Effectiveness of localized ultrasound-targeted microbubble destruction with doxorubicin liposomes in H22 mouse hepatocellular carcinoma model

Objective: In order to increase local drug concentration and reduce systemic side effects of liver cancer chemotherapy, it is desirable to develop novel non-invasive technologies for drug targeting, such as ultrasound-targeted microbubble destruction (UTMD).

Methods: H22 hepatocellular carcinoma (HCC) xenograft transplantation model was generated in UTMD study. BALB/c mice were randomly divided into six groups: doxorubicin HCl liposomal injection (DOX), DOX?+?US, UTMD, DOX?+?UTMD, H22 liver tumor control (CH control) and blank control group. The therapeutic schedule started on day 4 after tumor inoculation.

Results: Average survival time of the animal model was approximately 18?d. The UTMD therapy parameters were optimized in the H22 mouse model to be: microbubble (MB) diameter, 2.30?±?0.25?μm; MB density, 4.0?×?10⁹ bubbles/ml; treatment dose, 0.2?ml per 20?g mouse body weight; sonication frequency, 1.3?MHz; and sonication power, 2.06?W/cm². Mice treated with DOX?+?UTMD had the smallest tumor volume and weight (p?<?0.001), and the highest tumor inhibition rate (p?<?0.01), intratumoral DOX concentration (p?<?0.001) and survival rate among all tumor-burden groups (p?<?0.001). Cell viability in different treatment groups was also assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.

Conclusion: An improved antitumor effect was observed with the combination therapy of DOX and UTMD, as compared with treatment with DOX, DOX?+?US or UTMD, which implicates a novel approach for HCC treatment.     

Co-delivery of docetaxel and bortezomib based on a targeting nanoplatform for enhancing cancer chemotherapy effects

Using facile polydopamine (PDA)-based surface modification and a pH-sensitive catechol-boronate binding mechanism, a novel drug delivery system was designed for the treatment of breast cancer. The system was able to achieve the following goals: active targeting, pH responsiveness, in vivo blood circulation for a prolonged period of time, and dual drug loading. After coating with PDA, the docetaxel (DTX)-loaded star-shaped copolymer cholic acid-poly(lactide-co-glycolide) nanoparticles (CA-PLGA@PDA/NPs) were functionalized with amino-poly(ethylene glycol)-folic acid (NH₂-PEG-FA) and bortezomib (BTZ) to form the targeting composition, DTX-loaded CA-PLGA@PDA-PEG-FA?+?BTZ/NPs. The novel NPs exhibited similar drug release characteristics compared to unfunctionalized CA-PLGA/NPs. Meanwhile, the incorporated NH₂-PEG-FA contributed to active targeting which was illustrated by cellular uptake experiments and biodistribution studies. Moreover, the pH responsive binding between BTZ and PDA was demonstrated to be effective to release BTZ at the tumor acidic environment for synergistic action with DTX. Both in vitro cytotoxicity and in vivo antitumor studies demonstrated that the novel nanoplatform exhibited the most suitable therapeutic effects. Taken together, the versatile PDA modified DTX-loaded CA-PLGA@PDA-PEG-FA?+?BTZ/NPs offered a promising chemotherapeutic strategy for enhancing breast cancer treatment.     

Docetaxel-loaded-lipid-based-nanosuspensions (DTX-LNS): preparation, pharmacokinetics, tissue distribution and antitumor activity

