Complexos polieletrólitos de quitosana e xantana carregados com ativos naturais e sintéticos: estudo físico/químico e microbiológico para aplicação de drug delivery / Polyelectrolyte complexes of chitosan and xanthan loaded with natural and synthetic actives: physicochemical and microbiological study for drug delivery application

A eficácia dos implantes osseointegrados é amplamente reconhecida na literatura científica. Contudo, infiltrações bacterianas na junção implante-pilar podem desencadear inflamação nos tecidos circundantes, contribuindo para a evolução de condições mais sérias, como a peri-implantite. O objetivo desse estudo foi produzir complexos polieletrólitos (PECs) de quitosana (Q) e xantana (X) em forma de membranas, carregá-las com ativos naturais e sintéticos antimicrobianos, caracterizálas estruturalmente e avaliá-las frente a degradação enzimática, cinética de liberação e ações antimicrobianas com finalidade de aplicação para drug delivery. Membranas de QX a 1% (m/v) foram produzidas em três proporções, totalizando doze grupos experimentais: QX (1:1); QX (1:2), QX (2:1), QX-P (com própolis) (1:1); QX-P (1:2); QX-P (2:1); QX-C (com canela) (1:1); QX-C (1:2); QX-C (2:1) e CLX (com clorexidina 0,2%) (1:1); CLX (1:2); CLX (2:1). Para os estudos de caracterização foram feitas análises da espessura em estado seco; análises morfológicas superficial e transversal em Microscopia Eletrônica de Varredura (MEV); análise estrutural de espectroscopia de infravermelho por transformada de Fourier (FTIR); análise de degradação por perda de massa sob ação da enzima lisozima; e análise da cinética de liberação dos ativos em saliva artificial. Para os testes microbiológicos, análises de verificação de halo de inibição e ação antibiofilme foram feitas contra cepas de Staphylococcus aureus (S. aureus) e Escherichia coli (E. coli). Os resultados demonstraram que a espessura das membranas variou conforme a proporção, sendo que o grupo QX (1:2) apresentou a maior média de 1,022 mm ± 0,2, seguida respectivamente do QX (1:1) com 0,641 mm ± 0,1 e QX (2:1) com 0,249 mm ± 0,1. Nas imagens de MEV é possível observar uma maior presença de fibras, rugosidade e porosidade nos grupos QX (1:2) e QX (1:1) respectivamente, e, no QX (2:1) uma superfície mais lisa, uniforme e fina. No FTIR foram confirmados os picos característicos dos materiais isoladamente, além de observar as ligações iônicas que ocorreram para formação dos PECs. Na análise de degradação, os grupos com ativos naturais adicionados tiveram melhores taxas de sobrevida do que os grupos QX. No teste de liberação, os grupos QX-P tiveram uma cinética mais lenta que os QX-C, cuja liberação acumulada de 100% foi feita em 24 h. Já nos testes do halo inibitório, somente os grupos CLX tiveram ação sobre as duas cepas, e os QX-P tiveram sobre S. aureus. Nas análises antibiofilme, os grupos CLX apresentaram as maiores taxas de redução metabólica nas duas cepas (± 79%); os grupos QX-P apresentaram taxas de redução similares em ambas as cepas, porém com percentual um pouco maior para E. coli (60- 80%) e os grupos QX-C tiveram grande discrepância entre as duas cepas: de 35 a 70% para S. aureus e 14 a 19% para E. coli. Pode-se concluir que, frente as análises feitas, o comportamento do material foi afetado diretamente pelos ativos adicionados a matriz polimérica. As proporções de Q ou X afetaram somente a espessura final. Quanto a aplicação proposta de drug delivery, os dispositivos apresentaram grande potencial, principalmente os grupos CLX e QX-P. (AU)

