Mucin-mediated mucosal retention via end-terminal modified Pluronic F127-based hydrogel to increase drug accumulation in the lungs.

Noninvasive lung drug delivery is critical for treating respiratory diseases. Pluronic-based copolymers have been used as multifunctional materials for medical and biological applications. However, the Pluronic F127-based hydrogel is rapidly degraded, adversely affecting the mechanical stability for prolonged drug release. Therefore, this study designed two thermosensitive copolymers by modifying the Pluronic F127 terminal groups with carboxyl (ADF127) or amine groups (EDF127) to improve the viscosity and storage modulus of drug formulations. ß-alanine and ethylenediamine were conjugated at the terminal of Pluronic F127 using a two-step acetylation process, and the final copolymers were characterized using 1H nuclear magnetic resonance (1H NMR) and Fourier-transform infrared spectra. According to the 1H NMR spectra, Pluronic F127 was functionalized to form ADF127 and EDF127 with 85 % and 71 % functionalization degrees, respectively. Rheological studies revealed that the ADF127 (15 wt%) and EDF127 (15 wt%) viscosities increased from 1480 Pa.s (Pluronic F127) to 1700 Pa.s and 1800 Pa.s, respectively. Furthermore, the elastic modulus of ADF127 and EDF127 increased, compared with that of native Pluronic F127 with the addition of 5 % mucin, particularly for ADF127, thereby signifying the stronger adhesive nature of ADF127 and EDF127 with mucin. Additionally, ADF127 and EDF127 exhibited a decreased gelation temperature, decreasing from 33 °C (Pluronic F127 at 15 wt%) to 24 °C. Notably, the in vitro ADF127 and EDF127 drug release was prolonged (95 %; 48 h) by the hydrogel encapsulation of the liposome-Bdph combined with mucin, and the intermolecular hydrogen bonding between the mucin and the hydrogel increased the retention time and stiffness of the hydrogels. Furthermore, ADF127 and EDF127 incubated with NIH-3T3 cells exhibited biocompatibility within 2 mg/mL, compared with Pluronic F127. The nasal administration method was used to examine the biodistribution of the modified hydrogel carrying liposomes or exosomes with fluorescence using the IVIS system. Drug accumulation in the lungs decreased in the following order: ADF127 > EDF127 > liposomes or exosomes alone. These results indicated that the carboxyl group-modified Pluronic F127 enabled well-distributed drug accumulation in the lungs, which is beneficial for intranasal administration routes in treating diseases such as lung fibrosis.

Hofmeister effect-based soaking strategy for gelatin hydrogels with adjustable gelation temperature, mechanical properties, and ionic conductivity.

As a natural polymer with good biocompatibility, gelatin hydrogel has been widely used in the field of biomedical science for a long time. However, the lack of suitable gelation temperature and mechanical properties often limit the clinical applicability in diverse and complex environments. Here, we proposed a strategy based on the Hofmeister effect that gelatin hydrogels were soaked in the appropriate concentration of sodium sulfate solution, and the change in molecular chain interactions mainly guided by kosmotropic ions resulted in a comprehensive adjustment of multiple properties. A series of gelatin hydrogels treated with different concentrations of the salt solution gave rise to microstructural changes, which brought a decrease in the number and size of pores, a wide range of gelation temperature from 32 °C to 46 °C, a stress enhancement of about 40 times stronger to 0.8345 MPa, a strain increase of about 7 times higher to 238.05 %, and a certain degree of electrical conductivity to be utilized for versatile applications. In this regard, for example, we prepared microneedles and obtained a remarkable compression (punctuation) strength of 0.661 N/needle, which was 55 times greater than those of untreated ones. Overall, by integrating various characterizations and suggesting the corresponding mechanism behind the phenomenon, this method provides a simpler and more convenient performance control procedure. This allowed us to easily modulate the properties of the hydrogel as per the intended purpose, revealing its vast potential applications such as smart sensors, electronic skin, and drug delivery.

Fabrication of self-assembled vesicle nanoparticles of poly(l-lysine)-arachidic acid conjugates for a vascular endothelial growth factor carrier.

