Targeting CD38/ ADP-ribosyl cyclase as a novel therapeutic strategy for identification of three potent agonists for leukopenia treatment.

Leukopenia is the most common side effect of chemotherapy and radiotherapy. It potentially deteriorates into a life-threatening complication in cancer patients. Despite several agents being approved for clinical administration, there are still high incidences of pathogen-related disease due to a lack of functional immune cells. ADP-ribosyl cyclase of CD38 displays a regulatory effect on leukopoiesis and the immune system. To explore whether the ADP-ribosyl cyclase was a potential therapeutic target of leukopenia. We established a drug screening model based on an ADP-ribosyl cyclase-based pharmacophore generation algorithm and discovered three novel ADP-ribosyl cyclase agonists: ziyuglycoside II (ZGSII), brevifolincarboxylic acid (BA), and 3,4-dihydroxy-5-methoxybenzoic acid (DMA). Then, in vitro experiments demonstrated that these three natural compounds significantly promoted myeloid differentiation and antibacterial activity in NB4 cells. In vivo, experiments confirmed that the compounds also stimulated the recovery of leukocytes in irradiation-induced mice and zebrafish. The mechanism was investigated by network pharmacology, and the top 12 biological processes and the top 20 signaling pathways were obtained by intersecting target genes among ZGSII, BA, DMA, and leukopenia. The potential signaling molecules involved were further explored through experiments. Finally, the ADP-ribosyl cyclase agonists (ZGSII, BA, and DMA) has been found to regenerate microbicidal myeloid cells to effectively ameliorate leukopenia-associated infection by activating CD38/ADP-ribosyl cyclase-Ca2+-NFAT. In summary, this study constructs a drug screening model to discover active compounds against leukopenia, reveals the critical roles of ADP-ribosyl cyclase in promoting myeloid differentiation and the immune response, and provides a promising strategy for the treatment of radiation-induced leukopenia.

Curcumin-Loaded Platelet Membrane Bioinspired Chitosan-Modified Liposome for Effective Cancer Therapy.

Cancer is a serious threat to human health, and chemotherapy for cancer is limited by severe side effects. Curcumin (CUR) is a commonly used natural product for antitumor treatment without safety concerns. However, low bioavailability and poor tumor accumulation are great obstacles for its clinical application. Our previous research has demonstrated that platelet membrane-camouflaged nanoparticles can efficiently ameliorate the in vivo kinetic characteristics and enhance the tumor affinity of payloads. Nevertheless, the antitumor efficiency of this formulation still needs to be thoroughly investigated, and its drug release behavior is limited. Herein, CUR-loaded platelet membrane bioinspired chitosan-modified liposome (PCLP-CUR) was constructed to improve CUR release. PCLP-CUR was shown to have long retention time, improved bioavailability, strong tumor targeting capacity and effective cellular uptake. The incorporation of chitosan enabled PCLP-CUR to release cargoes quickly under mild acidic tumor conditions, leading to more complete drug release and favoring subsequent treatment. Both in vitro and in vivo investigations showed that PCLP-CUR could significantly enhance the anticancer efficacy of CUR with minimal side effects through biomimetic membrane and chitosan modification. In summary, this developed delivery system can provide a promising strategy for tumor-targeting therapy and phytochemical delivery.

Fabrication, Optimization, and Evaluation of Paclitaxel and Curcumin Coloaded PLGA Nanoparticles for Improved Antitumor Activity.

Codelivery of chemotherapeutic drugs in nanoparticles can enhance the therapeutic effects against tumors. However, their anticancer properties and physiochemical characteristics can be severely influenced by many formulation parameters during the preparation process. It is a complicated development phase to select the optimal parameters for preparation of nanoparticles based on the commonly used one single parameter method, which consumes a lot of money, time, and effort, and sometimes even fails. Therefore, the statistical analysis based on Box-Behnken design (BBD) has attracted much attention in bioengineering fields because it can illustrate the influence of parameters, build mathematical models, and predict the optimal combinational factors in a decreased number of experiments. In this study, we used a three-factor three-level BBD design to optimize the preparation of poly(lactic-co-glycolic acid) (PLGA) nanoparticles coloaded with two anticancer drugs curcumin and paclitaxel (PLGA-CUR-PTX nanoparticles). The surfactant concentration, polymer concentration, and oil-water ratio were selected as independent variables. An optimized model of the formulation for PLGA-CUR-PTX nanoparticles was validated. The optimal nanoparticles possessed a uniform spherical shape, with an average size of 99.94 nm, and the drug encapsulation efficiencies of CUR and PTX were 63.53 and 80.64%, respectively. The drug release from nanoparticles showed a biphasic release behavior, with a release mechanism via diffusion and fundamentally quasi-Fickian diffusion. The optimized nanoparticles demonstrated an enhanced cytotoxicity effect with lower IC50 values to 4T1 and MCF-7 breast cancer cell lines compared to free drugs. In summary, BBD optimization of CUR and PTX coloaded nanoparticles yielded a favorable drug carrier that holds potential as an alternative treatment for anticancer therapy.