The effectiveness of osseointegrated implants is widely recognized in scientific literature. However, bacterial infiltrations at the implant-abutment interface may trigger inflammation in surrounding tissues, contributing to the development of more serious conditions, such as peri-implantitis. The aim of this study was to produce chitosan (Q) and xanthan (X) polyelectrolyte complexes (PECs) in the form of membranes, load and evaluate them for enzymatic degradation, release kinetics, and antimicrobial actions for drug delivery applications. QX membranes at 1% (w/v) were produced in three proportions, totaling twelve experimental groups: QX (1:1), QX (1:2), QX (2:1), QX-P (with propolis) (1:1), QX-P (1:2), QX-P (2:1), QX-C (with cinnamon) (1:1), QX-C (1:2), QX-C (2:1), and CLX (with 0.2% chlorhexidine) (1:1), CLX (1:2), CLX (2:1). Characterization studies included analyses of dry state thickness, surface and crosssectional morphology using Scanning Electron Microscopy (SEM), structural analysis by Fourier Transform Infrared (FTIR) spectroscopy, mass loss degradation analysis under lysozyme action, and active release kinetics analysis in artificial saliva. Microbiological tests included verification analyses of inhibition halos and antibiofilm action against strains of Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Results showed that membrane thickness varied according to proportion, with group QX (1:2) presenting the highest average of 1.022 mm ± 0.2, followed by QX (1:1) with 0.641 mm ± 0.1, and QX (2:1) with 0.249 mm ± 0.1. SEM images showed greater presence of fibers, roughness, and porosity in groups QX (1:2) and QX (1:1) respectively, while QX (2:1) exhibited a smoother, more uniform, and thinner surface. FTIR confirmed characteristic peaks of the materials individually, besides showing ionic bonds formed for PECs. Degradation analysis revealed that groups with added natural actives had better survival rates than QX groups. In release tests, QX-P groups exhibited slower kinetics than QX-C, with 100% cumulative release achieved in 24 h. inhibitory halo tests, only CLX groups exhibited action against both strains, while QX-P acted against S. aureus. Antibiofilm analyses showed CLX groups with the highest metabolic reduction rates in both strains (± 79%); QX-P groups showed similar reduction rates in both strains, slightly higher for E. coli (60-80%), and QX-C groups had a significant discrepancy between strains: 35-70% for S. aureus and 14-19% for E. coli. In conclusion, material behavior was directly affected by added actives to the polymeric matrix. Proportions of Q or X only affected final thickness. Regarding proposed drug delivery applications, the devices showed great potential, especially CLX and QX-P groups.(AU)

Applications and recent advances in transdermal drug delivery systems for the treatment of rheumatoid arthritis

Rheumatoid arthritis is a chronic, systemic autoimmune disease predominantly based on joint lesions with an extremely high disability and deformity rate. Several drugs have been used for the treatment of rheumatoid arthritis, but their use is limited by suboptimal bioavailability, serious adverse effects, and nonnegligible first-pass effects. In contrast, transdermal drug delivery systems (TDDSs) can avoid these drawbacks and improve patient compliance, making them a promising option for the treatment of rheumatoid arthritis (RA). Of course, TDDSs also face unique challenges, as the physiological barrier of the skin makes drug delivery somewhat limited. To overcome this barrier and maximize drug delivery efficiency, TDDSs have evolved in terms of the principle of transdermal facilitation and transdermal facilitation technology, and different generations of TDDSs have been derived, which have significantly improved transdermal efficiency and even achieved individualized controlled drug delivery. In this review, we summarize the different generations of transdermal drug delivery systems, the corresponding transdermal strategies, and their applications in the treatment of RA.

Advancing drug delivery to articular cartilage: From single to multiple strategies

Articular cartilage (AC) injuries often lead to cartilage degeneration and may ultimately result in osteoarthritis (OA) due to the limited self-repair ability. To date, numerous intra-articular delivery systems carrying various therapeutic agents have been developed to improve therapeutic localization and retention, optimize controlled drug release profiles and target different pathological processes. Due to the complex and multifactorial characteristics of cartilage injury pathology and heterogeneity of the cartilage structure deposited within a dense matrix, delivery systems loaded with a single therapeutic agent are hindered from reaching multiple targets in a spatiotemporal matched manner and thus fail to mimic the natural processes of biosynthesis, compromising the goal of full cartilage regeneration. Emerging evidence highlights the importance of sequential delivery strategies targeting multiple pathological processes. In this review, we first summarize the current status and progress achieved in single-drug delivery strategies for the treatment of AC diseases. Subsequently, we focus mainly on advances in multiple drug delivery applications, including sequential release formulations targeting various pathological processes, synergistic targeting of the same pathological process, the spatial distribution in multiple tissues, and heterogeneous regeneration. We hope that this review will inspire the rational design of intra-articular drug delivery systems (DDSs) in the future.

