Multibarrier-penetrating drug delivery systems for deep tumor therapy based on synergistic penetration strategy.

Nanotherapies, valued for their high efficacy and low toxicity, frequently serve as antitumor treatments, but do not readily penetrate deep into tumor tissues and cells. Here we developed an improved tumor-penetrating peptide (TPP)-based drug delivery system. Briefly, the established TPP iNGR was modified to generate a linear NGR peptide capable of transporting nanotherapeutic drugs into tumors through a CendR pathway-dependent, neuropilin-1 receptor-mediated process. Although TPPs have been reported to reach intended tumor targets, they often fail to penetrate cell membranes to deliver tumoricidal drugs to intracellular targets. We addressed this issue by harnessing cell penetrating peptide technology to develop a liposome-based multibarrier-penetrating delivery system (mbPDS) with improved synergistic drug penetration into deep tumor tissues and cells. The system incorporated doxorubicin-loaded liposomes coated with nona-arginine (R9) CPP and cyclic iNGR (CRNGRGPDC) molecules, yielding Lip-mbPDS. Lip-mbPDS tumor-targeting, tumor cell/tissue-penetrating and antitumor capabilities were assessed using CD13-positive human fibrosarcoma-derived cell (HT1080)-based in vitro and in vivo tumor models. Lip-mbPDS evaluation included three-dimensional layer-by-layer confocal laser scanning microscopy, cell internalization/toxicity assays, three-dimensional tumor spheroid-based penetration assays and antitumor efficacy assays conducted in an animal model. Lip-mbPDS provided enhanced synergistic drug penetration of multiple biointerfaces for potentially deep tumor therapeutic outcomes.

Tailored Supersaturable Immediate Release Behaviors of Hypotensive Supersaturating Drug-Delivery Systems Combined with Hot-Melt Extrusion Technique and Self-Micellizing Polymer.

The short-term immediate release of supersaturated drug-delivery systems (SDDSs) presents an interesting process that can be tailored to multi-stage release events including initial release after dosing and dissolution, evolved release over longer dissolution periods for biological absorption, and terminal release following the end of immediate release. However, although comprehensive analysis of these critical release behaviors is often ignored yet essential for understanding the supersaturable immediate-release events for supersaturable solid formations when employing new techniques or polymers matched to a particular API. Hot-melt extrusion (HME) has become a popular continuous thermodynamic disordering technique for amorphization. The self-micellizing polymer Soluplus® is reported to be a potential amorphous and amphiphilic graft copolymer frequently used in many nano/micro supersaturable formulations. Our current work aims to develop hypotensive supersaturating solid dispersion systems (faSDDSHME) containing the BCS II drug, felodipine, when coordinately employing the HME technique and self-micellizing Soluplus®, and to characterize their amorphization as well as immediate release. Other discontinuous techniques were used to prepare control groups (faSDDSSE and faSDDSQC). Tailored initial/evolved/terminal three-stage supersaturable immediate-release behaviors were identified and possible mechanisms controlling the release were explored. HME produced the highest initial release in related faSDDSHME. During the evolved-release period, highly extended "spring-parachute" process was found in HME-induced amorphization owing to its superior supersaturation duration. Due to the enhanced crystallization inhibition effect, faSDDSHME displayed the strongest terminal release as measured by solubility. For release mechanisms associated with HME, molecular interaction is not the likely dominant mechanism responsible for the improved properties induced by faSDDSHME. For release mechanisms involved with the polymer Soluplus® itself, they were found to inhibit drug recrystallization, spontaneously solubilize the drug and lead to improved molecular interactions in all SDDS systems, which were the factors responsible for the improved release. These mechanisms play an important role for the generation of an extended multi-stage immediate release produced via HME or self-micellizing polymer. This study provides a deeper understanding on amorphization and superior multi-stage supersaturable immediate-release behaviors for a particular hypotensive supersaturated delivery system combined with an HME-based continuous manufacturing technique and self-micellizing polymer strategy.

Traditional Chinese Medicine Rhodiola Sachalinensis Borissova from Baekdu Mountain (RsBBM) for Rheumatoid Arthritis: Therapeutic Effect and Underlying Molecular Mechanisms.