Bioinspired Platelet-like Nanovector for Enhancing Cancer Therapy via P-Selectin Targeting.

Cancer is a major threat to the health of humans. Recently, various natural products including curcumin (CCM) have attracted enormous interest for efficacious cancer therapy. However, natural therapeutic agents still encounter certain challenges such as rapid clearance, low bioavailability, and poor tumor targeting. Recently, the platelet membrane (PM) camouflaged nanoparticle has provided a promising solution for cancer targeting therapy. Nevertheless, only limited efforts have been dedicated to systematically explore the mechanism of affinity between PM bioinspired nanoparticles and various tumor cells. Herein, a CCM-encapsulated platelet membrane biomimetic lipid vesicle (CCM@PL) with a size of 163.2 nm, zeta potential of -31.8 mV and encapsulation efficiency of 93.62% was developed. The values of the area under the concentration-time curve and mean residence time for CCM@PL were 3.08 times and 3.04 times those of CCM, respectively. Furthermore, this PM biomimetic carrier showed an excellent affinity against Huh-7, SK-OV-3 and MDA-MB-231 cell lines due to the biomolecular interaction between P-selectin on the PM and tumoral CD44 receptors. In addition, CCM@PL displayed enhanced cytotoxicity compared with free CCM and the synthetic formulation. Overall, our results suggest that this developed PM biomimetic lipid nanovector has great potential for targeted cancer treatment and natural components delivery.

Macrophage cell membrane-based nanoparticles: a new promising biomimetic platform for targeted delivery and treatment.

Synthetic nanoparticles with surface bioconjugation are promising platforms for targeted therapy, but their simple biological functionalization is still a challenging task against the complex intercellular environment. Once synthetic nanoparticles enter the body, they are phagocytosed by immune cells by the immune system. Recently, the cell membrane camouflage strategy has emerged as a novel therapeutic tactic to overcome these issues by utilizing the fundamental properties of natural cells. Macrophage, a type of immune system cells, plays critical roles in various diseases, including cancer, atherosclerosis, rheumatoid arthritis, infection and inflammation, due to the recognition and engulfment function of removing substances and pathogens. Macrophage membranes inherit the surface protein profiles and biointerfacing properties of source cells. Therefore, the macrophage membrane cloaking can protect synthetic nanoparticles from phagocytosis by the immune cells. Meanwhile, the macrophage membrane can make use of the natural correspondence to accurately recognize antigens and target inflamed tissue or tumor sites. In this review, we have summarized the advances in the fabrication, characterization and homing capacity of macrophage membrane cloaking nanoparticles in various diseases, including cancers, immune diseases, cardiovascular diseases, central nervous system diseases, and microbial infections. Although macrophage membrane-camouflaged nanoparticles are currently in the fetal stage of development, there is huge potential and challenge to explore the conversion mode in the clinic.

A comprehensive comparison of medication strategies for platinum-sensitive recurrent ovarian cancer: A Bayesian network meta-analysis.

Background: The Platinum-based combination has been proven to have an outstanding effect on patients with platinum-sensitive recurrent ovarian cancer (PSROC), but the best scientific combination has not been established yet. The present study is aimed to seek the best treatment plan for PSROC. Methods: We did a systematic review and Bayesian network meta-analysis, during which lite before March 2022 were retrieved on PubMed, Embase, Web of Science, and Cochrane Central Registry of Controlled databases. We included randomized controlled clinical trials comparing chemotherapy combinations with other treatments for patients with PSROC. The important outcomes concerned were progression-free survival (PFS) (the primary outcome), overall survival (OS), objective response rate (ORR), adverse events (AEs), and AEs-related discontinuation. All outcomes were ranked according to the surface under the cumulative ranking curve. Results: 26 trials involving 10441 patients were retrieved in this study. For the initial treatment of PSROC, carboplatin plus pegylated liposomal doxorubicin (PLD) plus bevacizumab had the best PFS [hazard ratio (HR) 0.59, 95% credible interval (CI) 0.51-0.68]; Carboplatin plus paclitaxel plus bevacizumab resulted in the best OS (HR 1.22, 95% CI 1.09-1.35) and ORR [odds ratio (OR) 1.22, 95% CI 1.09-1.35]. For the maintenance therapy in PSROC, poly (ADP-ribose) polymerase inhibitors (PARPi) following platinum-based chemotherapy provided the best PFS (HR 0.64, 95% CI 0.61-0.68), the highest frequency of adverse events of grade three or higher (OR 0.18, 95% CI 0.07-0.44) but the treatment discontinuation was generally low. Subgroup analysis suggested that trabectedin plus PLD was comparable to single platinum in prolonging PFS in the platinum-free interval (6-12 months). Conclusion: Both platinum-based chemotherapy plus PARPi and platinum-based chemotherapy plus bevacizumab had higher survival benefits than other treatments in PSROC. Trabectedin plus PLD might be a potential alternative treatment strategy for the partially platinum-sensitive subpopulation with intolerance to platinum. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?], identifier [CRD42022326573].

