Folic Acid-Chitosan Oligosaccharide Conjugates Decorated Nanodiamond as Potential Carriers for the Oral Delivery of Doxorubicin.

Oral administration of doxorubicin (DOX) is preferred but challenged owing to poor permeability in the gastrointestinal tract (GIT), efflux of P-glycoprotein, short residence time in the intestine, and rapid hydrolysis. Herein, folic acid-chitosan oligosaccharide conjugate (FA-COS)-modified hydroxylated nanodiamond (ND-OH) was designed to enhance the oral bioavailability of DOX. The carboxyl surface of ND was modified into hydroxyl terminal group to increase the colloidal stability of the system under different pH conditions in GIT. FA-COS modification could prolong retention time, endow the drug with sustained release properties, and actively target intestinal FA receptors. In contrast to DOX/ND-OH, the particle size of DOX/ND-OH/FA-COS increased from 189.5 ± 2.8 to 224.5 ± 1.4 nm, and the zeta potential reversed from - 9.1 ± 0.2 to 14.8 ± 0.4 mV. At 48 h, DOX/ND-OH and DOX/ND-OH/FA-COS released 69.07 ± 5.70% and 35.87 ± 5.64%, respectively. FA-COS modification effectively enhanced the cytotoxicity and intracellular uptake of ND-OH/DOX by Caco-2 cells and prolonged intestinal retention in rats. The internalization of DOX/ND-OH and DOX/ND-OH/FA-COS was mainly mediated by energy-dependent clathrin- and caveolae-mediated endocytosis pathways. Pharmacokinetic study demonstrated that the AUC0-t of DOX/ND-OH and DOX/ND-OH/FA-COS was enhanced by 3.94- and 6.08-fold compared to DOX solution, respectively. These results illustrated that DOX/ND-OH/FA-COS could be an effective strategy to enhance the oral bioavailability of DOX.

Nanodiamond-based multifunctional platform for oral chemo-photothermal combinational therapy of orthotopic colon cancer.

Combination therapy system has become a promising strategy for achieving favorable antitumor efficacy. Herein, a novel oral drug delivery system with colon localization and tumor targeting functions was designed for orthotopic colon cancer chemotherapy and photothermal combinational therapy. The polydopamine coated nanodiamond (PND) was used as the photothermal carrier, through the coupling of sulfhydryl-polyethylene glycol-folate (SH-PEG-FA) on the surface of PND to achieve systematic colon tumor targeting, curcumin (CUR) was loaded as the model drug, and then coated with chitosan (CS) to achieve the long gastrointestinal tract retention and colon localization functions to obtain PND-PEG-FA/CUR@CS nanoparticles. It has high photothermal conversion efficiency and good photothermal stability and exhibited near-infrared (NIR) laser-responsive drug release behavior. Folate (FA) modification effectively promotes the intracellular uptake of nanoparticles by CT26 cells, and the combination of chemotherapy and photothermal therapy (CT/PTT) can enhance cytotoxicity. Compared with free CUR group, nanoparticles prolonged the gastrointestinal tract retention time, accumulated more in colon tumor tissues, and exhibited good photothermal effect in vivo. More importantly, the CT/PTT group exhibited satisfactory tumor growth inhibition effects with good biocompatibility in vivo. In summary, this oral drug delivery system is an efficient platform for chemotherapy and photothermal combinational therapy of orthotopic colon cancer.

Eudragit S100 coated nanodiamond-based nanoparticles as an oral chemo-photothermal delivery system for local treatment of colon cancer.