Research advances in peptide‒drug conjugates

Peptide‒drug conjugates (PDCs) are drug delivery systems consisting of a drug covalently coupled to a multifunctional peptide via a cleavable linker. As an emerging prodrug strategy, PDCs not only preserve the function and bioactivity of the peptides but also release the drugs responsively with the cleavable property of the linkers. Given the ability to significantly improve the circulation stability and targeting of drugs in vivo and reduce the toxic side effects of drugs, PDCs have already been extensively applied in drug delivery. Herein, we review the types and mechanisms of peptides, linkers and drugs used to construct PDCs, and summarize the clinical applications and challenges of PDC drugs.

Plant-derived nanovesicles: Further exploration of biomedical function and application potential

Extracellular vesicles (EVs) are phospholipid bilayer vesicles actively secreted by cells, that contain a variety of functional nucleic acids, proteins, and lipids, and are important mediums of intercellular communication. Based on their natural properties, EVs can not only retain the pharmacological effects of their source cells but also serve as natural delivery carriers. Among them, plant-derived nanovesicles (PNVs) are characterized as natural disease therapeutics with many advantages such as simplicity, safety, eco-friendliness, low cost, and low toxicity due to their abundant resources, large yield, and low risk of immunogenicity in vivo. This review systematically introduces the biogenesis, isolation methods, physical characterization, and components of PNVs, and describes their administration and cellular uptake as therapeutic agents. We highlight the therapeutic potential of PNVs as therapeutic agents and drug delivery carriers, including anti-inflammatory, anticancer, wound healing, regeneration, and antiaging properties as well as their potential use in the treatment of liver disease and COVID-19. Finally, the toxicity and immunogenicity, the current clinical application, and the possible challenges in the future development of PNVs were analyzed. We expect the functions of PNVs to be further explored to promote clinical translation, thereby facilitating the development of a new framework for the treatment of human diseases.

Effects of propofol and remifentanil in different TCI sequences on hypotension during induction of general anesthesia in hypertensive patients / 中华麻醉学杂志

Objective:To evaluate the effect of propofol and remifentanil in different target-controlled infusion(TCI) sequences on hypotension during induction of general anesthesia in hypertensive patients.Methods:A total of 132 patients with hypertension of both sexes, aged 50-75 yr, of American Society of Anesthesiologists Physical Status classificationⅡ or Ⅲ, with body mass index of 18-30 kg/m 2, scheduled for elective tracheal intubation under general anesthesia, were divided into 3 groups( n=44 each) using a random number table method: group C, PR group and RP group. In group C, propofol(target effect-site concentration 5 μg/ml) and remifentanil(target effect-site concentration 5 ng/ml) were simultaneously given by TCI. Propofol was given by TCI followed by TCI of remifentanil in PR group. Remifentanil was given by TCI followed by TCI of propofol in RP group. The development of hypotension was observed within 10 min after induction of general anesthesia, and the consumption of propofol, remifentanil and ephedrine, time of loss of consciousness, time of tracheal intubation and adverse reactions during the perioperative period were recorded. Results:Compared with group C, the incidence of hypotension during induction was significantly decreased, the consumption of propofol and ephedrine was decreased, and the BIS value was increased when consciousness disappeared, the time of loss of consciousness and time of tracheal intubation were prolonged, the BIS value was increased at loss of consciousness in PR group, and the consumption of ephedrine was significantly decreased, and the time of loss of consciousness and time of tracheal intubation were prolonged in RP group( P<0.05). Compared with PR group, the consumption of ephedrine was significantly decreased, and the time of loss of consciousness was prolonged in RP group( P<0.05). There was no significant difference in the incidence of responses to tracheal intubation, injection pain, bucking, inhibition ratio, postoperative delirium, postoperative nausea and vomiting, and intraoperative awareness during induction among the three groups( P>0.05). Conclusions:TCI of remifentanil followed by TCI of propofol can decrease the development of hypotension during induction of general anesthesia in hypertensive patients.