The purpose of the study was to design lipid-based-nanosuspensions (LNS) for Docetaxel (DTX) without Tween 80 for clinical intravenous administration (i.v.). DTX-LNS were prepared by high pressure homogenization method, and then lyophilization was carried out to improve the stability. The physical-chemical properties in terms of particle size, size distribution, zeta potential and morphology were evaluated, respectively. The in vitro cytotoxic activity was assessed by MTT against SKOV-3 and malignant melanoma B16 cells. The in vivo pharmacokinetics, tissue distribution as well as antitumor efficacy were investigated in B16 melanoma-bearing Kunming mice. The particle size and zeta potential of DTX-LNS were (200.0 ± 3.42)nm and (-11.15 ± 0.99)mV, respectively. Compared with Duopafei, it was shown that DTX-LNS exhibited higher antitumor efficacy by reducing tumor volume (P<0.05) and increasing survival rate in B16 melanoma-bearing mice and strongly reduced the anticancer drug toxicity. The results of biodistribution studies clearly indicated the superiority of DTX-LNS to Duopafei in increasing the accumulation of DTX within tumor and the organs rich in macrophages (liver, lungs and spleen), while, the drug concentration in heart and kidney decreased. Together these results suggested that DTX-LNS could effectively inhibit tumor growth, reduce toxicity during the therapeutic procedure and hold the potential to be an appropriate choice for the clinical administration of DTX.     

Preparation and therapeutic application of docetaxel-loaded poly(d,l-lactide) nanofibers in preventing breast cancer recurrence

The aim of this study was to develop docetaxel (DTX)-loaded poly-d,l-lactide (PDLLA) nanofibers and evaluate their therapeutic effect in preventing local breast cancer recurrence. DTX was incorporated into biodegradable PDLLA nanofibers by electrospinning. The surface morphology of the DTX/PDLLA nanofibers was characterized using scanning electron microscopy and wide angle X-ray diffraction. The in vitro release behavior of DTX from the fiber mats was also studied in detail. The cytotoxicity of DTX/PDLLA nanofibers was evaluated by MTT assay in 4T1 breast cancer cells. Flow cytometry revealed that DTX/PDLLA nanofibers exhibited apoptotic activity in 4T1 cells. In vivo antitumor efficacy of DTX/PDLLA nanofibers was evaluated in BALB/c mice bearing local breast tumors. Locoregional recurrence after primary tumor resection decreased obviously in mice treated with subcutaneously (16.7%) administered DTX-loaded PDLLA nanofibers, compared with the blank PDLLA nanofibers (88.9%), systemic (75.0%) or locally (77.8%) administered DTX and the control group (100%) (p?<?0.05). Finally, after subcutaneous transplantation in mice, the DTX/PDLLA scaffolds presented excellent biocompatibility, as exhibited by the minimal presence of inflammatory cells in the region surrounding the scaffolds. Our results suggest that DTX/PDLLA nanofibers could have great potential for clinical application requiring local chemotherapy.     

Efficacy and safety of the single pill combination of amlodipine 10 mg plus valsartan 160 mg in hypertensive patients not controlled by amlodipine 10 mg plus olmesartan 20 mg in free combination

ABSTRACT

Background and objective: For patients with moderate hypertension (grade 2, defined as systolic blood pressure [SBP] 160–179?mmHg and/or diastolic blood pressure [DBP] 100–109?mmHg), current guidelines recommend initial combination therapy and rapid dose-adjustment to achieve blood pressure goal. In this study we investigated the efficacy and tolerability of the single pill combination of amlodipine 10?mg plus valsartan 160?mg (A?10?+?Val 160) in patients not controlled by the free combination of amlodipine 10?mg plus olmesartan 20?mg (A?10?+?O 20).

Methods: In this prospective, open-label, non-randomized trial, 257 patients with mean sitting DBP of 100–109?mmHg at trough entered a 4 week treatment phase with A?10?+?O 20 in free combination once daily. Patients in whom DBP remained uncontrolled were switched in a second 4 week treatment phase to A?10?+?Val 160. The primary efficacy variable was the reduction in DBP at week 8 compared to week 4 in the intent-to-treat population.

Results: In the total cohort, baseline SBP/DBP of 164.2?±?9.8/103.6?±?2.1?mmHg decreased by 19.2?±?12.4/14.1?±?7.4?mmHg at week 4. In patients who did not achieve BP control (n?=?175), subsequent treatment with A?10?+?Val 160 for 4 weeks reduced SBP from 149.6?±?11.1 at week 4 by 7.9?mmHg at week 8 (95% CI: 6.1–9.6, p?<?0.0001) and DBP from 93.4?±?3.9?mmHg by 9.1?mmHg (95% confidence interval: 8.1–10.2, p?<?0.0001). The combination of A?10?+?Val 160 was well tolerated, and the observed adverse events (15.3% of patients in phase 2) were consistent with the known drug profiles.

