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Aiming to address the insufficient endocytosis ability of traditional albumin drug conjugates, this paper reports elegant guanidine modification to improve efficacy for the first time. A series of modified albumin drug conjugates were designed and synthesized with different structures, including guanidine (GA), biguanides (BGA) and phenyl (BA), and different quantities of modifications. Then, the endocytosis ability and in vitro/vivo potency of albumin drug conjugates were systematically studied. Finally, a preferred conjugate A4 was screened, which contained 15 BGA modifications. Conjugate A4 maintains spatial stability similar to that of the unmodified conjugate AVM and could significantly enhance endocytosis ability (p*** = 0.0009) compared with the unmodified conjugate AVM. Additionally, the in vitro potency of conjugate A4 (EC50 = 71.78 nmol in SKOV3 cells) was greatly enhanced (approximately 4 times) compared with that of the unmodified conjugate AVM (EC50 = 286.00 nmol in SKOV3 cells). The in vivo efficacy of conjugate A4 completely eliminated 50% of tumors at 33 mg/kg, which was significantly better than the efficacy of conjugate AVM at the same dose (P** = 0.0026). In addition, theranostic albumin drug conjugate A8 was designed to intuitively realize drug release and maintain antitumor activity similar to conjugate A4. In summary, the guanidine modification strategy could provide new ideas for the development of new generational albumin drug conjugates. [ABSTRACT FROM AUTHOR]

In the therapy of placenta-originated diseases during pregnancy, the main challenges are fetal exposure to drugs, which can pass through the placenta and cause safety concerns for fetal development. The design of placenta-resident drug delivery system is an advantageous method to minimize fetal exposure as well as reduce adverse maternal off-target effects. By utilizing the placenta as a biological barrier, the placenta-resident nanodrugs could be trapped in the local placenta to concentrate on the treatment of this abnormal originated tissue. Therefore, the success of such systems largely depends on the placental retention capacity. This paper expounds on the transport mechanism of nanodrugs in the placenta, analyzes the factors that affect the placental retention of nanodrugs, and summarizes the advantages and concerns of current nanoplatforms in the treatment of placenta-originated diseases. In general, this review aims to provide a theoretical basis for the construction of placenta-resident drug delivery systems, which will potentially enable safe and efficient clinical treatment for placenta-originated diseases in the future. [ABSTRACT FROM AUTHOR]

Platelets are multifunctional effectors of inflammatory responses and inseparable from the occurrence and development of various inflammatory diseases. The platelet membrane (PM) is integrated onto the surface of a nano-drug delivery system to form the PM-cloaked nanoparticles (PM@NPs), which can increase the biocompatibility of the nano-drug delivery system and mitigate adverse drug reactions. Owing to the strong affinity of immune regulation and adhesion-related antigens on the surface of PM to the focal sites of inflammatory diseases, which endows PM@ NPs with the potential to actively target lesions and improve the therapeutic efficacy of drugs for inflammatory diseases. Based on latest developments in PM biomimetic technique and nanomedicine for the treatment of inflammatory diseases, this paper mainly elaborates three aspects: advantages of PM@NPs, experimental foundation of PM biomimetic nanotechnology, and applications of PM@NPs to the treatment of inflammatory diseases. The aim is to provide reference for the development and application of PM@NPs and novel insights into the treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis is a chronic autoimmune disease, with the features of recurrent chronic inflammation of synovial tissue, destruction of cartilage, and bone erosion, which further affects joints tissue, organs, and systems, and eventually leads to irreversible joint deformities and body dysfunction. Therapeutic drugs for rheumatoid arthritis mainly reduce inflammation through regulating inflammatory factors. Transdermal administration is gradually being applied to the treatment of rheumatoid arthritis, which can allow the drug to overcome the skin stratum corneum barrier, reduce gastrointestinal side effects, and avoid the first-pass effect, thus improving bioavailability and relieving inflammation. This paper reviewed the latest research progress of transdermal drug delivery in the treatment of rheumatoid arthritis, and discussed in detail the dosage forms such as gel (microemulsion gel, nanoemulsion gel, nanomicelle gel, sanaplastic nano-vesiclegel, ethosomal gel, transfersomal gel, nanoparticles gel), patch, drug microneedles, nanostructured lipid carrier, transfersomes, lyotropic liquid crystal, and drug loaded electrospinning nanofibers, which provide inspiration for the rich dosage forms of transdermal drug delivery systems for rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Chemotherapy for tumors occasionally results in drug resistance, which is the major reason for the treatment failure. Higher drug doses could improve the therapeutic effect, but higher toxicity limits the further treatment. For overcoming drug resistance, functional nano-drug delivery system (NDDS) has been explored to sensitize the anticancer drugs and decrease its side effects, which are applied in combating multidrug resistance (MDR) via a variety of mechanisms including bypassing drug efflux, controlling drug release, and disturbing metabolism. This review starts with a brief report on the major MDR causes. Furthermore, we searched the papers from NDDS and introduced the recent advances in sensitizing the chemotherapeutic drugs against MDR tumors. Finally, we concluded that the NDDS was based on several mechanisms, and we looked forward to the future in this field. [ABSTRACT FROM AUTHOR]

Arsenic trioxide (As2O3, ATO) has limited therapeutic benefit to treat solid tumors, whether used alone or in combination. Nanoscale drug delivery vehicles have great potential to overcome the limitation of the utility of ATO by rapid renal clearance and dose-limiting toxicity. Polymeric materials ranging from gelatin foam to synthetic polymers such as poly(vinyl alcohol) were developed for vascular embolic or chemoembolic applications. Recently, we have introduced sevelamer, an oral phosphate binder, as a new polymeric embolic for vascular interventional therapy. In this paper, sevelamer arsenite nanoparticle with a polygonal shape and a size of 50-300 nm, synthesized by anionic exchange from sevelamer chloride, was developed as a Pi-responsive bifunctional drug carrier and embolic agent for chemoembolization therapy. At the same arsenic dosage, sevelamer arsenite-induced severer tumor necrosis than ATO on the VX2 cancer model. In vitro tests evidenced that Pi deprivation by sevelamer could enhance ATO's anticancer effect. The results showed that ATO in Pi starvation reduced cell viability, induced more apoptosis, and diminished the mitochondrial membrane potential (Δwm) of cells since Pi starvation helps ATO to further down-regulate Bcl-2 expression, up-regulate Bax expression, enhance the activation of caspase-3 and increase the release of cytochrome c, and the production of excessive reactive oxygen species (ROS). Sevelamer arsenite not only plays a Pi-activated nano-drug delivery system but also integrated anticancer drug with embolic for interventional therapy. Therefore, our results presented a new administration route of ATO as well as an alternative chemoembolization therapy. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 (HER2) regulates cell mitosis, proliferation, and apoptosis. Trastuzumab is a HER2-targeted monoclonal antibody (mAB), which can prolong the overall survival rate of patients with HER2 overexpression in later periods of gastric cancer and breast cancer. Although anti-HER2 monoclonal antibody has a curative effect, adjuvant chemotherapy is still necessary to upgrade the curative effect maximumly. Antibody-drug conjugate (ADC) is a kind of therapeutic drug that contains antigen-specific antibody and cytotoxic payload, which can improve the survival time of tumor patients. To date, there are several HER2-ADC products on the market, for which two anti-HER2 ADC (trastuzumab emtansine and trastuzumab deruxtecan) have been authorized by the FDA for distinct types of HER2-positive carcinoma in the breast. Disitamab vedotin (RC48) is a newly developed ADC drug targeting HER2 that is comprised of hertuzumab coupling monomethyl auristatin E (MMAE) via a cleavable linker. This paper aims to offer a general insight and summary of the mechanism of action and the currently completed and ongoing clinical studies of RC-48 in HER-2 positive solid tumors. [ABSTRACT FROM AUTHOR]

The article focuses on several subject headings related to drug delivery systems and that appeared in several periodicals. Some of the subject headings are: A device for the spatio-regional delivery of a photocurable drug formulation, by H. Sonoda, H. Yasui, H, and T. Matsuda; A surface-modified dendrimer set for potential application as drug delivery vehicles: Synthesis, in vitro toxicity, and intracellular localization, by S. Fuchs, T. Kapp, H. Otto, T. Schoneberg, P. Franke, R. Gust, and A.D. Schiuter; etc.

