In vivo effect of oracin on doxorubicin reduction,biodistribution and efficacy in Ehrlich tumor bearing mice

BackgroundThe limitation of carbonyl reduction represents one possible way to increase the effectiveness of anthracycline doxorubicin (DOX) in cancer cells and decrease its toxicity in normal cells. In vitro, isoquinoline derivative oracin (ORC) inhibited DOX reduction and increased the antiproliferative effect of DOX in MCF-7 breast cancer cells. Moreover, ORC significantly decreases DOX toxicity in non-cancerous MCF-10A breast cells and in hepatocytes. The present study was designed to test in mice the in vivo effect of ORC on plasma and tissue concentrations of DOX and its main metabolite DOXOL. The effect of ORC on DOX efficacy in mice bearing solid Ehrlich tumors (EST) was also studied.MethodsDOX and DOX + ORC combinations were iv administered to healthy mice. Blood samples, livers and hearts were collected during the following 48 h. DOX and DOXOL concentrations were assayed using HPLC. The mice with inoculated EST cells were treated repeatedly iv with DOX and DOX + ORC combinations, and the growth of tumors was monitored.ResultsORC in combination with DOX significantly decreased DOXOLplasma concentrations during four hours after administration, but this significantly affected neither DOX plasma concentrations nor DOX or DOXOLconcentrations in the liver and heart at any of intervals tested. In EST bearing mice, ORC did not significantly affect DOX efficacy on tumor growth. However, EST was shown to be an improper model for the testing of ORC efficacy in vivo, as ORC did not inhibit DOXOL formation in EST.ConclusionsIn vivo, ORC was able to retard DOXOLformation but was not able to improveDOXefficacy in EST-bearing mice.     

Anti-cancer activity of anti-GLUT1 antibody-targeted polymeric micelles co-loaded with curcumin and doxorubicin

Abstract

Background: Treatment of late stage cancers has proven to be a very difficult task. Targeted therapy and combinatory drug administration may be the solution.

Purpose: The study was performed to evaluate the therapeutic efficacy of PEG-PE micelles, co-loaded with curcumin (CUR) and doxorubicin (DOX), and targeted with anti-GLUT1 antibody (GLUT1) against HCT-116 human colorectal adenocarcinoma cells both in vitro and in vivo.

Methods: HCT-116 cells were treated with non-targeted and GLUT1-targeted CUR and DOX micelles as a single agent or in combination. Cells were inoculated in female nude mice. Established tumors were treated with the micellar formulations at a dose of 4?mg/kg CUR and 0.4?mg/kg DOX every 2?d for a total of 7 injections.

Results: CUR?+?DOX-loaded micelles decorated with GLUT1 had a robust killing effect even at low doses of DOX in vitro. At the doses chosen, non-targeted CUR and CUR?+?DOX micelles did not exhibit any significant tumor inhibition versus control. However, GLUT1-CUR and GLUT1-CUR?+?DOX micelles showed a significant tumor inhibition effect with an improvement in survival.

Conclusion: We showed a dramatic improvement in efficacy between the non-targeted and GLUT1-targeted formulations both in vitro and in vivo. Hence, we confirmed that GLUT1-CUR?+?DOX micelles are effective and deserve further investigation.     

PEGylation alleviates the non-specific toxicities of Alpha-Momorcharin and preserves its antitumor efficacy in vivo

