatocyte-derived carcinoma cell line. The safety profiles of the degradable polymers (ALT and chitosan) over non-degradable PEI were demonstrated in vitro and in vivo. In addition, ALT nanoparticles were able to deliver siRNA in vivo with significantly higher efficiency than chitosan nanoparticles. The results in the present study give evidence of the great implications of ALT nanoparticles in biomedical applications due to their biocompatibility, low cytotoxicity, high stability and simple preparation method.

Nanomedicine in management of hepatocellular carcinoma: Challenges and opportunities.

Hepatocellular carcinoma is the second leading cause of cancer deaths worldwide. It is characterized by unique features that can be utilized for selective and targeted therapy, which aids in preserving healthy tissues from deteriorating effects of traditional chemotherapeutics. In this minireview, a brief overview of recent drug delivery attempts for the management of hepatocellular carcinoma with the aid of nanomedical structures is presented. The beneficial impact of nanomaterials in terms of prolonged retention in blood and target sites, controlled biodistribution and improved stability of the encapsulated payloads, will be described, together with the possibility of incorporating more than one cargo into the same nanostructure. Incorporation of stimuli-responsive components, decoration with targeting moieties and the use of molecularly targeted drugs for treatment of hepatocellular carcinoma are also highlighted.

Hepaticojejunostomy with gastric access loop versus conventional hepaticojejunostomy: a randomized trial.

Roux-en-Y hepaticojejunostomy (RYHJ) with the provision of "gastric access loop" was developed to shorten the distance traveled by the endoscope to reach hepaticojejunostomy (HJ) anastomotic site. The aim of our study was to assess modified RYHJ with gastric access loop (RYHJ-GA) and compare it with conventional RYHJ (RYHJ-C) regarding short- and long-term outcomes and, moreover, to evaluate the feasibility and results of future endoscopic access of the modified bilio-enteric anastomosis. Patients eligible for RYHJ between September 2017 and December 2019 were allocated randomly to receive either RYHJ-C or RYHJ-GA. Fifty-two patients were randomly assigned to RYHJ-C (n = 26) or RYHJ-GA (n = 26). Three cases in RYHJ-C and 4 cases in RYHJ- GA developed HJ anastomotic stricture (HJAS) (P=0.68). 3 cases of RYHJ-GA had successful endoscopic dilation and balloon sweeping of biliary mud (one case) or stones (2 cases). Revisional surgery was needed in 2 cases of RYHJ-C and 1 case in RYHJ-GA (P=0.68). Modified RYHJ with gastric access loop is comparable to the classic hepaticojejunostomy regarding complications. However, gastric access enables easy endoscopic access for the management of future HJAS. This modification should be considered in patients with a high risk of HJAS during long-term follow-up.The trial registration number (TRN) and date of registration:ClinicalTrials.gov (NCT03252379), August 17, 2017.

Therapeutic Role of Subcutaneous Access Loop Created Adjunct to Hepaticojejunostomy for Management of Bile Duct Injury.

BACKGROUND: Roux-en-Y hepaticojejunostomy (RYHJ) is usually required for major bile duct injury (BDI) as a definitive treatment. Hepaticojejunostomy anastomotic stricture (HJAS) is the most feared long-term complication following RYHJ. The ideal management of HJAS remains undefined. The provision of permanent endoscopic access to the bilio-enteric anastomotic site can make endoscopic management of HJAS feasible and attractive option. In this cohort study, we aimed to evaluate short- and long-term outcomes of subcutaneous access loop created adjunct to RYHJ (RYHJ-SA) for management of BDI and its usefulness for endoscopic management of anastomotic stricture if occurred. MATERIALS AND METHODS: This is a prospective study including patients who were diagnosed with iatrogenic BDI and underwent hepaticojejunostomy with subcutaneous access loop between September 2017 and September 2019. RESULTS: This study included a total number of 21 patients whom ages ranged between 18 and 68 years. During follow-up, three cases had HJAS. One patient had the access loop in subcutaneous position. Endoscopy was done but failed to dilate the stricture. The other 2 patients had the access loop in subfascial position. Endoscopy of them failed to enter the access loop due to failure of fluoroscopy to identify the access loop. The three cases underwent redo-hepaticojejunostomy. Parajejunal (parastomal) hernia occurs in 2 patients in whom the access loop was fixed subcutaneous position. CONCLUSION: In conclusion, modified RYHJ with subcutaneous access loop (RYHJ-SA) is associated with reduced quality of life and patient satisfaction. Moreover, its role in endoscopic management of HJAS after biliary reconstruction for major BDI is limited.