Camptothecins, traditional chemotherapy drugs, have been clinically used in antibody-drug conjugates (ADCs), which refreshes the recognition that ADCs preferably incorporate highly potent payloads. However, SN-38, active metabolite of irinotecan from camptothecins, tended to be incorporated into ADCs with an unstable acid sensitive bond, not with the widely used Cathepsin B (CTSB) sensitive bond, which may pose the risk of off-target. Herein, we reported a novel strategy to construct highly releasable and structurally stable SN-38-conjugates, in which CTSB linkers directly connected to the 10-OH group through ether bond, not to the common 20-OH group of lactones of SN-38. In this paper, rapid release of SN-38 was skillfully demonstrated by utilizing the fluorescence properties of SN-38. The SN-38-ether-ADC displayed highly stable serum stability with the half-life over 10 days. Moreover, the drug-antibody-ratio (DAR) of ADC could be elevated to 7.1 through the introduction of polyethylene glycol (PEG) moieties without aggregation. The optimized ADC exhibited potent in vitro activities up to 5.5 nM, comparable to SN-38. Moreover, this ADC group significantly delayed tumor growth in vivo. In conclusion, the novel strategy has the potential to promote the development of SN38-ADCs and enrich the conjugation approaches for hydroxyl-bearing payloads. [ABSTRACT FROM AUTHOR]

The in vivo release and absorption of drugs are dependent on the interplay between many factors related to compound, formulation, and physiological properties. The mathematical models of oral drug absorption attempt to strike a balance between a complete description that takes into consideration as many independent factors as possible, and simple models that operate with fewer parameters, based mainly on critical factors. The latter models are by far more robust and easier to apply to predict the extent and sometimes even the rate of absorption. The present paper attempted to develop a simple model to describe the time course of absorption of the hydrophilic drug captopril (CPT) at the early phases of absorption, with implications mainly in the induction and early stages of achieving its therapeutic effect. As a phenomenological model, the instantaneous release of CPT was considered in the gastrointestinal fluid, leading to a constant drug concentration for a prolonged time, followed by a 'long path diffusion' inside the intestinal wall and a very low concentration at the interface intestinal wall-blood. These conditions regarding CPT concentration were translated into initial and boundary mathematical conditions for the diffusion equation in the intestinal wall. The solution of the diffusion equation led in the end to a square root law describing the dependence between the fraction of the drug absorbed and time. The model was successfully applied to data obtained in five bioequivalence studies: three comparing plasma levels achieved after the administration of a single dose of CPT 50mg, one evaluating CPT pharmacokinetics after a 100mg dose, and a fifth comparing CPT pharmacokinetics of two fixed-dose combinations of CPT 50mg and hydrochlorothiazide 25 mg. [ABSTRACT FROM AUTHOR]

The objective of this paper is to confine piperine, a poor oral bioavailable herbal drug into bile salt based nano vesicles for improving its aqueous solubility, hence, its therapeutic activity. Piperine-loaded bilosomes were fabricated adopting thin film hydration technique according to 3².2¹ full factorial design to investigate the impact of different formulation variables on the characters of bilosomes: entrapment efficiency (EE%), particle size, and % of drug released post 8 h (Q8hr). The selected optimum formula was F2 (enclosing 1% bile salt, brij72 as a surfactant, and ratio of surfactant:cholesterol was 9:1) with desirability value 0.801, exhibiting high EE% (97.2 ± 0.8%) nanosized spherical vesicles (220.2 ± 20.5 nm) and Q8hr (88.2%±5.6). The superiority of the optimized formula (F2) over the drug suspension was revealed via ex vivo permeation study, also pharmacokinetic study denoted to the boosted oral bioavailability of piperine-loaded bilosome compared to piperine suspension. Moreover, antiviral activity and safety margin of F2 was significantly higher than that of the drug suspension. The ability of piperine to interact with the key amino acids in the receptor binding domain 4L3N as indicated by its docking configuration, rationalized its observed activity. Furthermore, F2 significantly reduce oxidant markers, inflammatory cytokines in MERS-CoV-infected mice. Hence, bilosomes can be considered as a carrier of choice for piperine with potential antiviral and anti-inflammatory activities. [ABSTRACT FROM AUTHOR]

Controlled drug delivery systems are of utmost importance for the improvement of drug bioavailability while limiting the side effects. For the improvement of their performances, drug release modeling is a significant tool for the further optimization of the drug delivery systems to cross the barrier to practical application. We report here on the modeling of the diclofenac sodium salt (DCF) release from a hydrogel matrix based on PEGylated chitosan in the context of Multifractal Theory of Motion, by means of a fundamental spinor set given by 2-2 matrices with real elements, which can describe the drug-release dynamics at global and local scales. The drug delivery systems were prepared by in situ hydrogenation of PEGylated chitosan with citral in the presence of the DCF, by varying the hydrophilic/hydrophobic ratio of the components. They demonstrated a good dispersion of the drug into the matrix by forming matrix-drug entities which enabled a prolonged drug delivery behavior correlated with the hydrophilicity degree of the matrix. The application of the Multifractal Theory of Motion fitted very well on these findings, the fractality degree accurately describing the changes in hydrophilicity of the polymer. The validation of the model on this series of formulations encourages its further use for other systems, as an easy tool for estimating the drug release toward the design improvement. The present paper is a continuation of the work 'A theoretical mathematical model for assessing diclofenac release from chitosan-based formulations,' published in Drug Delivery Journal, 27(1), 2020, that focused on the consequences induced by the invariance groups of Multifractal Diffusion Equations in correlation with the drug release dynamics. [ABSTRACT FROM AUTHOR]

In recent years, nanocrystal technology has been extensively investigated. Due to the submicron particle size and unique physicochemical properties of nanocrystals, they overcome the problems of low drug solubility and poor bioavailability. Although the structures of nanocrystals are simple, the further development of these materials is hindered by their stability. Drug nanocrystals with particle sizes of 1-1000 nm usually require the addition of stabilizers such as polymers or surfactants to enhance their stability. The stability of nanocrystal suspensions and the redispersibility of solid nanocrystal drugs are the key factors for the large-scale production of nanocrystal preparations. In this paper, the factors that affect the stability of drug nanocrystal preparations are discussed, and related methods for solving the stability problem are put forward. [ABSTRACT FROM AUTHOR]

In the present medical diagnostic method for the therapeutic of gestational diabetes mellitus (GDM), it is problematic and difficult to release successful and secure release of drugs to the exact site. Hence, many researchers have been carried out to bring antidiabetic using modern method to release of drugs for their production. This research work focusses on to provide an assemblage to the recent growth in the field of Ramulus mori extract (RME) loaded on polyacrylic gold nanoparticle for antidiabetics with special highlighting on nursing of GDM. Keynote of gold nanoparticle: diabetes mellitus, nursing, insulin, antidiabetic, drugs, and new system for drug delivery. Rat is used to test the drug delivery system. In vivo examination was not prepared seldom including in this research paper. This research investigation could be a new avenue for the development of drug delivery system of GDM. [ABSTRACT FROM AUTHOR]

