A chitosan-coated PCL/nano-hydroxyapatite aerogel integrated with a nanofiber membrane for providing antibacterial activity and guiding bone regeneration.

A guided bone regeneration (GBR) membrane can act as a barrier to prevent the invasion and interference from foreign soft tissues, promoting infiltration and proliferation of osteoblasts in the bone defect area. Herein, a composite scaffold with dual functions of osteogenesis and antibacterial effects was prepared for GBR. A polycaprolactone (PCL)/nano-hydroxyapatite (n-HA) aerogel produced by electrospinning and freeze-drying techniques was fabricated as the loose layer of the scaffold, while a PCL nanofiber membrane was used as the dense layer. Chitosan (CS) solution served as a middle layer to provide mechanical support and antibacterial effects between the two layers. Morphological results showed that the loose layer had a porous structure with n-HA successfully dispersed in the aerogels, while the dense layer possessed a sufficiently dense structure. In vitro antibacterial experiments illustrated that the CS solution in the middle layer stabilized the scaffold structure and endowed the scaffold with good antibacterial properties. The cytocompatibility results indicated that both fibroblasts and osteoblasts exhibited superior cell activity on the dense and loose layers, respectively. In particular, the dense layer made of nanofibers could work as a barrier layer to inhibit the infiltration of fibroblasts into the loose layer. In vitro osteogenesis analysis suggested that the PCL/n-HA aerogel could enhance the bone induction ability of bone mesenchymal stem cells, which was confirmed by the increased expression of the alkaline phosphatase activity. The loose structure facilitated the infiltration and migration of bone mesenchymal stem cells for better osteogenesis. In summary, such a composite scaffold exhibited excellent osteogenic and antibacterial properties as well as the barrier effect, thus holding promising potential for use as GBR materials.

On the mucoadhesive properties of synthetic and natural polyampholytes.

HYPOTHESIS: The mucoadhesive characteristics of amphoteric polymers (also known as polyampholytes) can vary and are influenced by factors such as the solution's pH and its relative position against their isoelectric point (pHIEP). Whilst the literature contains numerous reports on mucoadhesive properties of either cationic or anionic polymers, very little is known about these characteristics for polyampholytes EXPERIMENTS: Here, two amphoteric polymers were synthesized by reaction of linear polyethylene imine (l-PEI) with succinic or phthalic anhydride and their mucoadhesive properties were compared to bovine serum albumin (BSA), selected as a natural polyampholyte. Interactions between these polymers and porcine gastric mucin were studied using turbidimetric titration and isothermal titration calorimetry across a wide range of pHs. Model tablets were designed, coated with these polymers and tested to evaluate their adhesion to porcine gastric mucosa at different pHs. Moreover, a retention study using fluorescein isothiocyanate (FITC)-labelled polyampholytes deposited onto mucosal surfaces was also conducted FINDINGS: All these studies indicated the importance of solution pH and its relative position against pHIEP in the mucoadhesive properties of polyampholytes. Both synthetic and natural polyampholytes exhibited strong interactions with mucin and good mucoadhesive properties at pH < pHIEP.

Hydroxyethyl cellulose functionalised with maleimide groups as a new excipient with enhanced mucoadhesive properties.

Hydroxyethylcellulose (HEC) is a non-ionic water-soluble polymer with poor mucoadhesive properties. The mucoadhesive properties of hydroxyethylcellulose can be improved by modifying it through conjugation with molecules containing maleimide groups. Maleimide groups interact with the thiol groups present in cysteine domains in the mucin via Michael addition reaction under physiological conditions to form a strong mucoadhesive bond. This will prolong the residence time of a dosage form containing this modified polymer and drug on mucosal surfaces. In this study HEC was modified by reaction with 4-bromophenyl maleimide in varying molar ratios and the successful synthesis was confirmed using 1H NMR and FTIR spectroscopies. The safety of the newly synthesised polymer derivatives was assessed with in vivo planaria assays and in vitro MTT assay utilising Caco-2 cell line. The synthesized maleimide-functionalised HEC solutions were sprayed onto blank tablets to develop a model dosage form. The physical properties and mucoadhesive behavior of these tablets were evaluated using a tensile test with sheep buccal mucosa. The maleimide-functionalised HEC exhibited superior mucoadhesive properties compared to unmodified HEC.

Galactosamine-modified PEG-PLA/TPGS micelles for the oral delivery of curcumin.