Oral colonic nano-drug delivery system has received more and more attention in the treatment of colon cancer due to local precision treatment and reduction of drug system distribution. However, the complex and harsh gastrointestinal environment and the retention of nanoparticles in the colon limit its development. To this end, we designed Eudragit S100 (ES) coated nanoparticles (ES@PND-PEG-TPP/DOX). Polydopamine coated nanodiamond (PND) was modified with amino-functionalized polyethylene glycol (NH2-PEG-NH2) and triphenylphosphine (TPP) successively. Due to the high specific surface area of PND, it can efficiently load the model drug doxorubicin hydrochloride (DOX). In addition, PND also has high photothermal conversion efficiency, generating heat to kill cancer cells under near infrared (NIR) laser, realizing the combination of chemotherapy and photothermal therapy (CT-PTT). TPP modification enhanced nanoparticle uptake by colon cancer cells and prolonged preparations retention time at the colon. ES shell protected the drug from being destroyed and prevented the nanoparticles from sticking to the small intestine. Ex vitro fluorescence imaging showed that TPP modification can enhance the residence time of nanoparticles in the colon. In vivo pharmacodynamics demonstrated that CT-PTT group has the greatest inhibitory effect on tumor growth, which means that the nanocarrier has potential clinical value in the in-situ treatment of colon cancer.

Reconstructed Hierarchically Structured Keratin Fibers with Shape-Memory Features Based on Reversible Secondary-Structure Transformation.

Biocompatible and biodegradable shape-memory polymers have gained popularity as smart materials, offering a wide range of applications and environmental benefits. Herein, the possibility of fabricating regenerated water-triggered shape-memory keratin fibers from wool and cellulose in a more effective and environmentally friendly manner is investigated. The regenerated keratin fibers exhibit comparable shape-memory performance to other hydration-responsive materials, with a shape-fixity ratio of 94.8 ± 2.15% and a shape-recovery rate of 81.4 ± 3.84%. Owing to their well-preserved secondary structure and cross-linking network, keratin fibers exhibit outstanding water-stability and wet stretchability, with a maximum tensile strain of 362 ± 15.9%. In this system, the reconfiguration of the protein secondary structure between α-helix and ß-sheet is investigated as the fundamental actuation mechanism in response to hydration. This responsiveness is studied under force loading and unloading along the fiber axis. Hydrogen bonds act as the "switches" clicked by water molecules to trigger the shape-memory effect, while disulfide bonds and cellulose nanocrystals play the role of "net-points" to maintain the permanent shape of the material. Water-triggered shape-memory keratin fibers are manipulable and exhibit potential in the fabrication of textile actuators, which may be applied in smart apparel and programmable biomedical devices.

Discovery of the Potent and Highly Selective PARP7 Inhibitor as a Novel Immunotherapeutic Agent for Tumors.

PARP7, a polyadenosine diphosphate-ribose polymerase, has been identified as a negative regulator in type I interferon (IFN) signaling. An overexpression of PARP7 is typically found in a wide range of cancers and can lead to the suppression of type I IFN signaling and innate immune response. Herein, we describe the discovery of compound I-1, a novel PARP7 inhibitor with high inhibitory potency (IC50 = 7.6 nM) and selectivity for PARP7 over other PARPs. Especially, I-1 has excellent pharmacokinetic properties and low toxicity in mice and exhibits significantly stronger in vivo antitumor potency (TGI: 67%) than RBN-2397 (TGI: 30%) without the addition of 1-aminobenzotriazole (a nonselective and irreversible inhibitor of cytochrome P450) in CT26 syngeneic mouse models. Our findings reveal that I-1 mainly acts as an immune activator through PARP7 inhibition in the tumor microenvironment, which highlights the potential advantages of I-1 as a tumor immunotherapeutic agent.

A composite System Combining Self-Targeted Carbon Dots and Thermosensitive Hydrogels for Challenging Ocular Drug Delivery.

We developed a composite system combining self-targeted carbon dots and thermosensitive in situ hydrogels for ocular drug delivery of diclofenac sodium (DS). DS-CDC-HP nanoparticles were prepared by loading DS on the surface of CDC-HP via electrostatic interactions. An orthogonal experimental design was selected to screen the optimal thermosensitive hydrogel matrices and then DS-CDC-HP nanoparticles were embedded to form the composite system. The physicochemical properties and release behavior of this system were characterized, and in vivo fluorescence imaging was carried out. Corneal penetrability and in vitro cellular studies (cytotoxicity, cell imaging and cell uptake) were performed to test the feasibility and potential of this ocular delivery system. Finally, the optimal gel matrix consisting of Poloxamer 407: Poloxamer 188: HPMC E50 was 21:1:1 (w/v %), and the gelation temperature before adding artificial tear fluid was 26.67°C and 34.29°C, respectively. This system has the characteristics of biphasic drug release. In addition, the corneal penetrability and in vivo fluorescence study indicated that corneal transmittance was enhanced and drug retention time was extended. Cellular studies revealed that the DS-CDC-HP-Gel has good cytocompatibility and CD44 targeting. In summary, this composite system combines carbon dots with hydrogels, offering new potential for ocular drug delivery.