Alpha-Momorcharin (α-MMC) is a ribosome inactivating protein from Momordica charantia with anti-tumor activity. Previously, we had observed that modification of α-MMC with polyethylene glycol (PEG) could reduce toxicity, but it also reduces its anti-tumor activity in vitro. This study aims to investigate whether the metabolism-extended properties of α-MMC resulting from PEGylation could preserve its anti-tumor efficacy in vivo through pharmacokinetics and antitumor experiments. The pharmacokinetics experiments were conducted in rats using the TCA (Trichloroacetic Acid) method. Antitumor activity in vivo was investigated in murine mammary carcinoma (EMT-6) and human mammary carcinoma (MDA-MB-231) transplanted tumor mouse models. The results showed that PEGylation increased the plasma half-life of α-MMC in rats from 6.2–7.5?h to 52–87?h. When administered at 1?mg/kg, α-MMC-PEG and α-MMC showed similar anti-tumor activities in vivo, with a T/C% of 38.56% for α-MMC versus 35.43% for α-MMC-PEG in the EMT-6 tumor model and 36.30% for α-MMC versus 39.88% for α-MMC-PEG in the MDA-MB-231 tumor model (p?>?0.05). Importantly, at the dose of 3?mg/kg, all the animals treated with α-MMC died while the animals treated with α-MMC-PEG exhibited only moderate toxic reactions, and α-MMC-PEG exhibited improved anti-tumor efficacy with a T/C% (relative tumor growth rate) of 25.18% and 21.07% in the EMT-6 and MDA-MB-231 tumor models, respectively. The present study demonstrates that PEGylation extends the half-life of α-MMC and alleviates non-specific toxicity, thereby preserving its antitumor efficacy in vivo, and a higher lever of dosage can be used to achieve better therapeutic efficacy.     

Lipid nanoparticles loaded with 7-ethyl-10-hydroxycamptothecin-phospholipid complex: in vitro and in vivo studies

Abstract

7-Ethyl-10-hydroxy-camptothecin (SN38), the active metabolite of irinotecan (CPT-11), is an effective antineoplastic agent against many malignancies. Although it is 100-fold to 1000-fold more potent than CPT-11, the clinical utility of SN38 has been extremely restricted because of its poor solubility in any pharmaceutically acceptable solvents. The aim of this study was to develop SN38 nanoparticles (SN38-PC-LNs) using pharmaceutically acceptable excipients, and investigate the therapeutic efficacies in vitro and in vivo. SN38-phospholipid complex (SN38-PC) was prepared and loaded into lipid nanoparticles. The particle size was approximately 200?nm with a narrow size distribution. A high encapsulation efficiency of 88.11%?±?1.41% and drug loading of 9.55%?±?0.84% were achieved under the optimal condition. SN38-PC-LNs exhibited potent cytotoxic effects against a panel of human tumor cell lines (HT-29, HepG2, A549 and MCF-7). In vivo evaluation proved the enhanced antitumor efficacy of SN38-PC-LNs in mice bearing S180 tumor as well. The results from this study demonstrated an effective formulation of SN38 has been developed, which is promising for the delivery of SN38 for tumor chemotherapy.     

Single-walled carbon nanotube-loaded doxorubicin and Gd-DTPA for targeted drug delivery and magnetic resonance imaging

An aspargine-glycine-arginine (NGR) peptide modified single-walled carbon nanotubes (SWCNTs) system, developed by a simple non-covalent approach, could be loaded with the anticancer drug doxorubicin (DOX) and magnetic resonance imaging (MRI) contrast agent gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA). This DOX- and Gd-DTPA-loaded NGR functionalized SWCNTs (DOX/NGR-SWCNTs/Gd-DPTA) retained both cytotoxicity of DOX and MRI contrast effect of Gd-DPTA. This drug delivery system showed excellent stability in physiological solutions. This DOX/NGR-SWCNTs/Gd-DPTA system could accumulate in tumors and enter into tumor cells, which facilitated combination chemotherapy with diagnosis of tumor in one system. An excellent in vitro anti-tumor effect was shown in MCF-7 cells treated by DOX/NGR-SWCNTs/Gd-DPTA, compared with DOX solution, DOX/SWCNTs and DOX/SWCNTs/Gd-DPTA. In vivo data of DOX/NGR-SWCNTs/Gd-DPTA group in tumor-bearing mice further confirmed that this system performed much higher tumor targeting capacity and anti-tumor efficacy than other control groups.     

Folate-decorated poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) nanoparticles for targeting delivery: optimization and in vivo antitumor activity

Abstract

Context: Doxorubicin (DOX)-loaded folate-targeted poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) [P(HB-HO)] nanoparticles [DOX/FA-PEG-P(HB-HO) NPs] have potential application in clinical treatments for cervical cancer due to specific affinity of folate and folate receptor in HeLa cells.