Polymeric nanocarriers for nose-to-brain drug delivery in neurodegenerative diseases and neurodevelopmental disorders

Neurodegenerative diseases are progressive conditions that affect the neurons of the central nervous system (CNS) and result in their damage and death. Neurodevelopmental disorders include intellectual disability, autism spectrum disorder, and attention-deficit/hyperactivity disorder and stem from the disruption of essential neurodevelopmental processes. The treatment of neurodegenerative and neurodevelopmental conditions, together affecting ∼120 million people worldwide, is challenged by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier that prevent the crossing of drugs from the systemic circulation into the CNS. The nose-to-brain pathway that bypasses the BBB and increases the brain bioavailability of intranasally administered drugs is promising to improve the treatment of CNS conditions. This pathway is more efficient for nanoparticles than for solutions, hence, the research on intranasal nano-drug delivery systems has grown exponentially over the last decade. Polymeric nanoparticles have become key players in the field owing to the high design and synthetic flexibility. This review describes the challenges faced for the treatment of neurodegenerative and neurodevelopmental conditions, the molecular and cellular features of the nasal mucosa and the contribution of intranasal nano-drug delivery to overcome them. Then, a comprehensive overview of polymeric nanocarriers investigated to increase drug bioavailability in the brain is introduced.

Real-time SERS monitoring anticancer drug release along with SERS/MR imaging for pH-sensitive chemo-phototherapy

In situ and real-time monitoring of responsive drug release is critical for the assessment of pharmacodynamics in chemotherapy. In this study, a novel pH-responsive nanosystem is proposed for real-time monitoring of drug release and chemo-phototherapy by surface-enhanced Raman spectroscopy (SERS). The Fe3O4@Au@Ag nanoparticles (NPs) deposited graphene oxide (GO) nanocomposites with a high SERS activity and stability are synthesized and labeled with a Raman reporter 4-mercaptophenylboronic acid (4-MPBA) to form SERS probes (GO-Fe3O4@Au@Ag-MPBA). Furthermore, doxorubicin (DOX) is attached to SERS probes through a pH-responsive linker boronic ester (GO-Fe3O4@Au@Ag-MPBA-DOX), accompanying the 4-MPBA signal change in SERS. After the entry into tumor, the breakage of boronic ester in the acidic environment gives rise to the release of DOX and the recovery of 4-MPBA SERS signal. Thus, the DOX dynamic release can be monitored by the real-time changes of 4-MPBA SERS spectra. Additionally, the strong T2 magnetic resonance (MR) signal and NIR photothermal transduction efficiency of the nanocomposites make it available for MR imaging and photothermal therapy (PTT). Altogether, this GO-Fe3O4@Au@Ag-MPBA-DOX can simultaneously fulfill the synergistic combination of cancer cell targeting, pH-sensitive drug release, SERS-traceable detection and MR imaging, endowing it great potential for SERS/MR imaging-guided efficient chemo-phototherapy on cancer treatment.

Encapsulation of benznidazole in nanostructured lipid carriers and increased trypanocidal activity in a resistant Trypanosoma cruzi strain

Abstract Chagas disease is a neglected parasitic disease caused by Trypanosoma cruzi, whose treatment has remained unsatisfactory for over 50 years, given that it is limited to two drugs. Benznidazole (BZN) is an efficient antichagasic drug used as the first choice, although its poor water-solubility, irregular oral absorption, low efficacy in the chronic phase, and various associated adverse effects are limiting factors for treatment. Incorporating drugs with such characteristics into nanostructured lipid carriers (NLC) is a promising alternative to overcome these limiting obstacles, enhancing drug efficacy and bioavailability while reducing toxicity. Therefore, this study proposed NLC-BZN formulations in different compositions prepared by hot-melt homogenization followed by ultrasound, and the optimized formulation was characterized by FTIR, DRX, DSC, and thermogravimetry. Biological activities included in vitro membrane toxicity (red blood cells), fibroblast cell cytotoxicity, and trypanocidal activity against epimastigotes of the Colombian strain of T. cruzi. The optimized NLC-BZN had a small size (110 nm), negative zeta potential (-18.0 mV), and high encapsulation (1.64% of drug loading), as shown by infrared spectroscopy, X-ray diffraction, and thermal analysis. The NLC-BZN also promoted lower in vitro membrane toxicity (<3% hemolysis), and 50% cytotoxic concentration (CC50) for NLC-BZN in L929 fibroblast cells (110.7 µg/mL) was twice the value as the free BZN (51.3 µg/mL). Our findings showed that the NLC-BZN had higher trypanocidal activity than free BZN against the epimastigotes of the resistant Colombian strain, and this novel NLC-BZN formulation proved to be a promising tool in treating Chagas disease and considered suitable for oral and parenteral administration

