Pharmaceutical Methods for Enhancing the Dissolution of Poorly Water-Soluble Drugs.

Low water solubility is the main hindrance in the growth of pharmaceutical industry. Approximately 90% of newer molecules under investigation for drugs and 40% of novel drugs have been reported to have low water solubility. The key and thought-provoking task for the formulation scientists is the development of novel techniques to overcome the solubility-related issues of these drugs. The main intention of present review is to depict the conventional and novel strategies to overcome the solubility-related problems of Biopharmaceutical Classification System Class-II drugs. More than 100 articles published in the last 5 years were reviewed to have a look at the strategies used for solubility enhancement. pH modification, salt forms, amorphous forms, surfactant solubilization, cosolvency, solid dispersions, inclusion complexation, polymeric micelles, crystals, size reduction, nanonization, proliposomes, liposomes, solid lipid nanoparticles, microemulsions, and self-emulsifying drug delivery systems are the various techniques to yield better bioavailability of poorly soluble drugs. The selection of solubility enhancement technique is based on the dosage form and physiochemical characteristics of drug molecules.

Tumor microenvironment-responsive size-switchable drug delivery nanosystems.

INTRODUCTION: Compared with ordinary chemotherapeutic drugs, the variable-size nanoparticles (NPs) have better therapeutic effects and fewer side effects. AREAS COVERED: This review mainly summarizes the strategies used to construct smart, size-tunable nanocarriers based on characteristic factors of tumor microenvironment (TME) to dramatically increase the penetration and retention of drugs within tumors. EXPERT OPINION: Nanosystems with changeable sizes based on the TME have been extensively studied in the past decade, and their permeability and retention have been greatly improved, making them a very promising treatment for tumors.

The reversal of chemotherapy-induced multidrug resistance by nanomedicine for cancer therapy.

Multidrug resistance (MDR) of cancer is a persistent problem in chemotherapy. Scientists have considered the overexpressed efflux transporters responsible for MDR and chemotherapy failure. MDR extremely limits the therapeutic effect of chemotherapy in cancer treatment. Many strategies have been applied to solve this problem. Multifunctional nanoparticles may be one of the most promising approaches to reverse MDR of tumor. These nanoparticles can keep stability in the blood circulation and selectively accumulated in the tumor microenvironment (TME) either by passive or active targeting. The stimuli-sensitive or organelle-targeting nanoparticles can release the drug at the targeted-site without exposure to normal tissues. In order to better understand reversal of MDR, three main strategies are concluded in this review. First strategy is the synergistic effect of chemotherapeutic drugs and ABC transporter inhibitors. Through directly inhibiting overexpressed ABC transporters, chemotherapeutic drugs can enter into resistant cells without being efflux. Second strategy is based on nanoparticles circumventing over-expressed efflux transporters and directly targeting resistance-related organelles. Third approach is the combination of multiple therapy modes overcoming cancer resistance. At last, numerous researches demonstrated cancer stem-like cells (CSCs) had a deep relation with drug resistance. Here, we discuss two different drug delivery approaches of nanomedicine based on CSC therapy.

Redox-responsive hyaluronic acid-based nanoparticles for targeted photodynamic therapy/chemotherapy against breast cancer.

Specific cellular uptake and sufficient drug release in tumor tissues are important for effective cancer therapy. Hyaluronic acid (HA), a skeleton material, could specifically bind to cluster determinant 44 (CD44) receptors highly expressed on the surface of tumor cells to realize active targeting. Cystamine (cys) is sensitive highly reductive environment inside tumor cells and was used as a connecting arm to connect docosahexaenoic acid (DHA) and chlorin e6 (Ce6) to the HA skeleton to obtain redox-sensitive polymer HA-cys-DHA/Ce6 (CHD). Nanoparticles were fabricated and loaded with chemotherapeutic drug docetaxel (DTX) by physical encapsulation. The prepared nanoparticles had significantly increased uptake by MCF-7 cells that overexpressed CD44 receptors, and DTX was effectively released at high reducing condition. Compared with mono-photodynamic therapy (PDT) or mono-chemotherapy, the prepared nanoparticles exhibited superior anti-tumor effect by inhibiting microtubule depolymerization, blocking cell cycle and generating reactive oxygen species (ROS). In vivo anti-tumor experiments proved that DTX/CHD nanoparticles had the best antitumor response versus DTX and CHD nanoparticles under near-infrared (NIR) irradiation. These studies revealed that redox-responsive DTX-loaded CHD nanoparticles held great potential for the treatment of breast cancer.