The paper reports a new mathematical model for understanding the mechanism delivery from drug release systems. To do this, two drug release systems based on chitosan and diclofenac sodium salt as a drug model, were prepared by in situ hydrogelation in the presence of salicylaldehyde. The morphology of the systems was analyzed by scanning electron microscopy and polarized light microscopy and the drug release was in vitro investigated into a medium mimicking the in vivo environment. The drug release mechanism was firstly assessed by fitting the in vitro release data on five traditional mathematical model. In the context of pharmacokinetics behavioral analysis, a new mathematical procedure for describing drug release dynamics in polymer-drug complex systems was proposed. Assuming that the dynamics of polymer-drug system's structural units take place on continuous and nondifferentiable curves (multifractal curves), it was showed that in a one-dimensional hydrodynamic formalism of multifractal variables the drug release mechanism is given through synchronous dynamics at a differentiable and non-differentiable scale resolutions. [ABSTRACT FROM AUTHOR]

During the last decades, much attention has been focused on SNEDDS approach to resolve concerns of BCS II class drugs with accentuation on upgrading the solubility and bioavailability. The present hypothesis confirms the theory that SNEDDS can reduce the impact of food on Candesartan solubilization, thereby offering the potential for improved oral delivery without co-administration with meals. The present studies describe quality-by-design-based development and characterization of Candesartan loaded SNEDDS for improving its pharmacodynamic potential. D-optimal mixture design was used for systematic optimization of SNEDDS, which showed globule size of 13.91 nm, more rapid drug release rate of >90% in 30 min and 16 s for self-emulsification. The optimized formulations were extensively evaluated, where an in vitro drug release study indicated up to 1.99- and 1.10-fold enhancement in dissolution rate from SNEDDS over pure drug and marketed tablet. In vivo pharmacodynamic investigation also showed superior antihypertensive potential of SNEDDS in normalizing serum lipid levels as compared to pure drug and marketed tablet that was executed on male Wistar rats. Overall, this paper reports successful systematic development of candesartan-loaded SNEDDS with distinctly improved biopharmaceutical performance. This research work interpreted a major role of SNEDDS for enhancing the rate of dissolution and bioavailability of poorly water soluble drugs. [ABSTRACT FROM AUTHOR]

Montmorillonite-loaded solid lipid nanoparticles with good biocompatibility, using Betaxolol hydrochloride as model drug, were prepared by the melt-emulsion sonication and low temperature-solidification methods and drug bioavailability was significantly improved in this paper for the first time to application to the eye. The appropriate physical characteristics were showed, such as the mean particle size, Zeta potential, osmotic pressure, pH values, entrapping efficiency (EE%) and drug content (DC%), all showed well suited for possible ocular application. In vitro release experiment indicated that this novel system could continuously release 57.83% drugs within 12 h owing to the dual drug controlled-release effect that was achieved by ion-exchange feature of montmorillonite and structure of solid lipid nanoparticles. Low irritability and good compatibility of nanoparticles were proved by both CAM-TBS test and cytotoxicity experiment. We first discovered from the results of Rose Bengal experiment that the hydrophilicity of the drug-loaded nanoparticles surface was increased during the loading and releasing of the hydrophilic drug, which could contribute to prolong the ocular surface retention time of drug in the biological interface membrane of tear-film/cornea. The results of in vivo pharmacokinetic and pharmacodynamics studies further confirmed that increased hydrophilicity of nanoparticles surface help to improve the bioavailability of the drug and reduce intraocular pressure during administration. The results suggested this novel drug delivery system could be potentially used as an in situ drug controlled-release system for ophthalmic delivery to enhance the bioavailability and efficacy. [ABSTRACT FROM AUTHOR]

The in situ hydrogel drug delivery system is a hot research topic in recent years. Combining both properties of hydrogel and solution, in situ hydrogels can provide many advantages for drug delivery application, including easy application, high local drug concentration, prolonged drug retention time, reduced drug dose in vivo, good biocompatibility and improved patient compliance, thus has potential in tumor treatment. In this paper, the related literature reports in recent years were reviewed to summarize and discuss the research progress and development prospects in the application of in situ hydrogels in tumor treatment. [ABSTRACT FROM AUTHOR]

In this paper, we prepared doxorubicin-loaded folic acid-functionalized pH-sensitive photothermal therapy (PTT) traceable hollow mesoporous silica nanoparticles (DOX-HPCF) as a drug carrier for liver cancer treatment. According to TEM characterization, hollow mesoporous silica nanoparticles (HMSN) are monodispersed spherical particles with hollow structure. In vitro drug release experiments showed that HPCF exhibited pH-sensitive release. Cell uptake experiments showed that HPCF was successfully absorbed by SMMC-7721 cells. In addition, DOX-HPCF significantly inhibited the proliferation of SMMC-7721 cells, and the near-infrared (NIR) light group showed a more obvious inhibitory effect. In vivo anti-tumor experiments showed that DOX-HPCF-assisted PTT inhibited tumor growth significantly. Therefore, HPCF is a promising photothermotherapy carrier for the treatment of liver cancer. [ABSTRACT FROM AUTHOR]

Due to their various biological activities that are beneficial to human health and antitumor effect, flavonoid compounds have attracted much attention in recent years. Hydrous icaritin (HICT) was such a flavonoid that can inhibit the growth of breast cancer and cancer stem cells. In order to overcome the insolubility problem, HICT was fabricated into nanorods (NRs) through anti-solvent precipitation in this paper using D-α tocopherol acid polyethylene glycol succinate and sodium oleate as a co-stabilizer meanwhile using the mixture of ethanol and acetone (1:2, v/v) as the organic solvent. The obtained HICT NRs showed an average particle size 222.0 nm with a small polydispersity index value of 0.124 and a high zeta potential of – 49.5 mV. HICT NRs could maintain similar particle size in various physiological medium and could be directly lyophilized without the addition of any cytoprotectants and then reconstituted into a colloidal system of similar size. The resultant HICT NRs had a high drug loading content of 55.6% and released HICT in a steady and constant pattern. MTT assay indicated NRs enhanced HICT's antitumor activity to ninefold against MCF-7 breast carcinoma cells. In vivo studies demonstrated oral administration free HICT had almost no tumor inhibitory effect while HICT NRs showed a tumor inhibition rate of 47.8%. When intravenously injected, HICT NRs displayed similar therapeutic efficacy to paclitaxel injections (70.4% vs. 74.5%, TIR). This may be partly due to the high accumulation of the injected HICT NRs in tumor ranking only second to that in the liver but much higher than in other organs. These results demonstrated that HICT NRs could be a promising antitumor agent for the treatment of breast cancer in clinic. [ABSTRACT FROM AUTHOR]

Tumor microenvironment is closely related to the occurrence and development of liver cancer. Tumor-associated macrophages (TAMs) are an important part of tumor microenvironment promoting tumor deterioration and metastasis by inhibiting immune cells. Previous studies showed that PI3Kγ inhibitor could reverse the phenotype of TAMs, relieve immunosuppression and sensitize chemotherapy drugs, suggesting that the combination of PI3Kγ inhibitor and chemotherapeutics is likely to bring new breakthroughs in the treatment of liver cancer. Based on it, this paper builds HES-TG100-115-CDM-PEG micelles with tumor microenvironment responsiveness that simultaneously loaded sorafenib and TG100-115 to synergistically treat liver cancer. Pharmacokinetic study showed that the prepared micelles had longer half-life than that of the free drug solutions, which was favorable for high propensity of extravasation through tumor vascular fenestrations. Under low pH and high α-amylasereductive conditions, micelles could depolymerize quickly due to the sensitivity of bonds and enhance significantly cytotoxic activity against Hep-3B liver cancer cell. Additionally, micelles demonstrated higher levels of antitumor efficiency and better tolerance against nude mouse with Hep-3B cell than the free drug solutions. These findings reveal that HES-TG100-115-CDM-PEG micelles are a promising drug delivery system in clinical comprehensive therapy of liver cancer. [ABSTRACT FROM AUTHOR]