Conclusions: In a study designed to reflect typical clinical practice, in patients not controlled by the free combination of A?10?+?O 20, the single pill combination of A?10?+?Val 160 produced a statistically and clinically significant additional BP reduction and was well tolerated. Potential limitations of the design (open-label, non-controlled design, short term treatment) have to be taken into account.     

Folic acid-modified and functionalized CuS nanocrystal-based nanoparticles for combined tumor chemo- and photothermal therapy

Recent studies have identified that CuS nanocrystal (CuS NCs) could be used as a new class of promising photo-thermal agents due to their excellent plasmonic absorption abilities in a wide near-infrared (NIR) region. However, most of nanocarriers lack target capacity for combining chemotherapy and photothermal therapy effects. Herein, we reported chitosan (CS)-encapsulated and folic acid (FA)-modified nanoparticles (NPs) simultaneously loading with functionalized CuS NCs and docetaxel (DTX) (FA-DTX-PVP/CuS-NPs). Compared with free DTX, the photothermal agent CuS NCs and DTX not only could be specially targeted to deliver into MCF-7 cancer cells via a receptor-mediated endocytosis pathway, but also could be effectively transferred into tumor tissues of S₁₈₀ tumor-bearing mice in vivo. More important, when combination with NIR laser irradiation, FA-DTX-PVP/CuS-NPs showed a higher antitumor efficacy than the individual therapies. Thus, as a remote and noninvasive tumor therapy strategy, these active targeting NPs may provide a great potential for tumor synergistic therapy.     

Selective delivery of PLXDC1 small interfering RNA to endothelial cells for anti-angiogenesis tumor therapy using CD44-targeted chitosan nanoparticles for epithelial ovarian cancer

Angiogenesis plays an essential role in the growth and metastasis of tumor cells, and the modulation of angiogenesis can be an effective approach for cancer therapy. We focused on silencing the angiogenic gene PLXDC1 as an important factor for anti-angiogenesis tumor therapy. Herein, we developed PLXDC1 small interfering siRNA (siRNA)-incorporated chitosan nanoparticle (CH-NP/siRNA) coated with hyaluronic acid (HA) to target the CD44 receptor on tumor endothelial cells. This study aimed to improve targeted delivery and enhance therapeutic efficacy for tumor anti-angiogenesis. The HA-CH-NP/siRNA was 200?±?10?nm in size with a zeta potential of 26.4?mV. The loading efficiency of siRNA to the HA-CH-NP/siRNA was up to 60%. The selective binding of HA-CH-NP/siRNA to CD44-positive tumor endothelial cells increased by 2.1-fold compared with that of the CD44 nontargeted CH-NP/siRNA. PLXDC1 silencing by the HA-CH-NP/siRNA significantly inhibited tumor growth in A2780 tumor-bearing mice compared with that in the control group (p?p?p?p?相似文献   

Assessment of the therapeutic activity of a combination of almitrine and raubasine on functional rehabilitation following ischaemic stroke

Background and objectives: Stroke is a major cause of disability. Certain experimental studies have suggested that a combination of almitrine?+?raubasine (Duxil) increases the supply of oxygen to cerebral tissues and may be beneficial in post-stroke rehabilitation. This multicentre clinical study was carried out in order to assess the efficacy of this combination on post-stroke rehabilitation.

Methods: The trial was a randomised, double-blind, placebo-controlled study. Patients that had experienced an ischaemic cerebrovascular accident (confirmed by CT scan) were included 4-6 weeks after the acute onset and received randomised treatment of either almitrine?+?raubasine or placebo 2 tablets daily for 3 months. Before treatment, there was a 2-week washout period for stopping all other drugs, except for antihypertensive and antidiabetic drugs. We assessed the patients by Barthel Index (BI), Neurological Functional Deficit Scores (NFDS), and Hasagawa Dementia Scales (HDS) each month after treatment.