The lack of effective rheumatoid arthritis (RA) therapies is a persistent challenge worldwide, prompting researchers to urgently evaluate traditional Chinese medicines (TCMs) as potential clinical RA treatments. The present investigation was conducted to evaluate the therapeutic effects and potential molecular mechanisms of the active components isolated from TCM Rhodiola sachalinensis Borissova from Baekdu Mountain (RsBBM) using an experimental adjuvant arthritis model induced by injection of rats with Freund's complete adjuvant. After induction of the adjuvant arthritis rat model, the extract-treated and untreated groups of arthritic rats were evaluated for RsBBM therapeutic effects based on comparisons of ankle circumferences and ELISA-determined blood serum inflammatory factor levels (TNF-α, IL-1ß, and PGE2). In addition, the joint health of rats was evaluated via microscopic examination of hematoxylin-eosin-stained synovial tissues. Furthermore, to explore whether NF-κB and RANK/RANKL/OPG signaling pathways participated in observed therapeutic effects from a molecular mechanistic viewpoint, mRNA and protein levels related to the expression of nuclear factor kappa-B (NF-κB), osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-Β ligand (RANKL) were analyzed via quantitative RT-PCR and Western blot analysis, respectively. Treatment of arthritic rats with the extract of RsBBM was shown to reduce ankle swelling, reduce blood serum levels of inflammatory factors, and alleviate arthritis-associated synovial inflammation and joint damage. Moreover, an RsBBM 50% ethanol extract treatment inhibited bone destruction by up-regulating OPG-related mRNA and protein expression and down-regulating RANKL-related mRNA and protein expression, while also reducing inflammation by the down-regulating of the NF-κB pathway activity. The results clearly demonstrated that the extract of RsBBM alleviated adjuvant arthritis-associated joint damage by altering activities of inflammation-associated NF-κB and the RANK/RANKL/OPG signaling pathways. Due to its beneficial effects for alleviating adjuvant arthritis, this RsBBM 50% ethanol extract should be further evaluated as a promising new therapeutic TCM treatment for RA.

Hot Melt Extrusion-Triggered Amorphization as a Continuous Process for Inducing Extended Supersaturable Drug Immediate-Release from saSMSDs Systems.

Hot melt extrusion (HME), a continuous manufacturing process for generating supersaturating amorphous self-micellizing solid dispersion systems (saSMSDs), holds promise for achieving amorphization of many pharmaceutical formulations. For saSMSDs generation, HME-triggered continuous processes offer advantages over traditional non-continuous processes such as fusion/quench cooling (FQC) and co-precipitation (CP). Here we employed HME, FQC, and CP to generate saSMSDs containing the water-insoluble BCS II drug nitrendipine (NIT) and self-micellizing polymer Soluplus®. Scanning electron microscopy, powder X-ray diffraction, and differential scanning calorimetry results revealed that saSMSDs formed when NIT-Soluplus® mixtures were subjected to the abovementioned amorphization methods. All saSMSDs outperformed crystalline NIT preparations and physical mixtures in achieving extended supersaturable immediate release states with superior solubility, "spring-parachute" process characteristics, and dissolution behaviors. Notably, Fourier transform-infrared spectroscopic results obtained for saSMSDs detected hydrogen bonding interactions between the drug and the carrier. Ultimately, our results revealed the advantages of HME-triggered amorphization as a continuous process for significantly improving drug dissolution, increasing solubility, and maintaining supersaturation as compared to traditional amorphization-based techniques.

Preparation and characterization of sulfated inulin-type fructans from Jerusalem artichoke tubers and their antitumor activity.

The modification of polysaccharides is important for enhancing their biological activities. In this study, a pure inulin-type fructan, denoted as Jerusalem artichoke polysaccharide (P-JAP), was purified from Jerusalem artichoke tubers and modified by sulfation via treatment with a sulfur trioxide-pyridine complex to produce its sulfated derivative (S-JAP). Fourier-transform infrared spectroscopic analysis confirmed the successful introduction of sulfate groups. The inhibitory effects of S-JAP on the proliferation of human liver hepatocellular carcinoma (HepG2) cells was evaluated via a CCK-8 assay, and the pro-apoptotic effects were assessed using annexin V-FITC/PI double staining. The inhibition rates of various concentrations of S-JAP on HepG2 cells after 24, 48, and 72 h were significantly higher than those of P-JAP; moreover, S-JAP succeeded in promoting cell apoptosis. Thus, the sulfate-modified polysaccharide extracted from Jerusalem artichoke tubers was shown to exhibit effective antitumor activity with potential for further development.