In this paper, the self-assembled folate-biotin-quaternized starch nanoparticles (FBqS NPs) were used as carrier system of doxorubicin (DOX) and siRNAIGF1R for the codelivery of both into human lung adenocarcinoma cell lines (A549 cells) in vitro. The cytotoxicity, targeted ligand competition, cell proliferation inhibition, cellular uptake, endocytosis mechanism and target protein suppression of drug-loaded FBqS NPs were evaluated in detail. Compared with several other drug formulations under same condition, siRNAIGF1R/DOX/FBqS NPs exhibited the greatest cytotoxicity to A549 cells and the cytotoxicity was competitively inhibited by free folate in dose-dependent manner. The A549 cells treated by siRNAIGF1R/DOX/FBqS NPs showed the lowest cell proliferation capacity. The energy-dependent clathrin- and caveolae-mediated endocytosis might be the primary cellular uptake mechanism of drug-loaded FBqS NPs. The expression of IGF1R protein in A549 cells treated by siRNAIGF1R/FBqS NPs declined dramatically. So the FBqS NPs were expected as the co-carrier system of chemotherapeutants and siRNAs for future clinical application. [ABSTRACT FROM AUTHOR]

To improve the liposolubility and blood-brain barrier permeability of magnoflorine, a new formulation of magnoflorine-phospholipid complex was prepared, characterized, and pharmacologically evaluated in the chronic unpredictable mild stress animal model. In this paper, the magnoflorine-phospholipid complex was synthesized and its characterization was determined. The antidepressant-like and antioxidant activity of magnoflorine-phospholipid complex was investigated by behavioral tests and western blotting analysis. As a result, the magnoflorine-phospholipid complex displayed high encapsulation efficiency and significantly improved the oil-water participate coefficient. In vivo blood-brain distribution study, the magnoflorine-phospholipid complex extended the duration of magnoflorine in blood and help magnoflorine to permeate the blood-brain barrier into brain. In behavioral tests, the magnoflorine-phospholipid complex significantly decreased immobility time compared to model control group in both FST and TST. Furthermore, the magnoflorine-phospholipid complex increased the expression of antioxidative stress-related proteins by the western blotting analysis. These findings strongly suggest that the phospholipid complex could significantly improve liposolubility, drug properties of magnoflorine and help magnoflorine permeate blood-brain barrier and exert the antidepressant effect. [ABSTRACT FROM AUTHOR]

Gout is a kind of joint disease characterized by the accumulation of monosodium urate (MSU) crystals in the joint and its surrounding tissue, causing persistent hyperuricemia. Colchicine is the first choice of treatment for acute gout attacks. Due to strong toxicity of colchicines oral tablets, there are high fluctuations of blood drug concentration and serious irritation of gastrointestinal tract, and hence a transdermal preparation can help to slow down the blood drug concentration, reduce the frequency of drug taking, and improve the patients' compliance of the drug. The ethosome is a lipid carrier with high concentration of ethanol and has been proved to promote the penetration of drugs into the skin. Borneol (BO) is an excellent penetration enhancer in Chinese medicine, which can promote the entry of drugs into the skin. This paper prepared the borneol-physically-modified colchicine ethosome (COL-bpES) and used the prepared borneol-dioleoyl phosphoethanloamine (BO-DOPE) to prepare borneol-chemically-modified colchicine ethosome (COL-bcES). Compared to the free colchicine aqueous solution (free COL) and normal colchicine ethosome (COL-ES), the borneol-modified colchicine ethosome (COL-bES) demonstrated better drug penetration effect, while the particle size of the COL-bcES was lower than that of the COL-bpES. Toxicity, in vitro diffusion, pharmacokinetics and pharmacodynamics are superior to those of COL-bpES, providing a better delivery system for the treatment of small molecule inflammatory drugs. [ABSTRACT FROM AUTHOR]

Galactose-modified selenium nanoparticles (GA-SeNPs) loading with doxorubicin (DOX) for hepatocellular carcinoma (HCC) therapy was investigated in this paper. Selenium nanoparticles (SeNPs) were modified with galactose as tumor targeting moiety to fabricate tumor-targeted delivery carrier GA-SeNPs, then doxorubicin was loaded onto the surface of GA-SeNPs for improving antitumor efficacy of DOX in HCC therapy. Chemical structure characterization of GA-Se@DOX showed that DOX was successfully loaded to the surface of GA-SeNPs to prepare functionalized antitumor drug delivery system GA-Se@DOX. GA-Se@DOX exhibited effective cellular uptake in HepG2 cells and entered HepG2 cells mainly by clathrin-mediated endocytosis pathway. GA-Se@DOX showed significant activity to induce the apoptosis of HepG2 cells in vitro. The western blotting result indicated that GA-Se@DOX induced HepG2 cells apoptosis via activating caspase signaling and Bcl-2 family proteins. Moreover, active targeting delivery system GA-Se@DOX exhibited excellent antitumor efficacy in vivo in comparison with passive targeting delivery system Se@DOX. Histology analysis showed that GA-Se@DOX exhibited no obvious damage to major organs including heart, liver, spleen, lung, and kidney under the experimental condition. Taken together, GA-Se@DOX may be one novel promising nanoscale drug candidate for HCC therapy. [ABSTRACT FROM AUTHOR]

Chlorpromazine and related phenothiazine antipsychotic compounds at the low concentration of 10[sup -5] M stimulated luciferase pRSVL DNA uptake and expression in HeLa cells. On the other hand, chloroquine at a 10[sup -5] M was without effect at this low concentration. However, at the higher normally used concentration of 10[sup -4] M (100 μM), chloroquine strongly stimulated luciferase expression and activity. Unfortunately, at 10[sup -4] M, the phenothiazines were toxic to the cells and could not be tested at this concentration. Further experimental work was carried out to elucidate the mechanism of action of phenothiazines and chloroquine on DNA uptake and expression. Interaction of [[sup 3]H] pBR 322 DNA with chlorpromazine, perphenazine, and chloroquine was studied using these compounds as their free bases dissolved in chloroform, followed by their impregnation onto Whatman No. 1 filter paper discs. Both phenothiazines on filter paper discs bound [[sup 3]H] pBR 322 DNA to a far greater extent than chloroquine. The method of assay (free base) suggests that the major contribution to binding is through intercalation. A further possible assay for studying the interaction of phenothiazines and chloroquine made use of the ethidium bromide/calf thymus DNA intercalation method. Intercalated calf thymus (CT) DNA complexes with ethidium bromide (EB) were examined for possible dissociation into free DNA and EB on the addition of either chloroquine. SO[sub 4] or chlorpromazine.HCl (soluble salts). Partial dissociation was observed with both compounds. Further experiments on the stability of pBR 322 DNA-polylysine complexes were also carried out using an alternative method of assay. Chloroquine (10[sup -2] - 10[sup -4] M) and chlorpromazine (10[sup -4] M) did not bring about a dissociation of [[sup 3]H] pBR 322 DNA-polylysine[sub 200] complexes when reactions were studied by nitrocellulose filter assays to measure released double-stranded DNA. The results indicate that chlorpromazine and related phenothiazines stimulate luciferase DNA uptake expression at 10[sup -5] M. Chloroquine at this concentration had practically no effect on expression of luciferase activity. Further studies of chloroquine and chlorpromazine on their interaction with plasmid DNA as well as DNA-polylysine complexes are reported. [ABSTRACT FROM AUTHOR]