Objective: The aim of this study was to develop an optimized formulation for DOX/FA-PEG-P(HB-HO) NPs, and investigate the targeting and efficacies of the nanoparticles.

Materials and methods: DOX/FA-PEG-P(HB-HO) NPs were prepared by W₁/O/W₂ solvent extraction/evaporation method, and an orthogonal experimental design [L₉ (3⁴)] was applied to establish the optimum conditions. The physico–chemical characteristics, microscopic observation and in vivo antitumor study of the nanoparticles were evaluated.

Results: The optimum formulation was obtained with DOX 10% (w/v), FA-PEG-P(HB-HO) 6.5% (w/v), PVA 3%(w/v) and oil phase/internal water phase volume ratio of 3/1. The size distribution, drug loading and encapsulation efficiency of the optimized nanoparticles were 150–350?nm, 29.6?±?2.9% and 83.5?±?5.7%, respectively. In vitro release study demonstrated that 80% of the drug could release from the nanoparticles within 11 days. Furthermore, in vitro microscopic observation and in vivo antitumor study showed that DOX/FA-PEG-P(HB-HO) NPs could inhibit HeLa cells effectively, and the tumor inhibition rate (TIR) in vivo was 76.91%.

Discussion and conclusions: DOX/FA-PEG-P(HB-HO) NPs have been successfully developed and optimized. In vitro drug release study suggested a sustained release profile. Moreover, DOX/FA-PEG-P(HB-HO) NPs could effectively inhibit HeLa cells with satisfying targeting, and reduce side effects and toxicity to normal tissues. DOX/FA-PEG-P(HB-HO) NPs were superior in terms of inhibiting HeLa tumor over non-targeted formulations therapy.     

Antitumor Activity of Folate Receptor-Targeted Liposomal Doxorubicin in a KB Oral Carcinoma Murine Xenograft Model

Purpose. The expression of folate receptor (FR) is amplified in many types of human cancers. Previously, FR-targeted liposomal doxorubicin (f-L-DOX) has been shown to exhibit superior and selective cytotoxicity against FR(+) tumor cells in vitro compared to nontargeted liposomal doxorubicin (L-DOX). This study further investigates f-L-DOX for its antitumor efficacy in vivo using a murine tumor xenograft model. Methods. F-L-DOX composed of DSPC/cholesterol/PEG-DSPE/folate-PEG-DSPE (65:31:3.5:0.5, mole/mole) was prepared by polycarbonate membrane extrusion followed by remote loading of DOX. Athymic mice on a folate-free diet were engrafted with FR(+) KB cells. Two weeks later, these mice were treated with f-L-DOX, L-DOX, or free DOX in a series of six injections (given intraperitoneally on every fourth day at 10 mg/kg DOX) and monitored for tumor growth and animal survival. The plasma clearance profiles of the DOX formulations and the effect of dietary folate on plasma folate concentration were also analyzed. Results. Plasma folate level remained in the physiologic range relative to that in humans. F-L-DOX exhibited an extended systemic circulation time similar to that of L-DOX. Mice that received f-L-DOX showed greater tumor growth inhibition and a 31% higher (p < 0.01) increase in lifespan compared to those that received L-DOX. Meanwhile, free DOX given at the same dose resulted in significant toxicity and was less effective in prolonging animal survival. Conclusions. FR-targeted liposomes are a highly efficacious vehicle for in vivo delivery of anticancer agents and have potential application in the treatment of FR(+) solid tumors.     

Genkwanin nanosuspensions: a novel and potential antitumor drug in breast carcinoma therapy

Recently, genkwanin (GKA) has been shown to display in vitro antitumor activity against some cancer cells, but its poor solubility restricted the in vivo study 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 stronger in vitro cytotoxicity against 4T1, MCF-7, MDA-MB-453, HeLa, HepG2, BT474, and A549 cells than free GKA. The in vivo study 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.     