In this study, galactosamine-modified poly(ethylene glycol)-poly(lactide) (Gal-PEG-PLA) polymers were synthesized and Gal-PEG-PLA/D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) micelles named as GPP micelles were designed to promote the oral absorption of a hydrophobic drug, curcumin (CUR). CUR-loaded Gal-PEG-PLA/TPGS micelles (CUR@GPP micelles) were fabricated using the thin-film dispersion method. CUR@GPP micelles had a size of about 100 nm, a near-neutral zeta potential, drug loading (DL) of 14.6%, and sustained release properties. GPP micelles with high Gal density (GPP3 micelles) were superior in facilitating uptake in epithelial cells and improving intestinal permeation. In situ intestinal absorption studies suggested that the jejunum and ileum were the best absorption segments in the intestinal tract. Additionally, biodistribution results revealed that GPP3 micelles could be remarkably taken up by the jejunum and ileum. Pharmacokinetics revealed that the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from 0 to 24 h (AUC0-24) for CUR@GPP3 micelles were both significantly increased, and that the relative bioavailability of CUR@GPP3 micelles to CUR-loaded mPEG-PLA/TPGS micelles (CUR@PP micelles) was 258.8%. Furthermore, CUR-loaded micelles could reduce damage to the liver and intestinal tissues. This study highlights the importance of Gal content in the design of targeting nanocarrier Gal-modified micelles, which have broad prospects for oral delivery of hydrophobic drugs. Therefore, they could serve as a promising candidate for targeted delivery to the liver.

Paclitaxel and quercetin co-loaded functional mesoporous silica nanoparticles overcoming multidrug resistance in breast cancer.

Multidrug resistance (MDR) in tumor has long been considered a major factor in the failure of tumor chemotherapy. P-glycoprotein (P-gp)-mediated drug efflux plays a significant role in the MDR of tumor. Herein, paclitaxel (PTX) and P-gp inhibitor quercetin (QC) co-loaded and chondroitin sulfate (ChS)-coated mesoporous silica nanoparticles (MSNs) (MSNs-ChS@PQ) were developed to reverse MDR in breast cancer and improve chemotherapy efficacy. The dual drug-loaded nanoparticles (NPs) showed a nanoscale size of ∼ 227.2 nm and redox-responsive drug release property. In vitro cell experiments showed that NPs exhibited CD44 receptor-mediated active targeting in MCF-7/ADR cells. The dual drug-loaded NPs had lower IC50 value, higher apoptosis rate, obvious G2M phase arrest as well as stronger microtubule destruction in MCF-7/ADR cells compared to PTX-loaded NPs, suggesting that QC addition, significantly, improved the sensitivity of MCF-7/ADR cells to PTX. Further study found that QC-loaded NPs down-regulated the expression of P-gp. Notably, the dual drug-loaded NPs exhibited tumor-targeting ability, prolonged tumor retention time and effective anti-tumor effect without obvious toxicity to normal tissues in vivo. Taken together, our research provides a viable approach to overcome MDR in breast cancer.

Development of stimuli-responsive intelligent polymer micelles for the delivery of doxorubicin.

Doxorubicin is still used as a first-line drug in current therapeutics for numerous types of malignant tumours (including lymphoma, transplantable leukaemia and solid tumour). Nevertheless, to overcome the serious side effects like cardiotoxicity and myelosuppression caused by effective doses of doxorubicin remains as a world-class puzzle. In recent years, the usage of biocompatible polymeric nanomaterials to form an intelligently sensitive carrier for the targeted release in tumour microenvironment has attracted wide attention. These different intelligent polymeric micelles (PMs) could change the pharmacokinetics process of drugs or respond in the special microenvironment of tumour site to maximise the efficacy and reduce the toxicity of doxorubicin in other tissues and organs. Several intelligent PMs have already been in the clinical research stage and planned for market. Therefore, related research remains active, and the latest nanotechnology approaches for doxorubicin delivery are always in the spotlight. Centring on the model drugs doxorubicin, this review summarised the mechanisms of PMs, classified the polymers used in the application of doxorubicin delivery and discussed some interesting and imaginative smart PMs in recent years.

Cell-penetrating peptide: a means of breaking through the physiological barriers of different tissues and organs.

The selective infiltration of cell membranes and tissue barriers often blocks the entry of most active molecules. This natural defense mechanism prevents the invasion of exogenous substances and limits the therapeutic value of most available molecules. Therefore, it is particularly important to find appropriate ways of membrane translocation and therapeutic agent delivery to its target site. Cell penetrating peptides (CPPs) are a group of short peptides harnessed in this condition, possessing a significant capacity for membrane transduction and could be exploited to transfer various biologically active cargoes into the cells. Since their discovery, CPPs have been employed for delivery of a wide variety of therapeutic molecules to treat various disorders including cranial nerve involvement, ocular inflammation, myocardial ischemia, dermatosis and cancer. The promising results of CPPs-derived therapeutics in various tumor models demonstrated a potential and worthwhile scope of CPPs in chemotherapy. This review describes the detailed description of CPPs and CPPs-assisted molecular delivery against various tissues and organs disorders. An emphasis is focused on summarizing the novel insights and achievements of CPPs in surmounting the natural membrane barriers during the last 5 years.