Selective photodynamic effects on cervical adenocarcinoma cells provided by F127 Pluronic®-based micelles modulating hypericin delivery

Abstract Cervical cancer is a leading cause of death among women. The endocervical adenocarcinoma (ECA) represents an aggressive and metastatic type of cancer with no effective treatment options currently available. We evaluated the antitumoral and anti-migratory effects of hypericin (HYP) encapsulated on Pluronic F127 (F127/HYP) photodynamic therapy (PDT) against a human cell line derived from invasive cervical adenocarcinoma (HeLa) compared to a human epithelial cell line (HaCaT). The phototoxicity and cytotoxicity of F127/HYP were evaluated by the following assays: colorimetric assay, MTT, cellular morphological changes by microscopy and long-term cytotoxicity by clonogenic assay. In addition, we performed fluorescence microscopy to analyze cell uptake and subcellular distribution of F127/HYP, cell death pathway and reactive oxygen species (ROS) production. The PDT mechanism was determined with sodium azide and D-mannitol and cell migration by wound-healing assay. The treatment with F127/HYP promoted a phototoxic result in the HeLa cells in a dose-dependent and selective form. Internalization of F127/HYP was observed mainly in the mitochondria, causing cell death by necrosis and ROS production especially by the type II PDT mechanism. Furthermore, F127/HYP reduced the long-term proliferation and migration capacity of HeLa cells. Overall, our results indicate a potentially application of F127/HYP micelles as a novel approach for PDT with HYP delivery to more specifically treat ECA.

Diseño y caracterización de un sistema de entrega de fármacos autoemulsificable (SEDDS) de estradiol por diagramas de fases pseudoternarios y pruebas fisicoquímicas

Introducción: el estradiol es una hormona esteroide sexual femenina usada ampliamente como terapia hormonal que presenta una baja biodisponibilidad, debido a su baja solubilidad acuosa y a su alta hidrofobicidad, perteneciendo a la clase II del sistema de clasificación de biofarmacéutica. Objetivos: diseñar y caracterizar un sistema de entrega de fármacos autoemulsificable (SEDDS) para el fármaco estradiol por pruebas fisicoquímicas con el fin de obtener la relación óptima que permitiera mejorar su solubilidad acuosa, velocidad de disolución y potencialmente su biodisponibilidad. Método: estudios de solubilidad en diferentes solventes, diagramas de fases pseudoternarios constituidos por aceites, tensioactivos, cotensioactivos y agua permitieron reconocer las diferentes regiones de formación de SEDDS e identificar los porcentajes de excipientes que conducen a la formación de soluciones isotrópicas; las formulaciones resultantes fueron caracterizadas en tiempo de autoemulsificación, robustez a la dilución, punto de nube y perfil de disolución en capsula dura. Resultados: las formulaciones que contenían Capmul MCM®, Kolliphor® RH40 y Transcutol®, tuvieron un tiempo de autoemulsificación de aproximadamente 1 min; fueron estables en tres distintos pH (1,2; 4,5 y 7,2), en diferentes volúmenes de dilución, exhibiendo una apariencia transparente, ligeramente azulada, sin precipitados, o separación de fases, puntos de nube mayores en comparación de las formulaciones que contenían Gelucire® 44/14. Conclusiones: las estrategias de caracterización empleadas en el desarrollo de esta investigación demostraron ser eficientes para la selección adecuada de excipientes y su proporción óptima para el diseño eficaz de un sistema de entrega de fármaco autoemulsificable (SEDDS).