Results: A total of 83 patients were entered into the study and data were available for 74. Of these, 38 patients received almitrine?+?raubasine and 36 received placebo. The baseline characteristics were comparable between both groups. Almitrine?+?raubasine was significantly more effective than placebo at increasing BI at 1, 2 or 3 months (14.6?±?13.8 versus 3.3?±?13.2, p?=?0.01; 19.3?±?13.6 versus 8.8?±?14.0, p?=?0.02; 22.6?±?14.7 versus 10.7?±?17.0, p?=?0.02 respectively) and reducing NFDS at 1 month (3.6?±?3.2 versus 1.9?±?3.5, p?=?0.034) after treatment. More almitrine?+?raubasine-treated patients' NFDS had improved compared with placebo-treated patients at 2 and 3 months (97 versus 78%, p?=?0.013; 100 versus 86%, p?=?0.023 respectively). Compared with pre-treatment, there was a strong tendency towards an improvement of HDS with almitrine + raubasine. The number of adverse events reported was low for the almitrine + raubasine-treated group and the placebo group and all events were mild, of short duration and resolved without treatment. Almitrine + raubasine had no clinically significant effect on blood pressure, heart rate or other laboratory tests.

Conclusion:The results indicate that almitrine + raubasine can accelerate neurological function recovery after stroke to some degree and is well tolerated.     

Docetaxel-loaded exosomes for targeting non-small cell lung cancer: preparation and evaluation in vitro and in vivo

Non-small cell lung cancer (NSCLC) is a highly lethal disease and the majority of NSCLC patients are desperate for therapies that can effectively target their cancer and ultimately improve their overall survival. Docetaxel (DTX) represents the first-line of the antitumor agent that is used to treat NSCLC; however, it has poor solubility in water and unsatisfactory encapsulation efficiency. In our study, exosomes were isolated from A549 cancer cells by ultracentrifugation and then characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot (WB). The particle size changes of EXO and EXO-DTX were measured daily for seven days to test the stability. DTX was selected payload by electroporation (EXO-DTX). For the in vitro evaluation, cell proliferation, cell cycle, cell apoptosis, reactive oxygen species (ROS) assay and cellular uptake were evaluated in the A549 cells. Also, this study evaluated the target and therapeutic effect of DTX as an antitumor agent in vivo. As a result, EXO-DTX with a particle size of 149.5 nm were successfully prepared and the cytotoxicity of the EXO-DTX was much greater than that of DTX monomers. Exosomes significantly increased the cellular uptake in vitro evaluation and showed better targeting to tumor tissue compared to the free DTX in the mice. We also explored the potential of tumor cell-derived exosomes as a drug delivery agent to target the parent cancer. Hence, we conclude that exosomes might be used as a potential antitumor drug delivery system (DDS).     

Multifunctional Tumor-Targeting Nanocarriers Based on Hyaluronic Acid-Mediated and pH-Sensitive Properties for Efficient Delivery of Docetaxel

Purpose

The objective of this work was to develop a multifunctional tumor-targeting nanocarrier based on the mechanism of CD44-mediated endocytosis and pH-induced drug release to improve the therapeutic efficacy of docetaxel (DTX).

Methods

Hyaluronic acid-coated docetaxel-loaded cholesteryl hemisuccinate vesicles (HA-CHEMS vesicles) were prepared. The physiochemical properties and pH-dependent drug release of HA-CHEMS vesicles were evaluated. The HA-CHEMS vesicles were investigated for CD44-mediated internalization and in vitro cell viability using MCF-7,A549 and L929 cells.In addition,tissue distribution as well as antitumor efficacy was also evaluated in MCF-7 tumor-bearing mouse model.