Identification of a Mitochondria-Related Gene Signature to Predict the Prognosis in AML.

Mitochondria-related metabolic reprogramming plays a major role in the occurrence, development, drug resistance, and recurrence of acute myeloid leukemia (AML). However, the roles of mitochondria-related genes (MRGs) in the prognosis and immune microenvironment for AML patients remain largely unknown. In this study, by least absolute shrinkage and selection operator (LASSO) Cox regression analysis, 4 MRGs' (HPDL, CPT1A, IDH3A, and ETFB) signature was established that demonstrated good robustness in TARGET AML datasets. The univariate and multivariate Cox regression analyses both demonstrated that the MRG signature was a robust independent prognostic factor in overall survival prediction with high accuracy for AML patients. Based on the risk score calculated by the signature, samples were divided into high- and low-risk groups. Gene set enrichment analysis (GSEA) suggested that the MRG signature is involved in the immune-related pathways. Via immune infiltration analysis and immunosuppressive genes analysis, we found that MRG risk of AML patients was strikingly positively correlated with an immune cell infiltration and expression of critical immune checkpoints, indicating that the poor prognosis might be caused by immunosuppressive tumor microenvironment (TME). In summary, the signature based on MRGs could act as an independent risk factor for predicting the clinical prognosis of AML and could also reflect an association with the immunosuppressive microenvironment, providing a novel method for AML metabolic and immune therapy based on the regulation of mitochondrial function.

Biomimetic lipidic nanovectors for effective asparaginase supramolecule delivery.

Effectiveness of enzyme therapy is limited by enzyme drawbacks such as short half-life, low bioavailability and high immunogenicity. We loaded asparaginase (Aase) into hydroxypropyl- or sulfonbutylether-beta cyclodextrin to form supramolecular amphiphilic molecules by self-assembly followed by entrapment inside the cores of two biomimetic lipidic nanovectors (AS-XLNs). Supramolecular structure was simulated by molecular docking. AS-XLNs maintained superior activity through isolating Aase from external environment due to docking with cyclodextrin and coating with biomimetic membrane. Fluorescent probes and computational simulations were used to reveal possible interactions between serum albumin/trypsin and Aase/nanovector membrane components which were partly responsible for enhanced bioavailability and bioactivity of AS-XLNs compared to Aase. AS-XLNs significantly increased cytotoxicity against pulmonary tumor cells due to synergistic effects of Aase and nanovector membrane components (killing tumor cells through apoptosis induced by asparagine depletion and autophagy inhibition or via targets such as vascular endothelial growth factor A, alpha-amylase, p-selectin or androgen receptor).

Preparation and optimization of poly (lactic-co-glycolic acid) rod-shaped particles in nano size range for paclitaxel delivery.

Nanoparticle shape has been acknowledged as an important design parameter due to its influence on nanoparticle interaction with biological systems. However, there is lacking of simple and scalable preparation technique for drug loaded non-spherical polymeric nanoparticles for a long time, thus hindering the potential applications. Although our previous research has modified the traditional emulsion solvent evaporation technique by adding guest molecules to prepare non-spherical poly (lactic-co-glycolic acid) (PLGA) particles, it is difficult to obtain nano-sized rods with minor axis less than 200 nm, which may have great potential in cancer therapy. Herein, in present research, the two-step ESE method was used and optimized to prepare poly (lactic-co-glycolic acid) nanorods for paclitaxel delivery. Firstly, the single-factor experiment was used to screen the influence of multi-factors including type of guest molecules, concentration of guest molecules, emulsification method, surfactant concentration, oil volume, poly (lactic-co-glycolic acid) concentration on the size and shape to determine the range of variables; based on the above range, a multi-factor and multi-level orthogonal experiment was designed. The formula is evaluated by the rod fabrication yield and the aspect ratio of major axis to minor axis. The results showed that the yield of nanorods in the optimal formula was 99% and the aspect ratio was 5.35 ± 2.05 with the minor axis of 135.49 ± 72.66 nm, and major axis of 657.77 ± 307.63 nm. In addition, the anti-cancer drug paclitaxel was successfully encapsulated in PLGA nanorods by the same technique. Our results not only enrich the ESE technique for preparing small sized poly (lactic-co-glycolic acid) nanorods, but also envision the potential application of nanorods for targeted cancer therapy with the delivery of paclitaxel.