"Felodipine-indomethacin" co-amorphous supersaturating drug delivery systems: "Spring-parachute" process, stability, in vivo bioavailability, and underlying molecular mechanisms.

Amorphous solid dispersions (ASD) are one of most commonly used supersaturating drug delivery systems (SDDS) to formulate insoluble active pharmaceutical ingredients. However, the development of polymer-guided stabilization of ASD systems faces many obstacles. To overcome these shortcomings, co-amorphous supersaturable formulations have emerged as an alternative formulation strategy for poorly soluble compounds. Noteworthily, current researches around co-amorphous system (CAS) are mostly focused on preparation and characterization of these systems, but more detailed investigations of their supersaturation ("spring-parachute" process), stability, in vivo bioavailability and molecular mechanisms are inadequate and need to be clarified. In present study, we chose pharmacological relevant BCS II drugs to fabricate and characterize "felodipine-indomethacin" CAS. To enrich the current inadequate but key knowledge on CAS studies, we carried out following highlighted investigations including dissolution/solubility, semi-continuous "spring-parachute" process, long-term stability profile of amorphous state, in vivo bioavailability and underlying molecular mechanisms (molecular interaction, molecular miscibility and crystallization inhibition). Generally, the research provides some key information in the field of current "drug-drug" CAS supersaturable formulations.

Global Evidence of Temperature Acclimation of COVID-19 D614G Linage.

The novel D614G linage is becoming the dominating species of SARS-CoV-2. The impact of meteorological and geographical factors on SARS-CoV-2 pandemic are presently not well understood. This research article presents a retrospective case series. Pandemic and meteorological data from 30 countries and 49 states from USA are collected as of June 10th, 2020. The primary outcome are the coefficients of correlations between meteorological factors and pandemic data. Hierarchical clustering analysis are used on SARS-CoV-2 genome, meteorological factors, and pandemic. Disseminating velocity of SARS-CoV-2 is negatively correlated with average temperature in majority of included countries and states from USA. Proportion of the GR clade is positively associated with temperature, but is negatively correlated with altitude in countries-set. Virus disseminating velocities in states from cluster A (Overwhelming proportion of G + GR + GH clades, GH > 60%) and C (Overwhelming proportion of G + GR + GH clades, G 20-30%) both has negative correlations with temperature, while cluster C has more significant negative correlation than cluster A. Climate and geographical environment are revealed to affect virus spreading. GH and GR clades of SARS-CoV-2 are probably acquiring higher temperature tolerance, while G clade may retain high temperature intolerance.

[Comparative study on pharmacokinetics of gentiopicroside and gentianae radix extract in rats].

OBJECTIVE: To compare the pharmacokinetics of gentiopicroside and Gentianae Radix extract in rats and assess the effect of other components in Gentianae Radix on the pharmacokinetics of gentiopicroside. METHODS: The rats were oral administrated with gentiopicroside and Gentianae Radix extract, the content of geritiopicroside was chosen as index and determined by HPLC. The pharmacokinetic parameters were calculated with DAS 2.1.1 program. RESULTS: The concentration-time curve of gentiopicroside and Gentianae Radix extract was described by two compartment model. The main pharmacokinetic parameters of gentiopicroside and Gentianae Radix extract were: C(max) (16.53 +/- 0.37) g/mL and (16.61 +/- 0.49) g/mL, T(max) 0.25 h and 1.5 h, t1/2(alpha) (0.20 +/- 0.04) h and (0.69 +/- 0. 14) h, t /2 (beta) (0.64 +/- 0.08) hand (0.80 +/- 0.11) h, AUC(0-infinity) (18.20 +/- 1.97) g x h/mL and (39.20 +/- 1.18) g x h/mL, CL( 2.75 +/- 0.32) L/(h x kg) and (1.22 +/- 0.04) L (h x kg), respectively. CONCLUSION: There are significantly differences in pharmacokinetic parameters between gentiopicroside and Gentianae Radix extract in rats.