In recent years, there has been a surge in the research and development of microneedles (MNs), a transdermal delivery system that combines the technology of transdermal patches and hypodermic needles. The needles are in the hundreds of micron length range and therefore allow relatively little or no pain. For example, biodegradable MNs have been researched in the literature and have several advantages compared with solid or hollow MNs, as they produce non-sharp waste and can be designed to allow rapid or slow release of drugs. However, they also pose a disadvantage as successful insertion into the stratum corneum layer of the skin relies on sufficient mechanical strength of the biodegradable material. This review looks at the various technologies developed in MN research and shows the rapidly growing numbers of research papers and patent publications since the first invention of MNs (using time series statistical analysis). This provides the research and industry communities a valuable synopsis of the trends and progress being made in this field. [ABSTRACT FROM AUTHOR]

Combination chemotherapy is widely exploited for suppressing drug resistance and achieving synergistic anticancer efficacy in the clinic. In this paper, the nanostructured targeting methotrexate (MTX) plus pemetrexed (PMX) chitosan nanoparticles (CNPs) were developed by modifying methoxy polye (thylene glycol) (mPEG), in which PEGylation CNPs was used as stealth nanocarriers (PCNPs) and MTX was employed as a targeting ligand and chemotherapeutic agent as well. Studies were undertaken on human lung adenocarcinoma epithelial (A549) and Lewis lung carcinoma (LLC) cell lines, revealing the anti-tumor efficacy of nanoparticle drug delivery system. The co-delivery nanoparticles (MTX-PMX-PCNPs) had well-dispersed with sustained release behavior. Cell counting kit-8 (CCK8) has been used to measure A549 cell viability and the research showed that MTX-PMX-PCNPs were much more effective than free drugs when it came to the inhibition of growth and proliferation. Cell cycle assay by flow cytometry manifested that the MTX-PMX-PCNPs exhibited stronger intracellular taken up ability than free drugs at the same concentration. In vivo anticancer effect results indicated that MTX-PMX-PCNPs exhibited a significantly prolong blood circulation, more tumoral location accumulation, and resulted in a robust synergistic anticancer efficacy in lung cancer in mice. The results clearly demonstrated that such unique synergistic anticancer efficacy of co-delivery of MTX and PMX via stealth nanocarriers, providing a prospective strategy for lung cancer treatment. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is a neurodegenerative disorder mainly characterized by β-amyloid deposit and tau hyperphosphorylation with no curative treatments. Curcumin (Cur) has been proved to have potential use in Alzheimer's disease with its anti-amyloid, anti-inflammatory, and anti-oxidant properties, etc. However, its hydrophobicity and low bioavailability hinder its application. In this paper, we designed a novel brain-target nanoparticle, poly(lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-PEG) conjugated with B6 peptide and was loaded with Cur (PLGA-PEG-B6/Cur) and administered it into HT22 cells and APP/PS1 Al transgenic mice. The in vitro assays including dynamic light scattering (DLS), flow cytometry (FCM), red blood cell (RBC) lysis, and thromboelastography (TEG) analysis indicated that this nanoparticle could narrow the diameter of Cur, increase its cellular uptake and possess good blood compatibility. The results from Morris water maze proved that PLGA-PEG-B6/Cur could tremendously improve the spatial learning and memory capability of APP/PS1 mice, compared with native Cur. The ex vivo assays including Bielschowsky silver staining, immunostaining, and western blotting demonstrated that PLGA-PEG-B6/Cur could reduce hippocampal β-amyloid formation and deposit and tau hyperphosphorylation. Thus, we suggested that PLGA-PEG-B6/Cur nanoparticles would be of potential and promising use for the treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Dry eye syndrome (DES) is one of the most common disorders of the eye for which combined treatment includes modification of the ocular environment and pathogenic therapies. Cyclosporine A (CsA), a immunosuppressive agent, has been demonstrated to be effective for the treatment of DES but is limited clinically by its low ocular bioavailability due to poor water solubility. In this paper, methoxy poly (ethylene glycol)-poly (lactide) polymer (mPEG-PLA) micelles were investigated as alternative vehicles for the solubilization and delivery of CsA to the eye. The in vitro stability indicated that CsA-loaded micellar lyophilized powder was stable for at least 3 months and the release profile showed a sustained release manner of CsA from micelles physically. In vivo ocular distribution studies demonstrated that the micellar formulations exhibited a 4.5-fold increase in retention effect at eyes compared with 0.05% CsA emulsion. In addition, the in vivo pharmacokinetics profile showed that the CsA-loaded micelles could enhance the retention time, achieving longer effect toward the DES. These studies proposed an effective micelle formulation as a novel ocular drug delivery system to improve solubility and bioavailability of ophthalmic CsA-controlled delivery. [ABSTRACT FROM AUTHOR]

Pingyangmycin (PYM) has been applied clinically for many years to treat vascular malformations (VM) in China. The major limitation of PYM injections is quick diffusion from the injection site, which increases side effects, especially the possibility of pulmonary injury. In this paper, chitosan/glycerophosphate disodium (CS/GP) thermogels containing liposomes for sustained and localized PYM delivery were prepared and optimized by a three-level three-factorial Box-Behnken experimental design to evaluate the effects of different variables (the PYM concentration, CS amount and GP content), on the selected responses (cumulative percentage PYM released in 1 day, 9 days and the rate constant k). The results revealed that the optimized PYM liposomal thermogels had a controlled PYM release for 14 days in vitro, which confirmed the validity of optimization. In vitro morphological observation, cell cycle and apoptosis analysis showed an effective anti-proliferation action of PYM liposomal thermogels on human vascular endothelial cells (EA.hy926). In vivo pharmacokinetics research in rabbits displayed that compared with PYM liposomes and PYM thermogels, PYM liposomal thermogels had a better controlled delivery of PYM. Histological examination of rabbit ear veins showed that after local application with PYM lipsomal thermogels for 21 days, obvious vein thrombosis and inflammatory reaction could be observed. The above results indicated that PYM-loaded lipsomal CS/GP thermogels might have a good prospect for the treatment of VM. [ABSTRACT FROM AUTHOR]

How to overcome drug resistance and prevent tumor metastasis is key to the success of malignant tumor therapy. In this paper, ADH-1 peptide-modified liposomes (A-LP) have been successfully constructed for restoring chemosensitivity and suppressing cancer cell migration. With a particle size of about 90 nm, this functionalized nanocarrier was loaded with fluorescent probe or paclitaxel (PTX). Cellular uptake studies showed that A-LP facilitated the delivery of anticancer drug to tumor cells undergoing EMT. Interestingly, this nanocarrier enhanced chemosensitivity by assessing the cell activity using CCK-8 assay. Further, the results of Wound scratch assay and Transwell migration assay showed the inhibition effect of this nanocarrier on tumor cell migration. Moreover, this nanocarrier exhibited significant tumor-targeting ability and anti-tumor efficacy in vivo. Collectively, A-LP might be a novel targeted drug delivery system to enhance the efficacy of chemotherapy and prevent tumor metastasis. [ABSTRACT FROM AUTHOR]