Easy Synthesis and Characterization of Novel Carbon Dots Using the One-Pot Green Method for Cancer Therapy.

In this study, hyaluronic acid (HA) and carboxymethyl chitosan (CMCS) were used for the synthesis of novel targeted nanocarrier carbon dots (CDC-H) with photo-luminescence using a one-step hydrothermal method. Doxorubicin (DOX), a common chemotherapeutic agent, was loaded with the CDC-H through electrostatic interactions to form DOX-CDC-H complexes as a targeted antitumor drug delivery system. The synthesized CDC-H show a particle size of approximately 6 nm and a high fluorescence quantum yield of 11.64%. The physical and chemical character properties of CDC-H and DOX-CDC-H complexes were investigated using various techniques. The results show that CDC-H have stable luminescent properties and exhibit excellent water solubility. The in vitro release study showed that DOX-CDC-H exhibited pH-dependent release for 24 h. Confocal laser scanning microscopy was applied to investigate the potential of CDC-H for cell imaging and the cellular uptake of DOX-CDC-H in different cells (NIH-3T3 and 4T1 cells), and the results confirmed the target cell imaging and cellular uptake of DOX-CDC-H by specifically binding the CD44 receptors on the surface of tumor cells. The r MTT results suggest that the DOX-CDC-H complex may induce apoptosis in 4T1 cells, reducing the cytotoxicity of free DOX-induced apoptosis. In vivo antitumor experiments of DOX-CDC-H exhibited enhanced tumor cancer therapy. CDC-H have potential applications in bioimaging and antitumor drug delivery.

Analysis of the clinical and genetic characteristics of a Chinese family with osteogenesis imperfecta type I.

BACKGROUND: Osteogenesis imperfecta type I (OI-I) is a rare genetic disorder characterized by skeletal deformity, bone fragility, blue sclerae, dentinogenesis imperfecta, and hearing loss. The current study aimed to confirm the clinical diagnosis and genetic cause of OI-I in a four-generation Chinese family. METHODS: Clinical investigation and pedigree analysis were conducted to characterize the phenotypic manifestations of a Chinese family with OI-I. Follow-up audiometry and imaging tests were used to evaluate the postoperative outcomes of stapes surgery in the proband with otosclerosis. Whole-exome sequencing (WES) and Sanger sequencing were used to identify the pathogenic gene variants and for cosegregating analysis. RESULTS: We described in detail the clinical features of the collected family with autosomal dominant OI-I, and firstly identified a pathogenic splicing variant (c.2344-1G>T) in intron 33 of COL1A1 in a Chinese family. The molecular analysis suggested that the mutation might cause splice site changes that result in a loss of gene function. The proband, who suffered from otosclerosis and presented two-side middle-severe conductive hearing loss, benefitted significantly from successive bilateral middle ear surgery. CONCLUSIONS: The diagnosis of OI-I in a Chinese family was established by clinical and genetic investigation. A heterozygous pathogenic splicing variant in COL1A1 was directly responsible for the bone fragility and hearing loss of this family. Otosclerosis surgery should be suggested to rehabilitate conductive hearing impairment in OI patients.

Opportunities and challenges of three-dimensional printing technology in pharmaceutical formulation development.

Three-dimensional printing is a technology that prints the products layer-by-layer, in which materials are deposited according to the digital model designed by computer aided design (CAD) software. This technology has competitive advantages regarding product design complexity, product personalization, and on-demand manufacturing. The emergence of 3D technology provides innovative strategies and new ways to develop novel drug delivery systems. This review summarizes the application of 3D printing technologies in the pharmaceutical field, with an emphasis on the advantages of 3D printing technologies for achieving rapid drug delivery, personalized drug delivery, compound drug delivery and customized drug delivery. In addition, this article illustrates the limitations and challenges of 3D printing technologies in the field of pharmaceutical formulation development.