SUMMARY Introduction: Estradiol is a female sex steroid hormone widely used as hormonal therapy that has low bioavailability, due to its low aqueous solubility and high hydro-phobicity, belonging to class II of the Biopharmaceutical Classification System. Aim: To design and characterize a self-emulsifying drug delivery system (SEDDS) for the drug estradiol by physicochemical tests to obtain the most optimal ratio that would improve its aqueous solubility, dissolution rate, and potentially its bioavailability. Method: Solubility studies in different solvents; pseudo ternary phase diagrams made up of oils, surfactants, co-surfactants, and water, allowed to recognize the different regions of SEDDS formation and identify the percentages of excipients that lead to the formation of isotropic solutions; The resulting formulations were characterized in autoemulsification time, robustness to dilution, cloud point and dissolution profile in a hard capsule. Results: The formulations containing Capmul MCM®, Kolliphor® RH40, and Transcutol®, had an autoemulsification time of approximately 1 minute; were stable at three different pHs (1.2, 4.5 and 7.2), at different dilution volumes, exhibiting a transparent, slightly bluish appearance, without precipitates, or phase separation, higher cloud points compared to the formulations containing Gelucire® 44/14. Conclusions: The characterization strategies used in the development of this research proved to be efficient for the adequate selection of excipients and their optimal ratio for the effective design of a self-emulsifying drug delivery system (SEDDS).

Introdução: o estradiol é um hormônio esteroide sexual feminino amplamente utilizado como terapia hormonal que apresenta baixa biodisponibilidade devido à sua baixa solubilidade aquosa e alta hidrofobicidade, pertencente à classe II do sistema de classificação biofarmacêutica. Objetivos: projetar e caracterizar um sistema de liberação de drogas autoemulsificante (SEDDS) para o fármaco estradiol por meio de testes físico-químicos a fim de obter a proporção ideal que melhore sua solubilidade aquosa, taxa de dissolução e potencialmente sua biodisponibilidade. Método: estudos de solubilidade em diferentes solventes, diagramas de fases pseudoternários compostos por óleos, tensoativos, cotensoativos e água permitiram reconhecer as diferentes regiões de formação de SEDDS e identificar as porcentagens de excipientes que levam à formação de soluções isotrópicas; as formulações resultantes foram caracterizadas quanto ao tempo de autoemulsificação, robustez à diluição, ponto de turvação e perfil de dissolução da cápsula dura. Resultados: as formulações contendo Capmul MCM®, Kolliphor® RH40 e Transcutol®, tiveram um tempo de autoemulsificação de aproximadamente 1 min; foram estáveis em três diferentes pH's (1,2; 4,5 e 7,2), em diferentes volumes de diluição, apresentando aspecto transparente, levemente azulado, sem precipitados ou separação de fases, pontos de turvação mais elevados em relação às formulações contendo Gelucire® 44/14. Conclusões: as estratégias de caracterização utilizadas no desenvolvimento desta pesquisa mostraram-se eficientes para a seleção adequada de excipientes e sua proporção ideal para o desenho eficaz de um sistema de liberação de fármacos autoemulsificante (SEDDS).

Progress of drug-loaded β-tricalcium phosphate in the treatment of bone defects / 国际外科学杂志

Bone defects caused by trauma, infection, tumor and other factors is a thorny problem in orthopedic clinic, and promoting bone repair and regeneration is the key and difficult point of treatment. In addition to autologous bone grafting, artificial bone materials are often used for large bone defects. β-tricalcium phosphate has good biocompatibility, bone conduction and bone induction properties, and has been studied deeply because of its excellent drug delivery performance and has shown broad application prospects. In this paper, the author will summarize the research progress of β-tricalcium phosphate composites loaded with different drugs in the treatment of bone defects caused by trauma, infection and tumor.