Early Hepatoduodenal Ligament Occlusion Versus Classic Technique During Recipient Hepatectomy for Living Donor Liver Transplant.

OBJECTIVES: Intraoperative bleeding is commonly encountered during living donor liver transplant procedures and is associated with greater need for blood transfusion, which increases morbidity. Herein, we hypothesized that early and continuous occlusion ofthe hepatic inflow would have a beneficial effect on the living donor liver transplant procedure regarding intraoperative blood loss and operative time. MATERIALS AND METHODS: This comparative study prospectively included 23 consecutive patients (the experimental group) who had early inflow occlusion during recipient hepatectomy for living donor liver transplant and compared the outcomes versus 29 consecutive patients who had previously received (immediately before the start of our study) living donor liver transplant by the classic technique. Blood loss and time for hepatic mobilization and dissection were compared between the 2 groups. RESULTS: Patient criteria and indication for living donor liver transplant showed no significant difference between the 2 groups. There was a significant decrease in blood loss during hepatectomy in the study group versus the control group (2912 vs 3826 mL, respectively; P = .017). Packed red blood cell transfusion was less in the study group versus the control group (1550 vs 2350 cells, respectively; P < .001). The skin-to-hepatectomy time was not different between the 2 groups. CONCLUSIONS: Early hepatic inflow occlusion is a simple and effective technique to reduce intraoperative blood loss and reduce the need for blood transfusion products during living donor liver transplant.

Bilio-entero-gastrostomy: prospective assessment of a modified biliary reconstruction with facilitated future endoscopic access.

BACKGROUND: Hepaticojejunostomy (HJ) is the classical reconstruction for benign biliary stricture. Endoscopic management of anastomotic complications after hepaticojejunostomy is extremely difficult. In this work we assess a modified biliary reconstruction in the form of bilio-entero-gastrostomy (BEG) regarding the feasibility of endoscopic access to HJ and management of its stenosis if encountered. METHODS: From October 2008 till February 2011 all patients presented to the authors with benign biliary stricture who needed bilio-enteric shunt were considered. For each patient bilio-entero-gastrostomy (BEG) of either type I, II or III was constructed. In the fourth week postoperatively, endoscopy was performed to explore the possibility to access the biliary anastomosis and perform cholangiography. RESULTS: BEG shunt was performed for seventeen patients, one of whom, with BEG type I, died due to myocardial infarction leaving sixteen patients with a diagnosis of postcholecystectomy biliary injury (9), inflammatory stricture with or without choledocholithiasis (5) and strictured biliary shunt (2). BEG shunts were either type I (3), type II (3) or type III (10). Endoscopic follow up revealed successful access to the anastomosis in 14 patients (87.5%), while the access failed in one type I and one type II BEG (12.5%). Mean time needed to access the anastomosis was 12.6 min (2-55 min). On a scale from 1-5, mean endoscopic difficulty score was 1.7. One patient (6.25%), with BEG type I, developed anastomotic stricture after 18 months that was successfully treated endoscopically by stenting. These preliminary results showed that, in relation to the other types, type III BEG demonstrated the tendency to be surgically simpler to perform, endoscopicall faster to access, easier and with no failure. CONCLUSIONS: BEG, which is a modified biliary reconstruction, facilitates endoscopic access of the biliary anastomosis, offers management option for its complications, and, therefore, could be considered for biliary reconstruction of benign stricture. BEG type III tend to be surgically simpler and endoscopically faster, easier and more successful than type I and II.