Numerous growth factors account for tissue and organ development and therapeutic efficiency. Hence, the delivery of growth factors is crucial in regenerative medical practice. However, the delivery of a single factor to regenerate tissues lacks clinical utility in many current approaches. We reported the delivery of the bioactive vascular endothelial growth factor (VEGF) from novel polymeric vesicles. Polymeric vesicles were prepared from the poly(l-lysine)-g-polylysine(AA) amphiphilic graft copolymer through the conjugation of arachidic acid (AA) with poly(l-lysine) for obtaining a VEGF carrier. The prepared copolymer can form a polymersome and effectively condense with VEGF without affecting its size and surface charges. The Gaussian curve fit (GCF) of amide I band were revealed that VEGF efficiently interact through the α-helix of the amphiphilic graft copolymer rather than ß-sheet dominated poly(l-lysine). The polymersome-VEGF complex showed a considerably higher binding affinity, transfection efficiency, and less toxicity because of the peptide-based polymer backbone. Compared with the poly(l-lysine)-VEGF complex, polymersome-VEGF revealed a high secretion of VEGF and low toxicity. These polymersomes can deliver angiogenic factors in a controlled manner in tissue regeneration and biomedical engineering.

Formation of gold decorated porphyrin nanoparticles and evaluation of their photothermal and photodynamic activity.

A core-shell gold (Au) nanoparticle with improved photosensitization have been successfully fabricated using Au nanoparticles and 5,10,15,20 tetrakis pentafluorophenyl)-21H,23H-porphine (PF6) dye, forming a dyad through molecular self-assembly. Au nanoparticles were decorated on the shell and PF6 was placed in the core of the nanoparticles. Highly stable Au nanoparticles were achieved using PF6 with poly(N-vinylcaprolactam-co-N-vinylimidazole)-g-poly(D,L-lactide) graft copolymer hybridization. This was compared with hybridization using cetyltrimethylammonium bromide and polyethylene glycol-b-poly(D,L-lactide) for shell formation with PF6-Au. The resulting PF6-poly(N-vinylcaprolactam-co-N-vinylimidazole)-g-poly(D,L-lactide)-Au core-shell nanoparticle were utilized for photothermal and photodynamic activities. The spectroscopic analysis and zeta potential values of micelles revealed the presence of a thin Au layer coated on the PF6 nanoparticle surface, which generally enhanced the thermal stability of the gold nanoparticles and the photothermal effect of the shell. The core-shell PF6-Au nanoparticles were avidly taken up by cells and demonstrated cellular phototoxicity upon irradiation with 300W halogen lamps. The structural arrangement of PF6 dyes in the core-shell particles assures the effectiveness of singlet oxygen production. The study verifies that PF6 particles when companied with Au nanoparticles as PF6-Au have possible combinational applications in photodynamic and photothermal therapies for cancer cells because of their high production of singlet oxygen and heat.

Drug-loading capacity and nuclear targeting of multiwalled carbon nanotubes grafted with anionic amphiphilic copolymers.

In this study, three types of hybrid nanotubes (NTs), ie, oxidized multiwalled carbon NTs (COOH MWCNTs), heparin (Hep)-conjugated MWCNTs (Hep MWCNTs), and diblock copolymer polyglycolic acid (PGA)-co-heparin conjugated to MWCNTs (PGA MWCNTs), were synthesized with improved biocompatibility and drug-loading capacity. Hydrophilic Hep substituents on MWCNTs improved biocompatibility and acted as nucleus-sensitive segments on the CNT carrier, whereas the addition of PGA enhanced drug-loading capacity. In the PGA MWCNT system, the amphiphilic copolymer (PGA-Hep) formed micelles on the side walls of CNTs, as confirmed by electron microscopy. The PGA system encapsulated the hydrophobic drug with high efficiency compared to the COOH MWCNT and Hep MWCNT systems. This is because the drug was loaded onto the PGA MWCNTs through hydrophobic forces and onto the CNTs by π-π stacking interactions. Additionally, most of the current drug-carrier designs that target cancer cells release the drug in the lysosome or cytoplasm. However, nuclear-targeted drug release is expected to kill cancer cells more directly and efficiently. In our study, PGA MWCNT carriers effectively delivered the active anticancer drug doxorubicin into targeted nuclei. This study may provide an effective strategy for the development of carbon-based drug carriers for nuclear-targeted drug delivery.

Development of pH-sensitive pectinate/alginate microspheres for colon drug delivery.