A sonosensitiser-based polymeric nanoplatform for chemo-sonodynamic combination therapy of lung cancer.

BACKGROUND: Lung cancer is the most common type of tumour worldwide. Its relative lethality is considerably high. However, since the tumour tissues are located deep within the human body, traditional technologies, such as photodynamic therapy, do not have the desired effect. Sonosensitisers can penetrate deeply into tissues, and sonodynamic therapy (SDT) effectively inhibits tumours by generating reactive oxygen species. Ultrasound can also penetrate deeply, with a favourable tumour inhibition effect. RESULTS: A redox/ultrasound-responsive Rhein-chondroitin sulphate-based nano-preparation encapsulating docetaxel was fabricated. The nanoparticles displayed increased cellular uptake with quick drug release, good stability, and a monodispersed form in the physiological environment. Rhein induced apoptosis and altered mitochondrial membrane potential, which enhanced the expression of apoptosis-related proteins. SDT inhibited the metastasis and angiogenesis of cancer cells and activated anti-tumour capacity by reducing the expression of M2 macrophages. CONCLUSIONS: The potential of Rhein for SDT was demonstrated. Production of reaction oxygen species was markedly enhanced after ultrasound treatment. The nanoplatform enhanced the synergistic anti-tumour effects of SDT and chemotherapeutic efficacy. The approach was biocompatibility. The findings could inform investigations of chemo-SDT for different cancers.

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.

A novel progress of drug delivery system for organelle targeting in tumour cells.

At present, malignant tumours have become one of the most serious diseases that endanger human health. According to a survey on causes of death in Chinese population in early 1990s, the malignant tumours were the second leading cause of death. In the treatment of tumours, the ideal situation is that drugs should target and accumulate at tumour sites and destroy tumour cells specifically, without affecting normal cells and stem cells with regenerative capacity. This requires drugs to be specifically transported to the target organs, tissues, cells, and even specific organelles, like mitochondria, nuclei, lysosomes, endoplasmic reticulum (ER), and Golgi apparatus (GA). The nano drug delivery system can not only protect drugs from degradation but also facilitate functional modification and targeted drug delivery to the tumour site. This article mainly reviews the targeting of nano drug delivery systems to tumour cytoplasmic matrix, nucleus, mitochondria, ER, and lysosomes. Organelle-specific drug delivery system will be a major mean of targeting drug delivery with lower toxicity, less dosage and higher drug concentration in tumour cells.

Quantitative prediction of the bitterness of atomoxetine hydrochloride and taste-masked using hydroxypropyl-ß-cyclodextrin: A biosensor evaluation and interaction study.

The bitterness of a drug is a major challenge for patient acceptability and compliance, especially for children. Due to the toxicity of medication, a human taste panel test has certain limitations. Atomoxetine hydrochloride (HCl), which is used for the treatment of attention deficit/hyperactivity disorder (ADHD), has an extremely bitter taste. The aim of this work is to quantitatively predict the bitterness of atomoxetine HCl by a biosensor system. Based on the mechanism of detection of the electronic tongue (E-tongue), the bitterness of atomoxetine HCl was evaluated, and it was found that its bitterness was similar to that of quinine HCl. The bitterness threshold of atomoxetine HCl was 8.61 µg/ml based on the Change of membrane Potential caused by Adsorption (CPA) value of the BT0 sensor. In this study, the taste-masking efficiency of 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CyD) was assessed by Euclidean distances on a principle component analysis (PCA) map with the SA402B Taste Sensing System, and the host-guest interactions were investigated by differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), nuclear magnetic resonance (NMR) spectroscopy and scanning electron microscopy (SEM). Biosensor evaluation and characterization of the inclusion complex indicated that atomoxetine HCl could actively react with 2-hydroxypropyl-ß-cyclodextrin.

Chondroitin sulfate derived theranostic and therapeutic nanocarriers for tumor-targeted drug delivery.

