Hyaluronic Acid Stabilized Doxorubicin Nano-Precipitations for Osteosarcoma Treatment

Doxorubicin (Dox) is a wide-spectrum drug to treat different kinds of cancers. However, in clinical practice, Dox usually showed untargeted distributions to the other organs, which can cause serious side effects, such as cardiotoxity. Herein, the formulation of Dox into nanoparticles is critical to enhance its distribution to tumors. Herein, we used polysaccharide, hyaluronic acid, to stabilize the Dox to form nano-precipitations (PD NPs) for the therapy of osteosarcoma. The PD NPs showed enhanced drug accumulation to tumor cells and realized better anticancer effects than free drugs.

A Nanogel with Effective Blood-Brain Barrier Penetration Ability through Passive and Active Dual-Targeting Function

Clinically, surgery assisted by chemotherapy is the most effective treatment of cancer. But from our clinical observation, the median survival of patients with glioblastoma is still not so good with only 15-16 months. The low therapeutic index is mainly due to the blood-brain barrier (BBB) which significantly hindered the chemotherapeutic drug accumulation in tumor tissue. One main composition of the BBB is astrocyte, which contains a lipophilic cell membrane, which prevents more than 98% of small-molecule drugs from entering the brain. Previously, we found that the nanogel with passive targeting function can increase the BBB penetration ability, which indicates that it could be used to overcome the above mentioned in vivo obstacles which promoted drug accumulation in the tumor. In this study, thermosensitive targeted nanogel delivery systems (DPPC) with cell-penetrating peptides (CPP) are introduced onto the particle surface for active astrocyte breaking. The hydrodynamic radius of DPPC is around 300 nm, the potential is about 0-5 mV, and the TEM and DLS studies further confirm its well spherical morphology and uniform distribution. The DPPC is verified as the biocompatible carriers for further application by cell viability tests. The in vitro-constructed BBB model successfully proves that DPPC can efficiently penetrate the BBB, which is attributed to both the temperature-sensitive passive targeting and the active CPP penetration. Consequently, the intracellular doxorubicin (DOX) promotes such functional DPPC at the relatively high temperature inside tumor microenvironment (TME) (~42°C), which obviously improves intratumor drug accumulation and tumor cell-killing effects. The dual-targeted nanogel delivery systems designed in this study provides a more effective strategy for the treatment of glioma.

Constant Voltage Iontophoresis Technique to Deliver Terbinafine via Transungual Delivery System: Formulation Optimization Using Box–Behnken Design and In Vitro Evaluation

Topical therapy of antifungals is primarily restricted due to the low innate transport of drugs through the thick multi-layered keratinized nail plate. The objective of this investigation was to develop a gel formulation, and to optimize and evaluate the transungual delivery of terbinafine using the constant voltage iontophoresis technique. Statistical analysis was performed using Box–Behnken design to optimize the transungual delivery of terbinafine by examining crucial variables namely concentration of polyethylene glycol, voltage, and duration of application (2–6 h). Optimization data in batches (F1–F17) demonstrated that chemical enhancer, applied voltage, and application time have influenced terbinafine nail delivery. Higher ex vivo permeation and drug accumulation into the nail tissue were noticed in the optimized batch (F8) when compared with other batches (F1–F17). A greater amount of terbinafine was released across the nails when the drug was accumulated by iontophoresis than the passive counterpart. A remarkably higher zone of inhibition was observed in nails with greater drug accumulation due to iontophoresis, as compared to the passive process. The results here demonstrate that the optimized formulation with low voltage iontophoresis could be a viable and alternative tool in the transungual delivery of terbinafine, which in turn could improve the success rate of topical nail therapy in onychomycosis.

Pharmacokinetics of KA2237, a novel selective inhibitor of PI3K-β and PI3K-δ, in patients: A first-in-human study using PK modelling to predict drug concentrations during dose escalation

Aims: KA2237, an oral, potent and selective, inhibitor of the PI3K β and δ isoforms, was evaluated for safety, tolerability and pharmacokinetics (PK) in patients with B-cell lymphoma. KA2237 is metabolised by CYP3A4/5 but also demonstrated mechanism-based inhibition (MBI) of CYP3A4/5. An MBI mechanistic dynamic model was used to predict drug accumulation after repeat dosing of KA2237. This model, along with clinical safety data, was used to guide safe dose escalation. Methods: An open-label, single arm, dose escalation study was carried out in patients, dosed orally with KA2237 at 50, 100, 200 and 400 mg once daily. Complete plasma profiles were obtained on Day 1 and Day 14 of dosing and pre-dose (Cmin) samples were obtained on Days 2-7. The MBI model was validated and used to calculate drug levels and predict potential drug accumulation during dose escalation. Results: KA2237 elimination half-life was around 20-30 h, compatible with once daily dosing regimens. The accumulation of KA2237 was around 4-fold after the highest dose of 400 mg and around 3-fold after administration of 200 mg, which is considered the maximum tolerated dose (MTD). The MBI model accurately predicted this accumulation. Conclusions: Drugs that demonstrate MBI and potential auto-inhibition can be successfully developed, provided that models are developed to assess the extent of accumulation prior to the start of FIH clinical studies. This, along with the close monitoring of drug levels and clinical safety data can be used to guide dose escalation and lead to the safe conduct of clinical studies.

Asymmetry in Drug Permeability through the Cornea

The permeability through the cornea determines the ability of a drug or any topically applied compound to cross the tissue and reach the intraocular area. Most of the permeability values found in the literature are obtained considering topical drug formulations, and therefore, refer to the drug permeability inward the eye. However, due to the asymmetry of the corneal tissue, outward drug permeability constitutes a more meaningful parameter when dealing with intraocular drug-delivery systems (i.e., drug-loaded intraocular lenses, intraocular implants or injections). Herein, the permeability coefficients of two commonly administered anti-inflammatory drugs (i.e., bromfenac sodium and dexamethasone sodium) were determined ex vivo using Franz diffusion cells and porcine corneas in both inward and outward configurations. A significantly higher drug accumulation in the cornea was detected in the outward direction, which is consistent with the different characteristics of the corneal layers. Coherently, a higher permeability coefficient was obtained for bromfenac sodium in the outward direction, but no differences were detected for dexamethasone sodium in the two directions. Drug accumulation in the cornea can prolong the therapeutic effect of intraocular drug-release systems.

Design of time-delayed safety switches for CRISPR gene therapy

CRISPR system is a powerful gene editing tool which has already been reported to address a variety of gene relevant diseases in different cell lines. However, off-target effect and immune response caused by Cas9 remain two fundamental problems. In our work, time-delayed safety switches are designed based on either artificial ultrasensitivity transmission module or intrinsic time delay in biomolecular activities. By addressing gene therapy efficiency, off-target effect, immune response and drug accumulation, we hope our safety switches may offer inspiration in realizing safe and efficient gene therapy in humans.