Gather wisdom to overcome barriers: Well-designed nano-drug delivery systems for treating gliomas

Due to the special physiological and pathological characteristics of gliomas, most therapeutic drugs are prevented from entering the brain. To improve the poor prognosis of existing therapies, researchers have been continuously developing non-invasive methods to overcome barriers to gliomas therapy. Although these strategies can be used clinically to overcome the blood‒brain barrier (BBB), the accurate delivery of drugs to the glioma lesions cannot be ensured. Nano-drug delivery systems (NDDS) have been widely used for precise drug delivery. In recent years, researchers have gathered their wisdom to overcome barriers, so many well-designed NDDS have performed prominently in preclinical studies. These meticulous designs mainly include cascade passing through BBB and targeting to glioma lesions, drug release in response to the glioma microenvironment, biomimetic delivery systems based on endogenous cells/extracellular vesicles/protein, and carriers created according to the active ingredients of traditional Chinese medicines. We reviewed these well-designed NDDS in detail. Furthermore, we discussed the current ongoing and completed clinical trials of NDDS for gliomas therapy, and analyzed the challenges and trends faced by clinical translation of these well-designed NDDS.

Fighting type 2 diabetes: Formulation strategies for peptide-based therapeutics

Diabetes mellitus is a major health problem with increasing prevalence at a global level. The discovery of insulin in the early 1900s represented a major breakthrough in diabetes management, with further milestones being subsequently achieved with the identification of glucagon-like peptide-1 (GLP-1) and the introduction of GLP-1 receptor agonists (GLP-1 RAs) in clinical practice. Moreover, the subcutaneous delivery of biotherapeutics is a well-established route of administration generally preferred over the intravenous route due to better patient compliance and prolonged drug absorption. However, current subcutaneous formulations of GLP-1 RAs present pharmacokinetic problems that lead to adverse reactions and treatment discontinuation. In this review, we discuss the current challenges of subcutaneous administration of peptide-based therapeutics and provide an overview of the formulations available for the different routes of administration with improved bioavailability and reduced frequency of administration.

Meta analysis of levonorgestrel releasing intrauterine system and mifepristone in the treatment of adenomyosis / 中国医师杂志

Objective:To evaluate the efficacy of levonorgestrel-releasing intrauterine system (LNG-IUS) (mirena) versus mifepristone therapy for adenomyosis.Methods:We retrived the Cochrane library, the Pubmed, EMbase, China National Knowledge Infrastructure (CNKI), WanFang Data, VIP, China Biomedical Literatue Database (CBM) and other databases to identify randomized controlled trials (RCTs) involving the comparison of levonorgestrel-releasing intrauterine system and mifepristone up to October 2018. The quality assessment and data extraction for RCTs were conducted by two reviewers independently. Then data were analyzed with Stata 11.0 software.Results:A total of 17 RCTs involving 1 772 patients were included. The results indicated that mirena was more effective than mifepristone [RR=1.25, 95% CI(1.19, 1.32), P<0.01]. The decrease in endometrial thickness [MD=-1.94, 95% CI(-2.19, -1.70), P<0.01], uterine volume [MD=-18.99, 95% CI(-19.90, -18.07), P<0.01] and the incidence of adverse reactions [RR=0.67, 95% CI(0.47, 0.95), P=0.026] in mirena group were significantly different compared with the mifepristone group. Also the dysmenorrhea score and menstrual blood volume of mirena group were lower than mifepristone group ( P<0.05). Conclusions:Current evidence shows that the efficacy and safety of mirena was better than mifepristone in the treatment for adenomyosis patients. Since the limitation of quantity and quality of included studies, large-scale high-quality RCTs are needed to verify the above conclusion.

Membrane-disruptive peptides/peptidomimetics-based therapeutics: Promising systems to combat bacteria and cancer in the drug-resistant era

Membrane-disruptive peptides/peptidomimetics (MDPs) are antimicrobials or anticarcinogens that present a general killing mechanism through the physical disruption of cell membranes, in contrast to conventional chemotherapeutic drugs, which act on precise targets such as DNA or specific enzymes. Owing to their rapid action, broad-spectrum activity, and mechanisms of action that potentially hinder the development of resistance, MDPs have been increasingly considered as future therapeutics in the drug-resistant era. Recently, growing experimental evidence has demonstrated that MDPs can also be utilized as adjuvants to enhance the therapeutic effects of other agents. In this review, we evaluate the literature around the broad-spectrum antimicrobial properties and anticancer activity of MDPs, and summarize the current development and mechanisms of MDPs alone or in combination with other agents. Notably, this review highlights recent advances in the design of various MDP-based drug delivery systems that can improve the therapeutic effect of MDPs, minimize side effects, and promote the co-delivery of multiple chemotherapeutics, for more efficient antimicrobial and anticancer therapy.