Neurodegenerative movement disorders mainly include Parkinson's disease, atypical parkinsonisms, Huntington disease, and hereditary ataxia. Riluzole is the only drug approved by the US Food and Drug Administration for amyotrophic lateral sclerosis. The neuroprotective effects of riluzole have been observed in experimental models of neurodegenerative movement disorders. In this paper, we aimed to systematically analyze the efficacy and safety of riluzole for patients with neurodegenerative movement disorder. We searched the electronic databases such as PubMed, EMBASE, CINAHL, Cochrane Library and China National Knowledge Infrastructure until June 2017 for the eligible randomized controlled trials, as well as the unpublished and ongoing trials. For continuous data, we calculated standardized mean differences with 95% confidence intervals if studies did not use the same scales to measure outcomes. For dichotomous data, we calculated risk differences if a trial reported no adverse events or dropouts. We pooled the results using a random-effects model. We included nine studies with 1320 patients with neurodegenerative movement disorders, which compared riluzole with placebo. No significant difference was found in the number of participants with adverse events but with motor improvement in hereditary ataxia. There were only two studies focusing on neuroprotective effect. Riluzole is well-tolerated in the patients with neurodegenerative movement disorders. Riluzole seems to be promising for patients with hereditary ataxia in symptomatic effect, which needs to be further confirmed by well-designed studies in the future. Moreover, it makes sense to design long-term study focusing on neuroprotective effect of riluzole in disease-modifying. [ABSTRACT FROM AUTHOR]

Nowadays, an exciting challenge in the drug chemistry and technology research is represented by the development of methods aimed to protect molecular integrity and therapeutic activity of drugs from effects of light. The photostability characterization is ruled by ICH (The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use), which releases details throughout basic protocols of stability tests to be performed on new medicinal products for human use. The definition of suitable photoprotective systems is fundamental for pharmaceutical manufacturing and for human healthy as well, since light exposure may affect either drugs or drug formulations giving rise even to allergenic or mutagenic by-products. Here, we summarize and discuss the recent studies on the formulation of photosensitive drugs into supramolecular systems, capable of entrapping the molecules in a hollow of their structure by weak noncovalent interactions and protecting them from light. The best known supramolecular matrices belong to the ‘auto-assembled’ structures, of which liposomes are the most representative, and the ‘host-guest’ systems, of which cyclodextrins represent the most common ‘host’ counterpart. A relevant number of papers concerning the use of both liposomes and cyclodextrins as photoprotection systems for drugs has been published over the last 20 years, demonstrating that this topic captures interest in an increasing number of researchers. [ABSTRACT FROM AUTHOR]

To prolong the circulation time of drug, PEGylation has been widely used via the enhanced permeability and retention (EPR) effect, thereby providing new hope for better treatment. However, PEGylation also brings the "PEG dilemma", which is difficult for the cellular absorption of drugs and subsequent endosomal escape. As a result, the activity of drugs is inevitably lost after PEG modification. To achieve successful drug delivery for effective treatment, the crucial issue associated with the use of PEG-lipids, that is, “PEG dilemma” must be addressed. In this paper, we introduced the development and application of nanocarriers with cleavable PEGylation, and discussed various strategies for overcoming the PEG dilemma. Compared to the traditional ones, the vehicle systems with different environmental-sensitive PEG-lipids were discussed, which cleavage can be achieved in response to the intracellular as well as the tumor microenvironment. This smart cleavable PEGylation provides us an efficient strategy to overcome “PEG dilemma”, thereby may be a good candidate for the cancer treatment in future. [ABSTRACT FROM AUTHOR]

Recently, genkwanin (GKA) has been shown to displayin vitroantitumor activity against some cancer cells, but its poor solubility restricted thein vivostudy and further investigation of its antitumor therapeutic efficacy. In this paper, genkwanin nanosuspensions (GKA-NSps) were successfully prepared using D-alpha tocopherol acid polyethylene glycol succinate (TPGS) as a stabilizer using the precipitation-homogenization method. The obtained GKA-NSps had an average particle size of 183.1 ± 4.4 nm, a PDI value of 0.16 ± 0.07, a zeta potential of −16.2 ± 0.1 mV, and a drug loading content of 49.36 ± 0.14%. GKA-NSps showed spherical morphology and very good stability in normal saline, phosphate buffer saline (PBS, pH 7.4), 5% glucose, artificial gastric juice, artificial intestinal juice and plasma; thus, it is suitable for both oral and intravenous administration. The resultant GKA-NSps displayed sustained drug release behavior and strongerin vitrocytotoxicity against 4T1, MCF-7, MDA-MB-453, HeLa, HepG2, BT474, and A549 cells than free GKA. Thein vivostudy in MCF-7 tumor-bearing nude mice indicated that GKA-NSps (60 mg/kg, i.v.) achieved similar therapeutic efficacy as PTX injection (8 mg/kg, i.v.) (62.09% vs. 61.27%), while the minimal lethal dose was more than 320 mg/kg, indicating good safety. By using nanotechnology, our study suggested that some antitumor flavonoids of low potency, such as GKA, are promising as safe but effective anticancer drugs. [ABSTRACT FROM AUTHOR]

The clinical application of central nervous system (CNS) drugs is limited by their poor bioavailability due to the blood–brain barrier (BBB). Borneol is a naturally occurring compound in a class of ‘orifice-opening’ agents often used for resuscitative purposes in traditional Chinese medicine. A growing body of evidence confirms that the ‘orifice-opening’ effect of borneol is principally derived from opening the BBB. Borneol is therefore believed to be an effective adjuvant that can improve drug delivery to the brain. The purpose of this paper is to provide a comprehensive review of information accumulated over the past two decades on borneol’s chemical features, sources, toxic and kinetic profiles, enhancing effects on BBB permeability and their putative mechanisms, improvements in CNS drug delivery, and pharmaceutical forms. The BBB-opening effect of borneol is a reversible physiological process characterized by rapid and transient penetration of the BBB and highly specific brain regional distribution. Borneol also protects the structural integrity of the BBB against pathological damage. The enhancement of the BBB permeability is associated with the modulation of multiple ATP-binding cassette transporters, including P-glycoprotein; tight junction proteins; and predominant enhancement of vasodilatory neurotransmitters. Systemic co-administration with borneol improves drug delivery to the brain in a region-, dose- and time-dependent manner. Several pharmaceutical forms of borneol have been developed to improve the kinetic and toxic profiles of co-administered drugs and enhance their delivery to the brain. Borneol is a promising novel agent that deserves further development as a BBB permeation enhancer for CNS drug delivery. [ABSTRACT FROM AUTHOR]

Sericin is a natural protein that has been used in biomedical and pharmaceutical fields as raw material for polypeptide-based drug delivery systems (DDSs). In this paper, it has been employed as pharmaceutical biopolymer for the production of sunitinib–polypeptide conjugate. The synthesis has been carried out by simple click reaction in water, using the redox couplel-ascorbic acid/hydrogen peroxide as a free radical grafting initiator. The bioconjugate molecular weight (50 kDa < Mw < 75 kDa) was obtained by SDS-PAGE, while the spectroscopic characteristics have been studied in order to reveal the presence of grafted sunitinib. In both FT-IR and UV/Vis spectra, signals corresponding to sunitinib functional groups have been identified. Since sunitinib is an anticancer drug characterized by low bioavailability and low permeability, the bioconjugation aimed at their enhancement.In vitrostudies demonstrated that bioavailability has been increased to almost 74%, compared with commercial formulation. Also cell membrane permeability has been augmented inin vitrotests, in which membrane models have been used to determine the lipid membrane/physiological fluid partition coefficient (Kp). The log(Kp) value of the bioconjugate was increased to over 4. This effect resulted in a three-fold decrease of IC50value against MCF-7 cells. [ABSTRACT FROM AUTHOR]

To specifically deliver cytotoxic drug to tumor cells and enhance cellular uptake is the key for effective cancer therapy. In this paper, we described a novel drug targeting system, which is designed to combine features of biological (cell-penetrating peptides, CPPs) and physical (magnetic) drug targeting for use in the magnetic hyperthermia-triggered release. A doxorubicin–CPPs conjugate (DOX-CPPs) was loaded into thermosensitive magnetic liposomes (TSMLs) (DOX-CPPs/TSMLs), andin vitroDOX-CPPs thermosensitive release activity, anti-proliferation effect,in vivotargeted delivery as well asin vivoantitumor activity were determined. The results demonstrated that the DOX-CPPs/TSMLs showed good physicochemical properties, effective anti-proliferation effect in MCF-7 cellsin vitro. Additionally,in vivostudy, DOX-CPPs/TSMLs under AC magnetic field displayed superiorin vivotargeted delivery efficacy, antitumor efficacy in an MCF-7 xenograft murine model. In conclusion, the application of DOX-CPPs/TSMLs under AC magnetic field may provide a strategy for the selective and efficient delivery of drug. [ABSTRACT FROM AUTHOR]