The progresses in curcuminoids-based metal complexes: especially in cancer therapy.

Curcuminoids (CURs), a series of derivatives in turmeric (Curcuma longa), are commonly discovered to control the deterioration of cancers. However, the physiochemical properties and the original side effects of many CURs complexes put barriers in their medical applications. To address them, the investigation of metal-based complexes with CURs is in progress. The complexes were summarized according to articles in recent years. The results showed that the complexes improved the physicochemical properties or therapeutic performances compared with pure CURs. Further, it is possible for the novel complexes to be applied in chemical detecting, paramagnetic-luminescent and bio-imaging fields. Therefore, the formation of the metal-based CURs complexes (MBCCs) is beneficial for the development of CURs especially in medical fields.

Advances in curcumin-loaded nanopreparations: improving bioavailability and overcoming inherent drawbacks.

Curcumin (CUR), one of the major extracts of turmeric, has gained extensive attention owing to its extraordinary benefits as anti-cancer, anti-bacterial, anti-ulcerative, anti-depressant, anti-inflammatory and wound healing agent. However, a major barrier in its application lies in its inherent nature of low water solubility, instability, and short half-life. Different strategies have been adopted to overcome these barriers like preparing nano-sized formulations and exploiting stable and hydrophilic derivatives, and collaborative drug delivery. Nanopreparations could maintain the pharmacological effect of drugs, even the holistic effects of drug extracts. In addition, nanopreparations based on novel materials make it a reality to regulate the drug release rate according to the various environmental conditions. The therapeutic applications and novel investigated nanopreparations of CUR for prevention and treatment of various diseases, especially, cancer and inflammatory disorders are discussed in this review.

Recent progress of drug nanoformulations targeting to brain.

Most of the potential therapeutic agents capable to modulate the pathophysiology or treat the neurological disorders and brain tumors are useless in the current modern and advanced era of neuroscience due to the impeding action of biological barriers. Among various therapeutic strategies applied for translocation of drug delivery across the blood-brain barrier (BBB), nanoformulations set an excellent platform for brain targeting by overcoming the biological and chemical barriers and protecting drug from efflux to promote the optimum therapeutic drug concentration in brain parenchyma tissues. Nanocarriers are the most widely studied delivery vehicles for BBB translocation with the efficiency of selectively targeting or exploiting inherent biological molecules, receptors, carriers or mechanisms of the brain. Nearly all of the available drug delivery nanocarriers explored in recent years for brain therapeutics and theranostics are based on lipid or polymeric materials. Polymeric nanoparticles (NPs) and lipid based nanocarriers including liposomes, solid lipid NPs (SLNs) and micelles, etc. are under the direct focus of neuroscientists due to the promising attributes and vast applications in neurological disorders. Surface modification of nanovehicles with proper targeting moiety or coating with surfactants promotes the interaction with endothelial cells and passage of nanocarriers to the brain. This review comprehensively depicts challenges to the brain targeted drug delivery, mechanisms of drug transportation across the BBB, and potential contributions of endogenous cells as NPs delivery cells and novel targeting ligands decorated nanoformulations in imaging, treating and controlling neurological disorders.

Current development in the formulations of non-injection administration of paclitaxel.

Paclitaxel (PTX) belongs to a class of taxane anti-tumor drug used for the clinic treatment of breast cancer, ovarian cancer, non-small-cell lung cancer, and so on. PTX has poor water solubility and oral bioavailability. It is generally administered via intravenous (i.v.) infusion. Traditional PTX injectable preparations contain Cremophor-EL and ethanol to improve its solubility, which would result in adverse reactions like severe hypersensitivity, neutropenia, etc. Adverse reactions can be reduced only by complicated pretreatment with glucocorticoid and antihistamines drugs and followed by PTX slow infusion for three hours, which has brought significant inconvenience to the patients. Though, a new-generation PTX formulation, Abraxane, free of Cremophor-EL and ethanol, is still being administrated by frequent i.v. infusions and extremely expensive. Therefore, non-injection administration of PTX is urgently needed to avoid the side effects as well as reduce inconvenience to the patients. Recently, a variety of non-injection drug delivery systems (DDSs) of PTX have been developed. This review aims to discuss the progress of non-injectable administration systems of PTX, including oral administration systems, vaginal administration systems, implantable DDSs, transdermal DDSs and intranasal administration for the future study and clinical applications.