Results

The particle size and zeta potential of HA-CHEMS vesicles were 131.4?±?6.2 nm and ?13.3?±?0.04 mV,respectively. The in vitro drug release results demonstrated a pH-responsive drug release under different pH conditions. In vitro cell viability tests suggested that the encapsulation of DTX in HA-CHEMS vesicles led to more than 51.6-fold and 46.3-fold improved growth inhibition in MCF-7 and A549 cell lines,respectively compared to Taxotere®. From the cell uptake studies,the coumarin 6-loaded HA-CHEMS vesicles enhanced intracellular fluorescent intensity in the CD44-overexpressing cell line (MCF-7). Biodistribution studies revealed selective accumulation of HA-CHEMS vesicles in the MCF-7 bearing BalB/c nude mice as a result of passive accumulation and active targeting (CD44-mediated endocytosis). Compared to Taxotere®,HA-CHEMS vesicles exhibited higher antitumor activity by reducing tumor volume (P?<?0.05) and drug toxicity,demonstrating the success of the multifunctional targeting delivery.

Conclusions

This work corresponds to the preparation of a multifunctional tumor-targeted delivery system. Our investigation shows that hyaluronan-bearing docetaxel-loaded cholesteryl hemisuccinate vesicles (HA-CHEMS vesicles) is a highly promising therapeutic system,leading to tumor regression after intravenous administration without visible toxicity.     

Evaluation of hepatorenal impairments in Wistar rats coexposed to low-dose lead,cadmium and manganese: insights into oxidative stress mechanism

The study aims to evaluate effects of chronic low-dose coexposure to lead (Pb), cadmium (Cd) and manganese (Mn) on hepatorenal toxicity and oxidative stress. Young male Wistar rats were treated with Pb acetate (1.4?mg/kg BW), Cd chloride (0.01?mg/kg BW), Mn chloride (0.14?mg/kg BW) and their combination (Pb?+?Cd?+?Mn) by oral gavage, for 15 weeks. Liver enzymes, albumin (Alb), globulin (Glb), total protein, creatinine, urea and electrolyte concentrations were measured in the serum. Hepatic and renal malondialdehyde (MDA), glutathione peroxidase-1 (GPx1) and metallothionein-1 (MT1) concentrations were measured by enzyme immunoassay technique. Chronic exposure to the metals significantly (p?<?.05) increased serum Glb concentration and decreased Alb/Glb ratio, compared to the controls. Serum creatinine concentration significantly (p?<?.05) decreased in the Pb, Cd and Pb?+?Cd?+?Mn groups, but elevated in the Mn group. Hepatic MDAs rose significantly (p?<?.05) in the Pb group, while hepatic GPx1 activities increased significantly (p?<?.05) in the Cd, Mn and Pb?+?Cd?+?Mn groups. Hepatic and renal MT1 concentration decreased (p?<?.05) in the Mn group only. Biochemical alterations were confirmed by light microscopy of the liver and kidneys, which showed degenerative changes. It is concluded that prolonged coexposure to environmentally relevant levels of Pb, Cd and Mn impairs liver and kidney functions via the induction of oxidative stress, and it underlines the importance of studying toxicants in combination.     

Self-delivering prodrug-nanoassemblies fabricated by disulfide bond bridged oleate prodrug of docetaxel for breast cancer therapy

Breast cancer leads to high mortality of women in the world. Docetaxel (DTX) has been widely applied as one of the first-line chemotherapeutic drugs for breast cancer therapy. However, the clinical outcome of DTX is far from satisfaction due to its poor drug delivery efficiency. Herein, a novel disulfide bond bridged oleate prodrug of DTX was designed and synthesized to construct self-delivering prodrug-based nanosystem for improved anticancer efficacy of DTX. The uniquely engineered prodrug-nanoassemblies showed redox-responsive drug release, increased cellular uptake and comparable cytotoxicity against 4T1 breast cancer cells when compared with free DTX. In vivo, oleate prodrug-based nanoparticles (NPs) demonstrated significantly prolonged systemic circulation and increased accumulation in tumor site. As a result, prodrug NPs produced a notable antitumor activity in 4T1 breast cancer xenograft in BALB/c mice. This prodrug-based self-assembly and self-delivery strategy could be utilized to improve the delivery efficiency of DTX for breast cancer treatment.     