The standard chemotherapy is facing the challenges of lack of cancer selectivity and development of drug resistance. Currently, with the application of nanotechnology, the rationally designed nanocarriers of chondroitin sulfate (CS) have been fabricated and their unique features of low toxicity, biocompatibility, and active and passive targeting made them drug delivery vehicles of the choice for cancer therapy. The hydrophilic and anionic CS could be incorporated as a building block into- or decorated on the surface of nanoformulations. Micellar nanoparticles (NPs) self-assembled from amphiphilic CS-drug conjugates and CS-polymer conjugates, polyelectrolyte complexes (PECs) and nanogels of CS have been widely implicated in cancer directed therapy. The surface modulation of organic, inorganic, lipid and metallic NPs with CS promotes the receptor-mediated internalization of NPs to the tumor cells. The potential contribution of CS and CS-proteoglycans (CSPGs) in the pathogenesis of various cancer types, and CS nanocarriers in immunotherapy, radiotherapy, sonodynamic therapy (SDT) and photodynamic therapy (PDT) of cancer are summarized in this review paper.

Dual-band refractometric terahertz biosensing with intense wave-matter-overlap microfluidic channel.

We theoretically and experimentally demonstrate a label-free terahertz biosensor with ultrahigh sensitivity and distinctive discretion. By constructing a metal-air-metal (MAM) metamaterial perfect absorber (MPA) with a metallic paired-ring resonator array, a hollow microfluidic channel, and a backed reflector, a novel dual-band absorptive sensing platform is proposed in the THz range. The near field coupling by dipole-induced trapped modes and the magnetic momentum caused a vertical to transverse power flux that dramatically enhanced the electromagnetic field on top of the metasurface and in the microfluidic channel, respectively. Both the resonant modes exhibit perfect absorption and produce ultrahigh normalized sensitivities of 0.47/RIU (refractive index unit, RIU) and 0.51/RIU at 0.76 THz and 1.28 THz, respectively. Compared with conventional microfluidic sensors, the salient advantages of our design are the perfect spatial overlap for light-matter interaction and polarization insensitivity. Characterized by THz time domain spectroscopic absorption quantification measurements with different concentrations of bovine serum albumin (BSA), the proposed sensor exhibits promising applications in microfluidic biosensing.

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.

Pluronic F127-functionalized molybdenum oxide nanosheets with pH-dependent degradability for chemo-photothermal cancer therapy.

Traditional cancer therapies carry a risk of serious side effects and toxicity. Developing an alternative treatment modality that is highly effective, has low toxicity and is noninvasive is urgently required. Here, we exploited molybdenum oxide (MoOx) nanosheets as a drug carrier and degradable photothermal agent to provide a chemo-photothermal combination cancer therapy. The MoOx nanosheets were synthesized by a one-pot hydrothermal method and then modified with pluronic F127 to improve physiological stability and biocompatibility. The F127-modified nanosheets (MoOX@F127) showed ultrahigh drug loading efficiency (DLE) of doxorubicin (DOX) (DLE%; 65%, W(load DOX)/[W(load DOX) + WMoOx@F127]), strong near-infrared (NIR) absorption and desirable pH-dependent degradability. After intravenous injection, MoOx@F127 nanosheets were degraded at physiological pH and were rapidly excreted from normal organs, while they were effectively accumulated and retained long-term in the more acidic tumor tissue. This simultaneously ensured effective tumor ablation after NIR irradiation and avoided long-term retention and toxicity in vivo. Compared to chemotherapy or photothermal therapy alone, in vitro and in vivo tumor ablation studies have shown a notably improved synergistic effect of the combination therapy. Our study presents a multifunctional nanosystem with a desirable degradability for chemo-photothermal combination cancer therapy that has great potential in biomedical applications.

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.

Recent advances in electrospun for drug delivery purpose.

Electrospun, an advanced technology, has been successfully employed for fibre production and offers many merits in novel drug delivery systems (DDSs). In recent years, electrospun has gained significant attention and attraction of the scientists in soaring numbers. This technology is superior to other technologies in fabricating the fibres which range from micrometers to manometers scale. The selection of appropriate polymers, electrospun processes and electrospun parameters play important roles in controlling the drug release while, treating serious illness. Besides, electrospraying process has similar characteristics to the electrospun and is presented briefly here. Further, in vivo and in vitro evaluations of the electrospun nanofibers are comprehensively discussed. In addition, the electrospun nanotechnology has been exploited to design drug release systems, investigate drug's pharmacokinetics and further develop DDS. The electrospun nanofibers improve bioactivity of various types of drugs including water-insoluble, soluble, anticancer and antibacterial drugs and genetic materials. In the end, the prospects and challenges in the process of designing drug-loaded electrospun nanofibers are discussed in detail.