Design of nanoconstructs that exhibit enhanced hemostatic efficiency and bioabsorbability.

Hemorrhage is a prime cause of death in civilian and military traumatic injuries, whereby a significant proportion of death and complications occur prior to paramedic arrival and hospital resuscitation. Hence, it is crucial to develop hemostatic materials that are able to be applied by simple processes and allow control over bleeding by inducing rapid hemostasis, non-invasively, until subjects receive necessary medical care. This tutorial review discusses recent advances in synthesis and fabrication of degradable hemostatic nanomaterials and nanocomposites. Control of assembly and fine-tuning of composition of absorbable (i.e., degradable) hemostatic supramolecular structures and nanoconstructs have afforded the development of smart devices and scaffolds capable of efficiently controlling bleeding while degrading over time, thereby reducing surgical operation times and hospitalization duration. The nanoconstructs that are highlighted have demonstrated hemostatic efficiency pre-clinically in animal models, while also sharing characteristics of degradability, bioabsorbability and presence of nano-assemblies within their compositions.

Major biliary complications in 2,714 cases of laparoscopic cholecystectomy without intraoperative cholangiography: a multicenter retrospective study.

BACKGROUND: The ongoing debate between routine and selective users of intraoperative cholangiography (IOC) during laparoscopic cholecystectomy (LC) has not yet come to an end. Routine users argue that IOC decreases the rate of biliary complications such as bile duct injury, biliary leak and missed common bile duct (CBD) stones, a claim that selective users do not fully support. On the other hand, a third policy that was adopted by many other centers is performing LC without IOC. In this retrospective study, we are exploring the results of a relatively large multicenter series of LC without IOC regarding major biliary complications. METHODS: We performed a retrospective analysis of LC cases operated by experienced laparoscopic surgeons, without resorting to IOC, in four surgical units of university hospitals in Egypt during a 6-year period (January 2004 through December 2009). Excluded from the study were cases with positive predictors of CBD stones, namely, sonographically detected CBD dilatation and/or CBD stones, elevated bilirubin and/or alkaline phosphatase, persistent biliary pancreatitis, cholangitis, and those who had preoperative magnetic resonance cholangiography. RESULTS: Of the 2,955 cases of LC reviewed, 241 were excluded, leaving 2,714 cases enrolled in the study. Fifty-five cases (2%) were converted to open surgery. Five cases (0.18%) had major bile duct injuries requiring surgical repair. Postoperative bile leakage was encountered in seven cases (0.26%). Missed CBD stones were reported in six cases (0.22%). There was no perioperative mortality in the present study. CONCLUSION: LC can be performed safely without the use of IOC, with acceptable low rates of biliary complications provided that proper detection of patients with silent CBD stones is done and facilities for pre- and postoperative endoscopic retrograde cholangiopancreatography are available.

Morphologic design of sugar-based polymer nanoparticles for delivery of antidiabetic peptides.

Zwitterionic polymer nanoparticles of diverse morphologies (spherical, cylindrical, and platelet-like) constructed from biocompatible sugar-based polymers are designed to extend the pharmacological activities of short- and long-acting insulin peptides, thereby providing potential for therapeutic systems capable of reducing the frequency of administration and improving patient compliance. Amphiphilic block copolymers composed of zwitterionic poly(d-glucose carbonate) and semicrystalline polylactide segments were synthesized, and the respective block length ratios were tuned to allow formation of nanoscopic assemblies having different morphologies. Insulin-loaded nanoparticles had similar sizes and morphologies to the unloaded nanoparticle counterparts. Laser scanning confocal microscopy imaging of three-dimensional spheroids of vascular smooth muscle cells and fibroblasts after treatment with LIVE/DEAD® stain and FITC-insulin-loaded nanoparticles demonstrated high biocompatibility for the nanoconstructs of the various morphologies and significant intracellular uptake of insulin in both cell lines, respectively. Binding of short-acting insulin and long-acting insulin glargine to nanoparticles resulted in extended hypoglycemic activities in rat models of diabetes. Following subcutaneous injection in diabetic rats, insulin- and insulin glargine-loaded nanoparticles of diverse morphologies had demonstrated up to 2.6-fold and 1.7-fold increase in pharmacological availability, in comparison to free insulin and insulin glargine, respectively. All together, the negligible cytotoxicity, immunotoxicity, and minimal cytokine adsorption onto nanoparticles (as have been demonstrated in our previous studies) provide exciting and promising evidence of biocompatible nanoconstructs that are poised for further development toward the management of diabetes.