Chitosan-modified lipid nanovesicles for efficient systemic delivery of l-asparaginase.

The goal of this study was to evaluate the enhanced catalytic activity, increased stability, in vitro anti-cancer effects on H446 cells and in vivo bioavailability of novel enzyme delivery nanovesicles (l-asparaginase containing chitosan modified lipid nanovesicles, ACLNs) when administered intravenously. It was the first time for the chitosan-modified lipid nanovesicles to be fabricated to deliver l-asparaginase (ASP, a therapeutic enzyme) efficiently. It was indicated that ACLNs markedly increased the enzymatic activity, improved the temperature/acid-base/proteolytic stabilities and favorably changed the in vivo kinetic characteristics. Moreover, ACLNs exhibited higher anti-lung-cancer activity than free ASP. The possible existence status of ASP in ACLNs and the fluorescence changes of ACLNs reflecting the conformational changes after heat treatment were preliminary explored. ACLNs might be novel promising nanovesicles for effective systemic delivery of therapeutic enzyme ASP.

Nanosomal Microassemblies for Highly Efficient and Safe Delivery of Therapeutic Enzymes.

Enzyme therapy has unique advantages over traditional chemotherapies for the treatment of hyperuricemia, but overcoming the delivery obstacles of therapeutic enzymes is still a significant challenge. Here, we report a novel and superior system to effectively and safely deliver therapeutic enzymes. Nanosomal microassemblies loaded with uricase (NSU-MAs) are assembled with many individual nanosomes. Each nanosome contains uricase within the alkaline environment, which is beneficial for its catalytic reactions and keeps the uricase separate from the bloodstream to retain its high activity. Compared to free uricase, NSU-MAs exhibited much higher catalytic activity under physiological conditions and when subjected to different temperatures, pH values and trypsin. NSU-MAs displayed increased circulation time, improved bioavailability, and enhanced uric acid-lowering efficacy, while decreasing the immunogenicity. We also described the possible favorable conformational changes occurring in NSU-MAs that result in favorable outcomes. Thus, nanosomal microassemblies could serve as a valuable tool in constructing delivery systems for therapeutic enzymes that treat various diseases.

[Pharmacokinetics and Intestinal Absorption of Curcumin Chitosan Hydrochloride Coated Liposome in Rats].

OBJECTIVE: To investigate the pharmacokinetics and intestinal absorption characteristic of curcumin chitosan hydrochloride coated liposome(CCLP) in SD rats. METHODS: Blood samples were collected after oral administration. Pharmacokinetic parameters were analyzed by DAS program. Rat single pass intestinal perfusion method was employed to investigate the absorption mechanism. RESULTS: The AUC0-t, AUC0-∞, t1/2, and Cmax of CCLP were 1. 73-fold, 1. 95-fold, 1. 56-fold and 1. 91-fold of the free drug. The intestinal absorption rate constant (Ka) of CCLP in duodenum, jejunum, ileum and colon were 1. 48, 1. 28, 1. 17 , and 4. 01 times as much as the free drug and the effective permeability(Peff) of CCLP were 1. 58, 1.-33, 1. 30 and 4. 55 times of the free drug, respectively. CONCLUSION: The bioavailability of CCLP in rats is increased remarkably and Ka is increased in various intestinal segments by CCLP, especially in colon, as well as Peff.

Azithromycin cationic non-lecithoid nano/microparticles improve bioavailability and targeting efficiency.

PURPOSE: The purpose of this study was to develop and evaluate the azithromycin cationic non-lecithoid nano/microparticles with high bioavailability and lung targeting efficiency. METHODS: The cationic niosomes with different sizes (AMCNS-S and AMCNS-L) along with varied built-in characteristics were produced to achieve high bioavailability and lung targeting efficiency of azithromycin (AM) via two administration routes widely used in clinical practice, i.e., oral and intravenous routes, instead of transdermal route (by which the only marketed niosome-based drug delivery dermatologic products were given). The possible explanations for improved bioavailability and lung targeting efficacy were put forward here. RESULTS: AMCNS-S (or AMCNS-L) had high bioavailability, for example, the oral (or intravenous) relative bioavailability of AMCNS-S (or AMCNS-L) to free AM increased to 273.19% (or 163.50%). After intravenous administration, AMCNS-S (or AMCNS-L) had obvious lung targeting efficiency, for example, the lung AM concentration of AMCNS-S (or AMCNS-L) increased 16 (or 28) times that of free AM at 12 h; the AM concentration of AMCNS-S (or AMCNS-L) in lung was higher than that in heart and kidney all the time. CONCLUSIONS: The development of niosome-based AM nanocarriers provides valuable tactics in antibacterial therapy and in non-lecithoid niosomal application.