Recently, microneedle arrays (MAs) have been developed for painless inoculation of vaccines and possess many prominent advantages, including convenience for inoculation, and exact delivery of vaccine to the exact epidermal and dermal or mucosal compartments which teem with antigen-presenting cells (APCs). Among different types of MAs, while the micro-environmental stimulus-responsive MAs represent one of the developmental trends in the field, the MAs combined with the conventional vaccines that are based on nonvirulent viruses, such as live attenuated or whole inactivated viruses, and antigen-encoding DNA viral vectors, have developed rapidly into the advanced stages, with certain products already on clinical trials. The pre- and clinical research outcomes showed that the painless MA delivery of the conventional vaccines through mammalian skin or mucosa can not only elicit robust systemic and even mucosal immunity to pathogens but also, in certain circumstances, redirect the immune response toward a specific Th1 pathway, resulting in cytotoxic T lymphocytes (CTL) to erase the cell-hidden pathogens, thanks to the robust adjuvant function of MAs exerted through damaging the contacted cells to release dangerous signals. This paper focuses on reviewing the latest research and advancements in MA delivery of the conventional vaccines that are based on nonvirulent viruses, underlining MA enhancement of the overall vaccine performance and the most advanced MA vaccine products that are relatively close to markets. [ABSTRACT FROM PUBLISHER]

Context: Paclitaxel (PTX) and carboplatin (CBP) are widely used for the combined chemotherapy of non-small cell lung cancer (NSCLC). However, the development of multidrug resistance of cancer cells, as well as systemic toxic side effects resulting from nonspecific localization of anticancer drugs to non-tumor areas are major obstacles to the success of chemotherapy in treating cancers. Objective: This study aimed to engineer a prodrug-based nano-drug delivery system for co-encapsulate hydrophilic (CBP) and hydrophobic anti-tumor drugs (PTX). This system was expected to resolve the multidrug resistance cause by single drug, and the dual-drug-loaded liposome was also planned to specifically target the cancer cells without obvious influence on normal cells and tissues. Methods: In this paper, PLGA-PEG-CBP was synthesized by the conjugation between the carboxylic group of PLGA-PEG-COOH and the amino group of CBP. Then, self-assembled nanoparticles for combination delivery of PTX and PLGA-PEG-CBP (PTX/CBP NPs) were prepared by solvent displacement technique. Thein vitroandin vivoanti-tumor efficacy was assessed in NCL-H460 human non-small cell lung carcinoma cell line. Results: PTX/CBP NPs achieved the highest cytotoxic effect among all formulationsin vitro, as compared with single drug delivery NPs.In vivoinvestigation on NSCLC animal models showed that co-delivery of PTX and CBP possessed high tumor-targeting capacity and strong anti-tumor activity. Conclusions: The PTX/CBP NPs constructed in this research offers an effective strategy for targeted combinational lung cancer therapy. [ABSTRACT FROM AUTHOR]

Context: Paclitaxel (PTX) and doxorubicin (DOX) are widely used for the combined chemotherapy of solid tumors. However, free drug combination has lower antitumor efficiency. It is necessary to design a drug delivery system to carry both of them. Objective: This study aimed to engineer a nano-drug delivery system for co-encapsulating PTX and DOX. This system was expected to resolve the multidrug resistance caused by single drug, and the dual–drug-loaded nanostructured lipid carriers were also planned to specifically target the cancer cells without obvious influence on normal cells and tissues. Methods: In this paper, nanostructured lipid carriers for combination delivery of PTX and DOX were prepared by the melt-emulsification technique.In vitrocytotoxicity against NCL-H460 human non-small cell lung carcinoma (NSCLS) cell line was investigated, andin vivoanti-tumor of NLC was evaluated on mice models grafting NCL-H460 cells. Results: PTX-DOX NLC achieved the highest cytotoxic effect among all formulationsin vitro, as compared to single drug delivery NLC.In vivoinvestigation on NSCLC animal models showed that co-delivery of PTX and DOX possessed high tumor-targeting capacity and strong anti-tumor activity. Conclusion: The PTX-DOX NLC constructed in this research offers an effective strategy for targeted combinational lung cancer therapy. [ABSTRACT FROM PUBLISHER]

The objective of this paper is to introduce some strategic guidance to a rational formulation strategy of new molecules as oral dosage forms, based on a sound scientific understanding of factors determining the oral bioavailability. The critical implication of permeability and solubility is discussed along with the efficient dose of the drug. The concept of dose-solubility number is introduced as a tool for chemists to assess the develop-ability of different molecules very early during discovery stage. Based on this understanding, a rational formulation strategy for preclinical and early clinical phases is provided. The technical considerations and limitations of different formulation technologies are discussed and illustrated via concrete examples. This approach has the advantage of streamlining the formulation process in order to avoid delaying the development of new drugs due to formulation related issues. [ABSTRACT FROM PUBLISHER]

Context: The sustained release implants can be directly implanted in tumor site by surgery and are promising for cancer treatment. Objective: RGD-modified PEGylated polyamidoamine (PAMAM) dendrimer with doxorubicin (DOX) conjugated by acid-sensitive linkage (RGD-PPCD) was a potential conjugate for tumor-targeted therapy. In order to enhance tumor retention ability and long-term effect of drug, we developed the DOX and its conjugate implants using poly( dl-lactic-co-glycolic acid) (PLGA), poly( dl-lactic acid) (PLA) and polyethylene glycol (PEG) as carrier materials. Methods: The implants were prepared by a simple solvent evaporation method. Different formulations with varying ratios of three polymers were designed, prepared and evaluated on the basis of viscosity, in vitro release and drying time. Furthermore, in vivo biodistribution and antitumor activity of the implants were studied in mice with subcutaneous C6 xenografts. Results: The optimized formulation was obtained with the 3:1 ratio of PLGA/PLA (w/w) and 1% PEG (wt.%). The drug release behavior of DOX, PPCD and RGD-PPCD implants prepared by the optimized formulation was similar according to the assessment of similarity factor f2, and the release curves were fell into three phases, including a lag-period, then the second phase which was consistent with zero-order model followed by a plateau. Data of total DOX remained in implants indicated the release were faster in vivo than in vitro. Moreover, intratumoral drug amount of RGD-PPCD implants was the highest 45 days after implantation. Correspondingly, the RGD-PPCD implants exhibited the strongest antitumor activity compared with PPCD and free DOX implants. Discussion and conclusion: This paper presents an exploratory research on macromolecule-drug conjugates, including RGD-PPCD and PPCD, which have the potential to be developed into long-term effect implants for tumor therapy with high efficiency and low systematic toxicity. [ABSTRACT FROM AUTHOR]