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.

Crosslinked self-assembled nanoparticles for chemo-sonodynamic combination therapy favoring antitumor, antimetastasis management and immune responses.

Sonodynamic therapy (SDT) has been proposed as a new modality for cancer management through low-intensity ultrasound induced activation of sonosensitizers. Here, we designed a novel redox/enzyme/ultrasound responsive chondroitin sulfate-chlorin e6-lipoic acid nanoplatform loading docetaxel, combining SDT and chemotherapy, for antiproliferation and antimetastasis of melanoma. The reversibly crosslinked and self-assembled nanoparticles possessed monodispersive size distribution, stability in physical conditions, while showing increased uptake with rapid drug release in simulated tumor microenvironment (reductive potentials and degradative hyaluronidase-1). With synthesized ultrasound sensitive polymer backbones, SDT induced the generation of cellular reactive oxygen species and mitochondrial damage, exerting the apoptotic effect through the release of cytochrome C, the expression of cleaved caspase-9 followed by the functional cleaved caspase-3. Chemo-sonodynamic therapy not only inhibited tumor growth and metastasis with reduced metastatic protein expression, but also caused immune response via the release of tumor-associated antigens. It was initially demonstrated that SDT could induce the tumor cell death, therefore having potentials to recruit cytotoxic lymphocytes into tumor sites. Notably, the nanoplatforms exhibited good in vivo stability and blood compatibility, indicating the safety and efficiency in drug delivery. Our work thus presents a convenient approach to fabricate intelligent multifunctional nanoparticles and paves a path for effective cancer therapies.

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.

Redox/enzyme sensitive chondroitin sulfate-based self-assembled nanoparticles loading docetaxel for the inhibition of metastasis and growth of melanoma.

In this report, redox/enzyme responsive chondroitin sulfate-ss-deoxycholic acid (CSCD) conjugates were synthesized using cystamine as the linkage which could self-assemble to form self-assembled nanoparticles (175.6 + 5.2 nm) in the aqueous environment. Docetaxel (DTX) was loaded in nanoparticles with desired loading efficiency for the inhibition of tumor growth and metastasis of melanoma. Interestingly, nanoparticles were demonstrated to respond to hyaluronidase-1 (Hyal-1) which could degrade chondroitin sulfate (CS) backbones. In this case, we designed dual-sensitive nanoparticles with enhanced drug release pattern under the presence of glutathione (GSH)/Hyal-1. Compared with Taxotere®, CSCD nanoparticles significantly improved the DTX distribution in tumors and lungs with about 4.4-fold higher area-under-the-curve (AUC) value. In situ tumor volume and pulmonary metastatic formation were reduced upon the administration of DTX-loaded CSCD nanoparticles via DTX-induced apoptosis and decreased metastasis-promotion protein expression. With only minor cytotoxicity, CSCD nanoparticles could be promising nano-drug delivery systems for successful management of melanoma.

Progress in brain targeting drug delivery system by nasal route.

The blood-brain barrier (BBB) restricts the transport of potential therapeutic moieties to the brain. Direct targeting the brain via olfactory and trigeminal neural pathways by passing the BBB has gained an important consideration for delivery of wide range of therapeutics to brain. Intranasal route of transportation directly delivers the drugs to brain without systemic absorption, thus avoiding the side effects and enhancing the efficacy of neurotherapeutics. Over the last several decades, different drug delivery systems (DDSs) have been studied for targeting the brain by the nasal route. Novel DDSs such as nanoparticles (NPs), liposomes and polymeric micelles have gained potential as useful tools for targeting the brain without toxicity in nasal mucosa and central nervous system (CNS). Complex geometry of the nasal cavity presented a big challenge to effective delivery of drugs beyond the nasal valve. Recently, pharmaceutical firms utilized latest and emerging nasal drug delivery technologies to overcome these barriers. This review aims to describe the latest development of brain targeted DDSs via nasal administration. CHEMICAL COMPOUNDS STUDIED IN THIS ARTICLE: Carbopol 934p (PubChem CID: 6581) Carboxy methylcellulose (PubChem CID: 24748) Penetratin (PubChem CID: 101111470) Poly lactic-co-glycolic acid (PubChem CID: 23111554) Tween 80 (PubChem CID: 5284448).