Enhanced Intracellular Uptake of Sterically Stabilized Liposomal Doxorubicin <Emphasis Type="Italic">in Vitro</Emphasis> Resulting in Improved Antitumor Activity <Emphasis Type="Italic">in Vivo</Emphasis>

Purpose To investigate the correlation between the in vitro intracellular uptake and the in vivo antitumor activity of anticancer drugs delivered by sterically stabilized liposomes (SSL).Methods Arginine-glycine-aspartic acid (RGD) peptide or RGD mimetic (RGDm) was coupled onto the surface of SSL to obtain the cell-binding carrier to facilitate the intracellular delivery of the encapsulated drugs. DOX-loaded SSL (SSL-DOX), DOX-loaded RGD-modified SSL (RGD-SSL-DOX) and DOX-loaded RGDm-modified SSL (RGDm-SSL-DOX) were prepared by lipid film dispersion followed by remote loading of DOX. The intracellular uptake of DOX from the various liposomal formulations was evaluated in vitro with melanoma B16 cells, and the pharmacokinetics, biodistribution, and antitumor activity were compared in C57BL/6 mice carrying melanoma B16 tumors.Results In vitro intracellular uptake of DOX by B16 cells and in vivo antitumor activity in terms of tumor growth inhibition and mice survival time prolongation for various liposomal DOX were in the following order: RGD-SSL-DOX > RGDm-SSL-DOX > SSL-DOX. The mean survival time of the mice treated with RGD-SSL-DOX, RGDm-SSL-DOX, and SSL-DOX was 55, 49, and 44 days, respectively. The three liposomal DOX formulations produced very close DOX accumulation in tumor, which is significantly higher than that of free DOX. RGD- or RGDm-SSL-DOX demonstrated prolonged circulation time similar to that of SSL-DOX, whereas they showed significantly lower DOX level in blood and remarkably higher uptake by spleen than SSL-DOX.Conclusions Enhanced intracellular uptake of DOX encapsulated in SSL could produce an improved therapeutic effect for the melanoma B16 tumors. Enhancing intracellular delivery of the anticancer drugs encapsulated in SSL may be a promising strategy to improve their therapeutic efficacy for solid tumors.     

A local drug delivery system based on visible light-cured glycol chitosan and doxorubicin⋅hydrochloride for thyroid cancer treatment in vitro and in vivo

Systemic drug delivery systems (SDDSs) for thyroid cancer treatment are associated with serious side effects including nausea, anorexia, and hair loss as a result of damage to normal tissues. In this study, we investigated the feasibility of a local DDS (LDDS) based on visible light-cured glycol chitosan (GC) hydrogel and doxorubicin?hydrochloride (DOX?HCl), called GC10/DOX, on thyroid cancer treatment in vivo. Visible light irradiation increased the storage modulus and swelling ratio of the GC10/DOX hydrogel precursor. The release of DOX?HCl from GC10/DOX exhibited two unique patterns comprising an initial burst within 18?hours, followed by a controlled and sustained release thereafter. In vitro cell viability testing showed that GC10/DOX had a greater antitumor effect than free DOX?HCl and GC10 hydrogel controls. In vivo, local injection of GC10/DOX near tumor tissue led to a superior antitumor effect compared with controls consisting of free DOX?HCl intravenously injected to the tail vein of thyroid cancer-bearing mouse and GC10 hydrogel subcutaneously injected near the tumor. Altogether, our results suggest that GC10/DOX may have clinical potential for thyroid cancer treatment.     

Development and evaluation of co-formulated docetaxel and curcumin biodegradable nanoparticles for parenteral administration

Context: Technology for development of biodegradable nanoparticles encapsulating combinations for enhanced efficacy.

Objective: To develop docetaxel (DTX) and curcumin (CRM) co-encapsulated biodegradable nanoparticles for parenteral administration with potential for prolonged release and decreased toxicity.

Materials and methods: Modified emulsion solvent-evaporation technique was employed in the preparation of the nanoparticles optimized by the face centered-central composite design (FC-CCD). The uptake potential was studied in MCF-7 cells, while the toxicity was evaluated by in vitro hemolysis test. In vivo pharmacokinetic was evaluated in male Wistar rats.