Intra-tracheal instillation of budesonide using surfactant as a vehicle significantly decreased the incidence of bronchopulmonary dysplasia or death in preterm infants. The formularity of surfactant supplemented with budesonide and biophysical and chemical stability of the suspension has not been well reported. The aims are to investigate the biophysical and chemical stability of two surfactant preparations, Survanta and Curosurf, supplemented with budesonide. Biophysical property of the surface tension of Survanta and Survanta/budesonide suspension and of Curosurf and Curosurf/budesonide suspension was conducted by a pulsating bubble surfactometer and by a drop shape tensiometer. Chemical stability of Survanta/budesonide and of Curosurf/budesonide suspensions was tested by high-performance liquid chromatography analysis (HPLC). Pulmonary distribution of Survanta/18F-budesonide suspension was examined by a Nano/PET digital scan in rats. The Marangoni effect of Survanta, Curosurf, and budesonide was tested by digital high speed photography. For Survanta supplemented with budesonide, with a concentration ratio of ≥50, the surface tension-lowering activity was minimally affected. Similarly, the surface tension-lowering activity of Curosurf was not significantly affected by addition of budesonide, if the concentration ratio was ≥160. With these concentration ratios of both suspensions, HPLC analysis revealed no new compounds identified. Curosurf as compared to Survanta exhibited a significantly higher Marangoni effect. We conclude that with current dosage recommended for Survanta and Curosurf, both surfactant/budesonide suspensions are biophysically and chemically stable. Both surfactants can act as an effective vehicle for budesonide delivery. [ABSTRACT FROM AUTHOR]

Nanotechnology has ignited a transformative revolution in disease detection, prevention, management, and treatment. Central to this paradigm shift is the innovative realm of cell membrane-based nanocarriers, a burgeoning class of biomimetic nanoparticles (NPs) that redefine the boundaries of biomedical applications. These remarkable nanocarriers, designed through a top-down approach, harness the intrinsic properties of cell-derived materials as their fundamental building blocks. Through shrouding themselves in natural cell membranes, these nanocarriers extend their circulation longevity and empower themselves to intricately navigate and modulate the multifaceted microenvironments associated with various diseases. This comprehensive review provides a panoramic view of recent breakthroughs in biomimetic nanomaterials, emphasizing their diverse applications in cancer treatment, cardiovascular therapy, viral infections, COVID-19 management, and autoimmune diseases. In this exposition, we deliver a concise yet illuminating overview of the distinctive properties underpinning biomimetic nanomaterials, elucidating their pivotal role in biomedical innovation. We subsequently delve into the exceptional advantages these nanomaterials offer, shedding light on the unique attributes that position them at the forefront of cutting-edge research. Moreover, we briefly explore the intricate synthesis processes employed in creating these biomimetic nanocarriers, shedding light on the methodologies that drive their development. [ABSTRACT FROM AUTHOR]

Click chemistries are efficient and selective reactions that have been leveraged for multi-stage drug delivery. A multi-stage system allows independent delivery of targeting molecules and drug payloads, but targeting first-phase materials specifically to disease sites remains a challenge. Stimuli-responsive systems are an emerging strategy where common pathophysiological triggers are used to target payloads. Oxidative stress is widely implicated in disease, and we have previously demonstrated that reactive oxygen species (ROS) can crosslink and immobilize polyethylene glycol diacrylate (PEGDA) in tissue mimics. To build on these promising results, we present a two-step, catch-and-release system using azide-DBCO click chemistry and demonstrate the capture and eventual release of a fluorescent payload at defined times after the formation of a PEGDA capturing net. The azide component is included with radical-sensitive PEGDA, and the payload is conjugated to the DBCO group. In cell-free and cell-based tissue mimic models, azides were incorporated at 0–30% in the first-phase polymer net, and DBCO was delivered at 2.5–10 µM in the second phase to control payload delivery. The payload could be captured at multiple timepoints after initial net formation, yielding a flexible and versatile targeting system. Matrix metalloproteinase (MMP)-degradable peptides were incorporated into the polymer backbone to engineer fluorescent payload release by MMPs, which are broadly upregulated in diseases, through degradation of the capture net and directly from the DBCO. Taken together, this research demonstrates proof-of-principle for a responsive and clickable biomaterial to serve as a multi-potent agent for the treatment of diseases compounded by high free radicals. [ABSTRACT FROM AUTHOR]

Magnetic Drug Targeting (MDT) is of particular interest to researchers because of its good loading efficiency, targeting accuracy, and versatile use in vivo. Cardiovascular Disease (CVD) is a global chronic disease with a high mortality rate, and the development of more precise and effective treatments is imminent. A growing number of studies have begun to explore the feasibility of MDT in CVD, but an up-to-date systematic summary is still lacking. This review discusses the current research status of MDT from guiding magnetic fields, magnetic nanocarriers, delivery channels, drug release control, and safety assessment. The current application status of MDT in CVD is also critically introduced. On this basis, new insights into the existing problems and future optimization directions of MDT are further highlighted. [ABSTRACT FROM AUTHOR]

Oral cancer is one of the leading causes of death worldwide. Oral precancerous lesions (OPL) are the precursors of oral cancer, with varying degrees of progression. Tetrahydrocurcumin (THC) is a major metabolite of curcumin with superior anticancer properties against various types of cancer. However, THC's clinical outcome is limited by its poor aqueous solubility. Herein, we developed novel mucoadhesive biopolymer-based composite sponges for buccal delivery of THC, exploiting nanotechnology and mucoadhesion for efficient prevention and treatment of oral cancer. Firstly, THC-nanocrystals (THC-NC) were formulated and characterized for subsequent loading into mucoadhesive composite sponges. The anticancer activity of THC-NC was assessed on a human tongue squamous carcinoma cell line (SCC-4). Finally, the chemopreventive activity of THC-NC loaded sponges (THC-NC-S) was examined in DMBA-induced hamster OPL. The selected THC-NC exhibited a particle size of 532.68 ± 13.20 nm and a zeta potential of −46.08 ± 1.12 mV. Moreover, THC-NC enhanced the anticancer effect against SCC-4 with an IC50 value of 80 µg/mL. THC-NC-S exhibited good mucoadhesion properties (0.24 ± 0.02 N) with sustained drug release, where 90% of THC was released over 4 days. Furthermore, THC-NC-S had a magnificent potential for maintaining high chemopreventive activity, as demonstrated by significant regression in the dysplasia degree and a decline in cyclin D1 (control: 40.4 ± 12.5, THC-NC-S: 12.07 ± 5.2), culminating in significant amelioration after 25 days of treatment. Conclusively, novel THC-NC-S represent a promising platform for local therapy of OPL, preventing their malignant transformation into cancer. [ABSTRACT FROM AUTHOR]

Canagliflozin (CFZ) is a sodium-glucose cotransporter-2 inhibitor (SGLT2) that lowers albuminuria in type-2 diabetic patients, cardiovascular, kidney, and liver disease. CFZ is classified as class IV in the Biopharmaceutical Classification System (BCS) and is characterized by low permeability, solubility, and bioavailability, most likely attributed to hepatic first-pass metabolism. Nanocrystal-based sublingual formulations were developed in the presence of sodium caprate, as a wetting agent, and as a permeability enhancer. This formulation is suitable for children and adults and could enhance solubility, permeability, and avoid enterohepatic circulation due to absorption through the sublingual mucosa. In the present study, formulations containing various surfactants (P237, P338, PVA, and PVP K30) were prepared by the Sono-homo-assisted precipitation ion technique. The optimized formula prepared with PVP-K30 showed the smallest particle size (157 ± 0.32 nm), Zeta-potential (−18 ± 0.01), and morphology by TEM analysis. The optimized formula was subsequently formulated into a sublingual tablet containing Pharma burst-V® with a shorter disintegration time (51s) for the in-vivo study. The selected sublingual tablet improved histological and biochemical markers (blood glucose, liver, and kidney function), AMP-activated protein kinase (AMPK), and protein kinase B (AKT) pathway compared to the market formula, increased CFZ's antidiabetic potency in diabetic rabbits, boosted bioavailability by five-fold, and produced faster onset of action. These findings suggest successful treatment of diabetes with CFZ nanocrystal-sublingual tablets. [ABSTRACT FROM AUTHOR]