Injectable and biodegradable poly(organophosphazene) hydrogel as a delivery system of docetaxel for cancer treatment

Abstract

Although docetaxel (DTX) is an advanced taxoid, further augmentation of its properties is still required, such as improvement in its low aqueous solubility. Herein, we report the development of biodegradable/injectable poly(organophosphazene) (PPZ) hydrogels for the delivery of DTX without the use of organic solvents. An aqueous solution of PPZ containing α-amino-ω-methoxy-poly(ethylene glycol) (AMPEG) 750 instead of AMPEG 550 was prepared, thereby increasing the erosion capacity of the hydrogel by judicious balance of the hydrophobic/hydrophilic moieties. The safety of the hydrogel was demonstrated using a biocompatibility test. The PPZ aqueous solution (8?wt%) containing DTX exhibited a thermosensitive sol–gel–sol transition that was independent of the concentration of DTX (1–3?mg/mL). The in vitro release study indicated that the dominant release mechanism was either erosion or diffusion/erosion-controlled release depending on the DTX content of the hydrogel. The in vivo anticancer effect of the intratumorally injected PPZ system in human gastric cancer cell-xenografted mice was evaluated, which demonstrated a significantly (p?<?0.01) enhanced effect of the DTX-PPZ hydrogel system compared to the control (DTX solution, i.v.). In conclusion, the PPZ hydrogel may be a promising candidate for DTX delivery, affecting a decrease in the size of tumors with little toxicity prior to exeresis.     

Evaluation of antihyperlipidemic and antitumor activities of isolated coumarins from Salvadora indica

Context. Salvadora indica Wight (Salvadoraceae) contains a number of medically beneficial properties including abrasives, astringents and antiseptics. Traditionally, it was used by ancient Arabs to whiten and polish teeth.

Objective: This study explores the antihyperlipidemic and antitumor effects of an ethanol extract of S. indica and its isolated phytoconstituents in rodents.

Material and methods: Flash chromatography was used for the isolation of phytoconstituents from the stems of S. indica. An antihyperlipidemic study was carried out in Triton loaded rats. Animal groups were given intraperitoneal (i.p.) injection of Triton WR 1339 at dose of 400?mg/kg body weight (b.w.). Furthermore, antitumor activity was investigated in hybrid mice (of C57BL strain?+?Swiss albino strain). The animals were observed for tumor growth after injection of B16F10 melanoma cells into the dorsal skin of mice.

Results: The stems of S. indica yielded xanthotoxin and umbelliferone through chromatographic separation techniques. The structures of the compounds were elucidated by spectroscopic data interpretation and showed antihyperlipidemic activity. The study showed significant reduction in total cholesterol (TC) (p?p?p?p?p?p?p?Discussion and conclusion: Acute treatment caused a stimulatory effect on high density lipoprotein level and inhibition in TC and TG elevation induced by Triton. Tumor regression studies showed a regression response for tumor growth in vivo of murine mouse melanoma as demonstrated by increasing the VDT and GD.     

The effects of Melissa officinalis (lemon balm) pretreatment on the resistance of the heart to myocardial injury

Context: The antihyperlipidemic, antiarrhythmic, neuroprotective and hepatoprotective effects of Melissa officinalis L. (Lamiaceae) have been reported. However, no study has examined its effects on the resistance of the heart to stressful conditions.

Objective: The objective of this study is to evaluate the effects of aqueous extract of M. officinalis aerial parts on Wistar rat heart with/without cardiac injury.

Materials and methods: Animals were grouped as control, isoproterenol (ISO), M. officinalis without (M50, M100, and M200) and with isoproterenol (M50?+?ISO, M100?+?ISO, and M200?+?ISO). The aqueous extract of M. officinalis was orally administered at dosages of 50, 100, and 200?mg/kg/d, respectively, for 7 consecutive days. On the 6th and 7th day, ISO, M50?+?ISO, M100?+?ISO, and M200?+?ISO groups received 85?mg/kg of isoproterenol for myocardial injury induction. On day 8, hemodynamic parameters were recorded and samplings were done.