Metal-organic frameworks for advanced drug delivery

Metal-organic frameworks (MOFs), comprised of organic ligands and metal ions/metal clusters

Emerging nanomedicine-based therapeutics for hematogenous metastatic cascade inhibition: Interfering with the crosstalk between "seed and soil"

Despite considerable progresses in cancer treatment, tumor metastasis is still a thorny issue, which leads to majority of cancer-related deaths. In hematogenous metastasis, the concept of "seed and soil" suggests that the crosstalk between cancer cells (seeds) and premetastatic niche (soil) facilitates tumor metastasis. Considerable efforts have been dedicated to inhibit the tumor metastatic cascade, which is a highly complicated process involving various pathways and biological events. Nonetheless, satisfactory therapeutic outcomes are rarely observed, since it is a great challenge to thwart this multi-phase process. Recent advances in nanotechnology-based drug delivery systems have shown great potential in the field of anti-metastasis, especially compared with conventional treatment methods, which are limited by serious side effects and poor efficacy. In this review, we summarized various factors involved in each phase of the metastatic cascade ranging from the metastasis initiation to colonization. Then we reviewed current approaches of targeting these factors to stifle the metastatic cascade, including modulating primary tumor microenvironment, targeting circulating tumor cells, regulating premetastatic niche and eliminating established metastasis. Additionally, we highlighted the multi-phase targeted drug delivery systems, which hold a better chance to inhibit metastasis. Besides, we demonstrated the limitation and future perspectives of nanomedicine-based anti-metastasis strategies.

Pure redox-sensitive paclitaxel-maleimide prodrug nanoparticles: Endogenous albumin-induced size switching and improved antitumor efficiency

A commercial albumin-bound paclitaxel nano-formulation has been considered a gold standard against breast cancer. However, its application still restricted unfavorable pharmacokinetics and the immunogenicity of exogenous albumin carrier. Herein, we report an albumin-bound tumor redox-responsive paclitaxel prodrugs nano-delivery strategy. Using diverse linkages (thioether bond and disulfide bond), paclitaxel (PTX) was conjugated with an albumin-binding maleimide (MAL) functional group. These pure PTX prodrugs could self-assemble to form uniform and spherical nanoparticles (NPs) in aqueous solution without any excipients. By immediately binding to blood circulating albumin after intravenous administration, NPs are rapidly disintegrated into small prodrug/albumin nanoaggregates

Challenges and strategies in progress of drug delivery system for traditional Chinese medicine Salviae Miltiorrhizae Radix et Rhizoma (Danshen) / 中草药·英文版

Traditional Chinese medicines (TCMs), with a history of thousands of years, are widely used clinically with effective treatment. However, the drug delivery systems (DDSs) for TCMs remains major challenges due to the characteristics of multi-components including alkaloids, flavones, anthraquinones, glycosides, proteins, volatile oils and other types. Therefore, the novel preparations and technology of modern pharmaceutics is introduced to improve TCM therapeutic effects due to instability and low bioavailability of active ingredients. Salviae Miltiorrhizae Radix et Rhizoma, the radix and rhizomes of Salvia miltiorrhiza Bunge (Danshen in Chinese), is a well known Chinese herbal medicine for protecting the cardiovascular system, with active ingredients mainly including lipophilic tanshinones and hydrophilic salvianolic acids. In this review, this drug is taken as an example to present challenges and strategies in progress of DDSs for TCMs. This review would also summary the characteristics of active ingredients in it including physicochemical properties and pharmacological effects. The purpose of this review is to provide inspirations and ideas for the DDSs designed from TCMs by summarizing the advances on DDSs for both single- and multi-component from Danshen.