Nanomedicine: a new paradigm to overcome drug incompatibilities.

OBJECTIVES: Drug incompatibilities may compromise the safety and effectiveness of combined drugs and result in mild-to-serious clinical complications, such as catheter obstruction, loss of drug efficacy, formation of toxic derivatives and embolism. Various preventive strategies have been implemented to overcome drug incompatibilities with limited success. This review presents an innovative approach to prevent drug incompatibilities via isolating the incompatible drugs into nanostructures. KEY FINDINGS: Several examples of incompatible drugs may be loaded separately into nanostructures of various types. Physicochemical characteristics and biocompatibility of the nanomaterials that are being utilized to prevent physicochemical incompatibilities should be carefully considered. CONCLUSIONS: There is a new era of exploiting nanomaterials in overcoming various types of physicochemical incompatibilities, with additional benefits of further improvements in pharmacokinetic profiles and pharmacological actions of the administered drugs.

Absorbable hemostatic hydrogels comprising composites of sacrificial templates and honeycomb-like nanofibrous mats of chitosan.

The development of hemostatic technologies that suit a diverse range of emergency scenarios is a critical initiative, and there is an increasing interest in the development of absorbable dressings that can be left in the injury site and degrade to reduce the duration of interventional procedures. In the current study, ß-cyclodextrin polyester (CDPE) hydrogels serve as sacrificial macroporous carriers, capable of degradation under physiological conditions. The CDPE template enables the assembly of imprinted chitosan honeycomb-like monolithic mats, containing highly entangled nanofibers with diameters of 9.2 ± 3.7 nm, thereby achieving an increase in the surface area of chitosan to improve hemostatic efficiency. In vivo, chitosan-loaded cyclodextrin (CDPE-Cs) hydrogels yield significantly lower amounts of blood loss and shorter times to hemostasis compared with commercially available absorbable hemostatic dressings, and are highly biocompatible. The designed hydrogels demonstrate promising hemostatic efficiency, as a physiologically-benign approach to mitigating blood loss in tissue-injury scenarios.

Pancreatic Pseudocyst Dilemma: Cumulative Multicenter Experience in Management Using Endoscopy, Laparoscopy, and Open Surgery.

BACKGROUND: Pancreatic pseudocyst (PP) is the commonest cystic lesion of the pancreas. Internal drainage of PPs can be accomplished by traditional open or recently by minimally invasive laparoscopic or endoscopic approaches. We aimed to evaluate and compare the clinical outcomes after endoscopic, laparoscopic, and open drainage. METHODS: Seventy-one patients with PP underwent endoscopic (n = 35), laparoscopic (n = 4), and open surgical drainage (n = 32). The primary outcome was the success rate. The secondary outcomes were the estimated blood loss, operative time, opioid requirement, morbidity and mortality, length of hospital stay, and recurrence rate. RESULTS: The primary success rate was significantly higher for laparoscopic and open groups than for the endoscopic group, but the overall success rate was equivalent across the groups. There were no significant differences in the morbidity, mortality, requirement of blood transfusion, reinterventions, and recurrence rate between the groups. Endoscopic drainage revealed significantly lower blood loss, operative time, opioid requirement, and hospital stay in comparison to open and laparoscopic drainage. CONCLUSION: Minimally invasive therapeutic techniques, whether endoscopic or laparoscopic for treatment of PP could be considered valuable, competitive, and promising alternatives for open surgery. Moreover, it is less invasive with less hospitalization and rapid return to work.