Results: The extract (50, 100, and 200?mg/kg) significantly reduced the heart rate (264?±?5, 259?±?5 and 281?±?3 versus 377?±?13 in control group, p?<?0.01). Blood pressure was significantly decreased in M50?+?ISO (75?±?5) versus M50 (110?±?6) and M100?+?ISO (72?±?6) versus M100 (105?±?5?mmHg, p?<?0.01). The malondialdehyde levels of the injured hearts were lower in M50?+?ISO and M100?+?ISO groups than in the ISO group (p?<?0.05). Serum cardiac troponin I was higher in the M200?+?ISO group (5.1?±?1.7) than in the ISO group (2.7?±?0.7?ng/ml, p?<?0.05).

Conclusion: The lower dose of extract, by improving the balance of the redox system and by reducing the heart rate, may increase the heart resistance to injury. However, the higher doses of extract may intensify the injury of ischemic heart.     

A microemulsion co-loaded with Schizandrin A–docetaxel enhances esophageal carcinoma treatment through overcoming multidrug resistance

Multidrug resistance (MDR) is the major underlying cause of the low 5-year survival rate of esophageal carcinoma. In this study, we developed a novel microemulsion system (SD-ME) co-loaded with docetaxel (DTX) and Schizandrin A, a potent chemotherapeutic agent and a potential drug resistance modulator, respectively. In the physicochemical characterization studies, SD-ME displayed a well-defined spherical shape and size (56.62?±?4.16?nm), a narrow polydispersity index (PDI, 0.132?±?0.002), and a negative surface charge (?19.81?±?3.11?mv). In the cellular uptake studies, SD-ME with a DTX concentration of 30?μg/mL exhibited a 3.9-fold enhancement of DTX internalization in DTX-resistant EC109 (EC109/DDR) cells in comparison to that observed for EC109 cells, and the mechanisms were associated with reducing P-gp expression and inhibiting P-gp ATPease. The half-maximal inhibitory concentrations (IC₅₀) of DTX and SD-ME against EC109/DDR cells were 40.57?±?0.39 and 3.59?±?0.06?μg/mL, respectively. Likewise, the apoptotic rate of EC109/DDR treated with SD-ME increased up to 20-fold compared to that observed with free DTX. In anticancer efficacy studies in vivo, SD-ME markedly retarded the tumor growth of nude mice bearing EC109/DDR tumor xenografts compared with D-ME and free DTX throughout the duration of study. Consequently, mice treated with SD-ME had the highest survival rate (37.5%) during the observation period (70 days). In addition, there were no apparent side effects after the administration of SD-ME. Overall, our study provides evidence for SD-ME as an effective drug delivery system for enhanced MDR tumor treatment.     

Novel application of pluronic lecithin organogels (PLOs) for local delivery of synergistic combination of docetaxel and cisplatin to improve therapeutic efficacy against ovarian cancer

The synergistic combination of docetaxel (DTX) and cisplatin (CIS) by local drug delivery with a pluronic lecithin organogel (PLO) to facilitate high drug concentrations at tumor sites and less nonspecific distribution to normal organs is thought to be beneficial in chemotherapy. In this study, using Capryol-90 (C90) with the addition of lecithin as the oil phase was developed to carry DTX, which was then incorporated into a PLO-containing CIS to formulate a dual-drug injectable PLO for local delivery. An optimal PLO composite, P₁₃L_0.15O_1.5, composed of PF127:lecithin:C90 at a 13:0.15:1.5 weight ratio was obtained. The sol–gel transition temperature of P₁₃L_0.15O_1.5 was found to be 33?°C. Tumor inhibition studies illustrated that DTX/CIS-loaded P₁₃L_0.15O_1.5 could efficiently suppress tumor growth by both intratumoral and peritumoral injections in SKOV-3 xenograft mouse model. Pharmacokinetic studies showed that subcutaneous administration of P₁₃L_0.15O_1.5 was able to sustain the release of DTX and CIS leading to their slow absorption into the systemic circulation resulting in lower area under the plasma concentration curve at 0–72?h (AUC_0–72) and maximum concentration (C_max) values but longer half-life (T_1/2) and mean residence time (MRT) values. An in vivo biodistribution study showed lower DTX and CIS concentrations in organs compared to other treatment groups after IT administration of the dual drug-loaded P₁₃L_0.15O_1.5. It was concluded that the local co-delivery of DTX and CIS by PLOs may be a promising and effective platform for local anticancer drug delivery with minimal systemic toxicities.     