Results and discussion: Co-encapsulated nanoparticles were developed of 219?nm size, 0.154 PDI, ?13.74?mV zeta potential and 67.02% entrapment efficiency. Efficient uptake was observed by the nanoparticles in MCF-7 cells with decreased toxicity in comparison with the commercial DTX intravenous injection, Taxotere®. The nanoparticles exhibited biphasic release with initial burst release followed by sustained release for 5 days. The nanoparticles displayed a 4.3-fold increase in AUC (391.10?±?32.94 versus 89.77?±?10.58?μg/ml min) in comparison to Taxotere® with a 6.2-fold increase in MRT (24.78?±?2.36 versus 3.58?±?0.21?h).

Conclusion: The nanoparticles exhibited increased uptake, prolonged in vitro and in vivo release, with decreased toxicity thus exhibiting potential for enhanced efficacy.     

Visual targeted therapy of hepatic cancer using homing peptide modified calcium phosphate nanoparticles loading doxorubicin guided by T1 weighted MRI

Effective treatment and real-time monitoring of hepatic cancer are essential. A multifunctional calcium phosphate nanoparticles loading chemotherapeutic agent doxorubicin and magnetic resonance imaging contrast agent diethylenetriaminepentaacetic acid gadolinium (A54-CaP/Gd-DTPA/DOX) was developed for visual targeted therapy of hepatic cancer via T1-weighted MRI in real-time. A54-CaP/Gd-DTPA/DOX exhibited a higher longitudinal relaxivity (6.02?mM^?1?s^?1) than commercial MR contrast agent Gd-DTPA (3.3765?mM^?1?s^?1). The DOX release from the nanoparticles exhibited a pH dependent behavior. The cellular uptake results showed that the internalization of A54-CaP/Gd-DTPA/DOX into BEL-7402 cells was1.9-fold faster than that of HepG2 cells via A54 binding. In vivo experiments presented that A54-CaP/Gd-DTPA/DOX had higher distribution and longer retention time in tumor tissue than CaP/Gd-DTPA/DOX and free DOX, and also displayed great antitumor efficacy (95.38% tumor inhibition rate) and lower toxicity. Furthermore, the Gd-DTPA entrapped in the nanoparticles could provide T1-weighted MRI for real-time monitoring the progress of tumor treatment.     

冰片和叶酸共修饰的阿霉素聚酰胺-胺复合物在动物体内的研究

目的 研究用冰片（borneol,BO）和叶酸（folic acid,FA）共修饰阿霉素（doxorubicin,DOX）聚酰胺-胺型树状[poly（amido amine）,PAMAM]大分子（FA-BO-PAMAM/DOX）,增加药物在脑胶质瘤部位递送。方法 第5代PAMAM树状大分子分别与BO和FA通过共价结合得FA-BO-PAMAM。以FA-BO-PAMAM为纳米载体,制备了FA-BO-PAMAM/DOX,通过尾静脉注射该复合物,考察荷瘤大鼠体内的药动学行为及组织分布情况。结果 BO-PAMAM/DOX和FA-BO-PAMAM/DOX组的大鼠血浆半衰期（plasma half-life,t_1/2）和平均滞留时间（mean retention time,MRT）均较原药组显著延长（P<0.01）;血药浓度-时间曲线下面积（area under the plasma concentration-time curve,AUC）较原药组显著增大（P<0.01）。与DOX相比,BO-PAMAM/DOX和FA-BO-PAMAM/DOX在肿瘤组织中的药物含量明显增加,而在心脏中的药物含量明显降低。结论 采用合成的药物载体FA-BO-PAMAM包载DOX后,可显著改变DOX的部分药动学参数,使药物在血浆中能维持较长时间。另外FA-BO-PAMAM/DOX具有较好的肿瘤靶向治疗效果和较小的心脏不良反应,对提高DOX的治疗指数具有较好的临床价值。     

Spatiotemporally Controlled Co-delivery of Anti-vasculature Agent and Cytotoxic Drug by Octreotide-Modified Stealth Liposomes

Purpose

Both combretastatin A-4 (CA-4) and doxorubicin (DOX) was loaded in different form in a targeted nanomedicine in order to achieve the active delivery of these two drugs followed by sequentially suppressing tumor vasculature and tumor cells.