Niosomes: A Strategy toward Prevention of Clinically Significant Drug Incompatibilities.

Drug incompatibilities are considered as one of the most critical problems in intensive care units. In the current study, the ability of nanomaterials to prevent drug incompatibilities in clinical settings has been investigated. As a proof-of-concept, the ability of niosomes to prevent physical and chemical incompatibilities that occur upon mixing acyclovir and vancomycin during management of acute meningitis has been explored. Nanosized spherical particles loaded separately with either vancomycin or acyclovir, with high entrapment efficiency (ca. 46-56%), could be prepared, and sustained release of their entrapped cargoes have been demonstrated over time. We have shown that precipitation, degradation and loss of biological activity of drugs occurred upon mixing solutions of the free drugs. On the contrary, drugs loaded separately inside niosomal structures exhibited high stability, exceptional physical and chemical compatibilities for up to 48 h with complete preservation of the antimicrobial activity of vancomycin. This study opens a venue for a new spectrum of applications of nanomaterials in preventing clinically significant drug incompatibilities, aiming at the reduction of adverse reactions, cost and hospitalization period, and improvement of patient compliance and therapeutic outcomes.

Ultrahigh antibacterial efficacy of meropenem-loaded chitosan nanoparticles in a septic animal model.

Antimicrobial resistance is one of the most significant health challenges worldwide. Meropenem is a broad spectrum beta-lactam antibiotic that possesses high activity against Gram-positive and Gram-negative bacteria. However, it has a short plasma half-life, and thus requiring frequent administration of high doses. For the first time, meropenem-loaded chitosan nanoparticles were prepared and evaluated as a potential tool to overcome antimicrobial resistance and to improve pharmacokinetics of the drug. Spherical nanosized particles were prepared and demonstrated ultrahigh encapsulation efficiency of meropenem (i.e. 76.3%). The nanoparticles could be stored in a freeze-dried powdered form while maintaining their physicochemical characteristics. In vitro, higher antibacterial activities of the drug-loaded nanoparticles were observed against methicillin-sensitive and methicillin-resistant Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae, as compared to the free drug. The nanoparticles were then tested in a septic rat model of Klebsiella pneumoniae and showed exceptional improvement of survival and bacterial clearance, as compared to the animals treated with the free drug. Hence, meropenem-loaded chitosan nanoparticles might have great potential for overcoming antimicrobial resistance.

In vitro and in vivo evaluation of biologically synthesized silver nanoparticles for topical applications: effect of surface coating and loading into hydrogels.

In the present study, silver nanoparticles (AgNPs) were synthesized via biological reduction of silver nitrate using extract of the fungus Fusarium verticillioides (green chemistry principle). The synthesized nanoparticles were spherical and homogenous in size. AgNPs were coated with polyethylene glycol (PEG) 6000, sodium dodecyl sulfate (SDS), and ß-cyclodextrin (ß-CD). The averaged diameters of AgNPs were 19.2±3.6, 13±4, 14±4.4, and 15.7±4.8 nm, for PEG-, SDS-, and ß-CD-coated and uncoated AgNPs, respectively. PEG-coated AgNPs showed greater stability as indicated by a decreased sedimentation rate of particles in their water dispersions. The antibacterial activities of different AgNPs dispersions were investigated against Gram-positive bacteria (methicillin-sensitive and methicillin-resistant Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli) by determination of the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs). MIC and MBC values were in the range of 0.93-7.5 and 3.75-15 µg/mL, respectively, which were superior to the reported values in literature. AgNPs-loaded hydrogels were prepared from the coated-AgNPs dispersions using several gelling agents (sodium carboxymethyl cellulose [Na CMC], sodium alginate, hydroxypropylmethyl cellulose, Pluronic F-127, and chitosan). The prepared formulations were evaluated for their viscosity, spreadability, in vitro drug release, and antibacterial activity, and the combined effect of the type of surface coating and the polymers utilized to form the gel was studied. The in vivo wound-healing activity and antibacterial efficacy of Na CMC hydrogel loaded with PEG-coated AgNPs in comparison to the commercially available silver sulfadiazine cream (Dermazin®) were evaluated. Superior antibacterial activity and wound-healing capability, with normal skin appearance and hair growth, were demonstrated for the hydrogel formulations, as compared to the silver sulfadiazine cream. Histological examination of the treated skin was performed using light microscopy, whereas the location of AgNPs in the skin epidermal layers was visualized using transmission electron microscopy.