The purposes of this study were to develop and evaluate calcium pectinate/alginate microspheres (PAMs) and to exploit their pH-sensitive properties for colon-targeted delivery of encapsulated cisplatin. PAMs were prepared using an electrospraying method. The PAMs, as cores, were then coated with Eudragit S100 using a polyelectrolyte multilayer coating technique in aqueous solution. The morphology of the microspheres was observed under scanning electron microscopy. In vitro drug release studies were performed in simulated gastrointestinal fluid, and the results indicated that approximately 5 % of the cisplatin was released from the Eudragit S100-coated PAMs, and 51 % of the cisplatin was released from the uncoated PAMs at 1 h. The release of cisplatin from the Eudragit S100-coated PAMs was more sustained in simulated gastric fluid than in simulated intestinal fluid due to the increased solubility of the coating polymer in media with pH >7.0. Drug release from the Eudragit S100-coated PAMs was best described by the Higuchi's square root model. From these results, it was concluded that Eudragit S100-coated PAMs are a potential carrier for delivery of cisplatin to the colon.

Relationship between neurogenic bowel dysfunction and health-related quality of life in persons with spinal cord injury.

OBJECTIVE: To assess the relationship between the severity of neurogenic bowel and health-related quality of life in persons with various degrees of spinal cord injury. DESIGN: Cross-sectional. SUBJECTS: A total of 128 people with spinal cord injury. METHODS: Two questionnaires were sent out by post. One included demographic characteristics and a neurogenic bowel dysfunction score to evaluate the severity of neurogenic bowel dysfunction. The other was a Short-Form 36-Item Health Survey that evaluated the quality of life in persons with spinal cord injury. RESULTS: Approximately half of the persons with spinal cord injury (46.9%) had moderate to severe degrees of neurogenic bowel dysfunction, the severity of which was associated with the physical functioning and physical component summary score in health-related quality of life. The results also showed that more severe neurological classifications led to lower physical component summary scores for impaired physical function and bodily pain. There was no correlation between the length of time elapsed since injury and health-related quality of life. Persons with more severe neurogenic bowel conditions were also found to be more likely to receive rehabilitative therapy. CONCLUSION: Neurogenic bowel dysfunction is associated with health-related quality of life expression in persons with spinal cord injury, especially in physical functioning and physical component summary.

Association of C-reactive protein and insulin resistance in patients with chronic spinal cord injury.

OBJECTIVE: To study the association between C-reactive protein levels and insulin resistance in patients with spinal cord injury. DESIGN: Cross-sectional study. SUBJECTS: Forty-two subjects who had sustained spinal cord injuries at least 6 months before enrollment. METHODS: Circulating glucose, insulin and C-reactive protein levels were measured after 12 hours' fasting. The homeo-stasis model insulin resistance index was used to evaluate insulin resistance. Insulin resistance and C-reactive protein levels were compared between complete/incomplete patients and between paraplegic/tetraplegic patients. The subjects were then divided into 3 groups (C-reactive protein levels < 1, 1-3, > 3 mg/l) to compare insulin resistance. RESULTS: Eighteen (43%) subjects had C-reactive protein levels > 3 mg/l. The C-reactive protein levels and insulin resistance did not significantly differ between complete/incomplete or between paraplegic/tetraplegic subjects. However, insulin resistance in the high C-reactive protein group (>3 mg/l) differed significantly from that of the other 2 groups, and there was a significant correlation between C-reactive protein and insulin resistance, with r=0.7745. CONCLUSION: Most young and middle-aged patients with chronic spinal cord injury with high C-reactive protein levels also have high insulin resistance, and their C-reactive protein levels have well correlated with insulin resistance.

Effect of glycemic control on electrophysiologic changes of diabetic neuropathy in type 2 diabetic patients.

Diabetic neuropathy is a common complication of diabetes mellitus. Effective blood glucose control retards changes in nerve conduction velocity in type 1 diabetes. This study examined the relationship between glycemic control and electrophysiologic changes in diabetic neuropathy in 57 type 2 diabetic patients. Nerve conduction in the peroneal motor nerve, tibial motor nerve, and sural nerve were measured at study entry and at follow-up 24+/-3.12 months later. Changes in individual nerves are expressed as a percentage change (PC) and overall electrophysiologic changes are expressed as the sum of individual PCs. The PCs for peroneal motor nerve velocity, tibial motor nerve velocity, and sural nerve velocity were all lower in patients with a mean HbA1c of 8.5% or less compared with those in patients with a mean HbA1c of more than 8.5%, and SPCV (sum of PC in velocity) was significantly inversely correlated with mean HbA1c. However, there was no significant difference in SPCV in subjects with or without hypertension, hypertriglyceridemia, or low high-density lipoprotein cholesterol concentration. In conclusion, hyperglycemia is the most important etiology for electrophysiologic progression in type 2 diabetic patients. Furthermore, a mean HbA1c of more than 8.5% will result in significant deterioration in electrophysiology.