A de novo mutation of the SOX10 gene associated with inner ear malformation in a Guangxi family with Waardenburg syndrome type II.

OBJECTIVE: Waardenburg syndrome type 2 (WS2) is a rare neural-crest disorder, characterized by heterochromic irides or blue eyes and sensorineural hearing loss. The aim of this study was to analyze the clinical features and investigate the genetic cause of WS2 in a small family from Guangxi Zhuang Autonomous region. METHODS: Whole-exome sequencing and mutational analysis were used to identify disease-causing genes in this family. RESULTS: A de novo missense mutation, C.355C > T (p. Arg119Cys), in exon 2 of SOX10 was related to inner ear malformation in the proband and identified by whole exon sequencing, but this mutation was absent in normal controls and any public databases. According to nucleic acid sequence and protein bioinformatic analysis, this mutation is considered the cause of WS2 without neurologic involvement in the proband. CONCLUSIONS: Our findings provide an accurate genetic diagnosis, counseling, and rehabilitation for family members and may contribute to further genotype-phenotype correlation studies of the SOX10 gene.

A novel alginate/gelatin sponge combined with curcumin-loaded electrospun fibers for postoperative rapid hemostasis and prevention of tumor recurrence.

Surgical resection of the tumor remains the preferred treatment for most solid tumors at an early stage, but surgical treatment often leads to massive bleeding and residual tumor cells. Therefore, a novel alginate/gelatin sponge combined with curcumin-loaded electrospun fibers (CFAGS) for rapid hemostasis and prevention of tumor recurrence was prepared by using an electrospinning and interpenetrating polymer network (IPN) strategy. The present results show that alginate/gelatin sponge display excellent hemostatic properties and possess more advantages than commercial gelatin hemostasis sponge. More importantly, CFAGS could control the release of curcumin, inducing curcumin to accumulate at the surgical site of the tumor, thereby inhibiting local tumor recurrence in the subcutaneous postoperative recurrence model. In addition, the sponge was safe to implant in the body and did not cause toxicity to normal tissues and organs. This approach represents a new strategy to implant a dual functional sponge at the postoperative site as an adjuvant to the surgical treatment of cancer.

One-Step Synthesis of Novel Renewable Vegetable Oil-Based Acrylate Prepolymers and Their Application in UV-Curable Coatings.

With the rapid development of social economy, problems such as volatile organic compound (VOC) pollution and the excessive consumption of global petroleum resources have become increasingly prominent. People are beginning to realize that these problems not only affect the ecological environment, but also hinder the development of the organic polymer material industry based on raw fossil materials. Therefore, the modification and application of bio-based materials are of theoretical and practical significance. In this study, a series of vegetable oil-based acrylate prepolymers were synthesized by one-step acrylation using palm oil, olive oil, peanut oil, rapeseed oil, corn oil, canola oil, and grapeseed oil as raw materials, and the effect of different double bond contents on the product structure and grafting rate was investigated. Furthermore, the as-prepared vegetable oil-based acrylate prepolymers, polyurethane acrylate (PUA-2665), trimethylolpropane triacrylate (TMPTA), and photoinitiator (PI-1173) were mixed thoroughly to prepare ultraviolet (UV)-curable films. The effect of different grafting numbers on the properties of these films was investigated. The results showed that as the degree of unsaturation increased, the acrylate grafting number and the cross-linking density increased, although the acrylation (grafting reaction) rate decreased. The reason was mainly because increasing the double bond content could accelerate the reaction rate, while the grafted acrylic groups had a steric hindrance effect to prevent the adjacent double bonds from participating in the reaction. Furthermore, the increase in grafting number brought about the increase in the structural functionality of prepolymers and the cross-linking density of cured films, which led to the enhancement in the thermal (glass transition temperature) and mechanical (tensile strength, Young's modulus) properties of the cured films.