Polyphosphoester nanoparticles as biodegradable platform for delivery of multiple drugs and siRNA.

Delivery of multiple therapeutics and/or diagnostic agents to diseased tissues is challenging and necessitates the development of multifunctional platforms. Among the various strategies for design of multifunctional nanocarriers, biodegradable polyphosphoester (PPE) polymers have been recently synthesized via a rapid and simple synthetic strategy. In addition, the chemical structure of the polymer could be tuned to form nanoparticles with varying surface chemistries and charges, which have shown exceptional safety and biocompatibility as compared to several commercial agents. The purpose of this study was to exploit a mixture of PPE nanoparticles of cationic and neutral surface charges for multiple delivery of anticancer drugs (ie, sorafenib and paclitaxel) and nucleic acids (ie, siRNA). Cationic PPE polymers could efficiently complex siRNA, and the stability of the nanoparticles could be maintained in physiological solutions and upon freeze-drying and were able to deliver siRNA in vivo when injected intravenously in mice. Commercially available cationic polyethylenimine polymer had LD50 of ca. 61.7 mg/kg in mice, whereas no animal died after injection of the cationic PPE polymer at a dose of >130 mg/kg. Neutral PPE nanoparticles were able to encapsulate two hydrophobic drugs, namely, sorafenib and paclitaxel, which are commonly used for the treatment of hepatocellular carcinoma. Mixing the neutral and cationic PPE nanoparticles did not result in any precipitation, and the size characteristics of both types of nanoparticles were maintained. Hence, PPE polymers might have potential for the delivery of multiple drugs and diagnostic agents to diseased tissues via simple synthesis of the individual polymers and assembly into nanoparticles that can host several drugs while being mixed in the same administration set, which is of importance for industrial and clinical development.

Novel technique for biliary reconstruction using an isolated gastric tube with a vascularized pedicle: a live animal experimental study and the first clinical case.

BACKGROUND: Biliary tract reconstruction continues to be a challenging surgical problem. Multiple experimental attempts have been reported to reconstruct biliary defects with different materials and variable outcome. Our aim was to evaluate a new method for biliary reconstruction using an isolated pedicled gastric tube in a live animal trial and also to present the first clinical case. METHODS: Seven mongrel dogs underwent biliary reconstruction using gastric tube harvested, completely separated from the greater curvature, and based on a vascularized pedicle with the right gastroepiploic vessels. The tube was interposed between the common bile duct (CBD) and the duodenum. Postoperative mortality, morbidity, liver functions, gross and microscopic histological picture were assessed. The first clinical case was also presented where, in a patient with post-cholecystectomy biliary injury, an isolated pedicled gastric tube was interposed between the proximal and distal ends of the CBD. RESULTS: One dog did not recover from anesthesia and another one died postoperatively from septic peritonitis. Five dogs survived the procedure and showed uneventful course and no cholestasis. The mean anastomotic circumference was 4.8 mm (range 4-6) for CBD anastomosis and 6.2 mm (range 5-7) for duodenal anastomosis. Histologically, anastomotic sites showed good evidence of healing. In the first clinical case, the patient showed clinical and biochemical improvement. Endoscopic retrograde cholangiography was feasible and assured patent biliary anastomoses. CONCLUSION: In mongrel dogs, biliary reconstruction using pedicled gastric tube interposition between CBD and duodenum is feasible with satisfactory clinical results, anastomotic circumference and histological evidence of healing. The technique is also feasible in human and seems to be promising.