Trimodal synergistic antitumor drug delivery system based on graphene oxide

A multifunctional antitumor drug delivery system was synthesized based on graphene oxide (GO) for near-infrared (NIR) light controlling chemotherapeutic/photothermal (PTT) /photodynamic (PDT) trimodal synergistic therapy. The system named ICG-Wed-GO was formed by co-loading wedelolactone (Wed) and indocyanine green (ICG) on the surface of GO through π–π stacking interaction. Under NIR laser irradiation, ICG-Wed-GO could effectively absorb and transform optical energy to heat, generate reactive oxygen species (ROS) to ablating and damage tumor cells. The temperature of ICG-Wed-GO solution reached up to 79.4?°C in 10?min with NIR irradiation. In in vitro and in vivo study, ICG-Wed-GO showed excellent antitumor effect. After 14-day treatment of ICG-Wed-GO with NIR laser irradiation, the tumor disappeared completely on tumor-bearing mice. The low biotoxicity of ICG-Wed-GO was also proved. The system achieved the synergistic trimodal chemotherapeutic/photothermal/photodynamic treatment and demonstrated excellent antitumor effect, which is expected to have a greater potential for cancer therapy.     

Folate-targeting annonaceous acetogenins nanosuspensions: significantly enhanced antitumor efficacy in HeLa tumor-bearing mice

Annonaceous acetogenins (ACGs) are one of the most active constituents isolated from Annona species with potent antitumor activity. However, the poor solubility and severe side effect greatly limit their use in clinic. In this study, folic acid (FA) modified annonaceous acetogenins nanosuspensions (FA-PEG-ACGs-NSps) had been successfully prepared using DSPE-PEG-FA and soybean lecithin (SPC) as stabilizers. The resultant FA-PEG-ACGs-NSps had a mean particle size of 119.7?nm, a zeta potential of –23.0?mV and a high drug payload of 49.68%. The obtained ACGs-NSps had a good stability in various physiological media, and showed sustained drug release. Compared to common ACGs nanoparticles (PEG-ACGs-NSps), FA-PEG-ACGs-NSps showed significantly enhanced in vitro cytotoxicity against folate receptor-positive HeLa cell lines (IC50, 0.483?μg/mL vs. 0.915?μg/mL, p?In vivo experiments demonstrated that FA-PEG-ACGs-NSps brought more drug molecules into tumors and greatly improved the antitumor efficacy (TIR, 76.45% vs. 25.29%, p?相似文献   

l-arginine and docetaxel synergistically enhance anti-tumor immunity by modifying the immune status of tumor-bearing mice

l-arginine (l-Arg) supplementation has been reported to enhance the function of immune cells, including dendritic cells (DCs) and T lymphocytes, in cancer models thereby countering the suppressive effects of myeloid-derived suppressor cells (MDSCs). The balance of the active immune cells is one factor that determines the progression of cancers in vivo. Docetaxel (DTX), an immunomodulatory chemotherapeutic agent, is now widely used in several types of malignancies including breast cancer. We hypothesized that the combination of DTX and l-Arg would elicit a more robust antitumor response than either molecule alone. To test this hypothesis we utilized BALB/c mice inoculated with 4T1 mammary carcinoma cells. DTX and l-Arg synergistically limited tumor growth in vivo and moderately increased the life span of tumor bearing mice. The anti-tumor effects were associated with the proliferation of splenic CD8⁺ CTL and CD4⁺ Th1 effector cells, as well as increased serum levels of interferon gamma. More importantly, DTX + l-Arg effectively increased anti-tumor immunity within the tumor microenvironment. Furthermore, the combined therapy increased the number of myeloid (mDCs) and plasmacytoid (pDCs) dendritic cells, potent activators of the T cell response, and enhanced expression of the maturation markers CD86 and MHC II (required for antigen presentation). The combination therapy also reduced the proliferation of MDSCs. These data suggest that DTX + l-Arg may be a novel therapeutic strategy for breast cancer patients.