Methods

Octreotide-modified stealth liposomes loaded with CA-4 and DOX (Oct-L[CD]) were prepared and characterized. Then in vitro release, cellular uptake, in vitro antitumor effect, pharmacokinetics, in vivo sequential killing effect, in vivo antitumor efficacy against somatostatin receptor (SSTR) positive cells, as well as the action mechanism of such system, were studied.

Results

A rapid release of CA-4 followed by a slow release of DOX was observed in vitro. The active targeted liposomes Oct-L[CD] showed a specific cellular uptake through ligand-receptor interaction and a higher antitumor effect in vitro against SSTR-positive cell line. The in vivo sequential killing effect of such system was found as evidenced by the fast inhibition of blood vessels and slow apoptosis-inducing of tumor cells. Oct-L[CD] also exhibited the strongest antitumor effect in MCF-7 subcutaneous xenograft models.

Conclusions

Oct-modified co-delivery system may have great potential as an effective carrier for cancer therapy.     

Pharmacokinetics and metabolism of AMG 232, a novel orally bioavailable inhibitor of the MDM2–p53 interaction,in rats,dogs and monkeys: in vitro–in vivo correlation

Abstract

1. AMG 232 is a novel inhibitor of the p53–MDM2 protein–protein interaction currently in Phase I clinical trials for multiple tumor indications. The objectives of the investigations reported in this article were to characterize the pharmacokinetic and drug metabolism properties of AMG 232 in pre-clinical species in vivo and in vitro, and in humans in vitro, and to predict its pharmacokinetics in humans through integrating PKDM data.

2. AMG 232 exhibited low clearance (<0.25?×?Qh) and moderate to high oral bioavailability in mice, rats and monkeys (>42%), but high clearance (0.74?×?Qh) and low oral exposure in dogs (18%).

3. Biotransformation was the major route of elimination of AMG 232 in rats, with only 7% of intravenously administered ¹⁴C-labeled AMG 232 recovered as parent molecule in bile. The major metabolite was an acyl glucuronide as measured by in vivo rat studies and in vitro hepatocyte incubations in multiple species.

4. The in vitro–in vivo correlation of AMG 232 clearance was within 2-fold in pre-clinical species using hepatocytes. AMG 232 was predicted to exhibit low clearance, high volume distribution and long half-life in humans. The predictions are consistent with the preliminary human pharmacokinetic parameters of AMG 232 in clinical trials.     

Quantification of DOX bioavailability in biological samples of mice by sensitive and precise HPLC assay

Context: Doxorubicin (DOX)-loaded folate-targeted poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) [P(HB-HO)] nanoparticles [DOX/FA-PEG-P(HB-HO) NPs] were prepared by the W₁/O/W₂ solvent extraction/evaporation method for applications in cancer treatment. However, the biodistribution, pharmacokinetics, and targeting of the nanoparticles (NPs) have not yet been studied.

Objective: The biodistribution, pharmacokinetics, and targeting of DOX/FA-PEG-P(HB-HO) NPs were evaluated in female BALB/c nude mice bearing HeLa tumors.

Materials and methods: Three DOX formulations were injected into the tail vein of the mice at a dosage of 5?mg/kg. At each time point, blood and various tissues were collected. All samples were then processed and analyzed by a validated high performance liquid chromatographic (HPLC) method.

Results: The t_1/2 values of DOX/P(HB-HO) NPs and DOX/FA-PEG-P(HB-HO) NPs were 2.7- and 3.5-times higher than that of free DOX. No significant difference (p?>?0.05) was found in C_max between the NPs and free DOX. The T_max values of the two NPs were prolonged from 0.25 to 1?h. The AUC_0–t values were 1.55- and 3.05-folds higher than that of free DOX, and MRT increased to 15.99?h for DOX/P(HB-HO) NPs and 25.14?h for DOX/FA-PEG-P(HB-HO) NPs. For DOX/FA-PEG-P(HB-HO) NPs, the DOX content in the tumors were 10.81- and 3.33-times higher than those for free DOX and DOX/P(HB-HO) NPs at 48?h, respectively.

Discussion and conclusions: DOX/FA-PEG-P(HB-HO) NPs displayed reduced cardiac toxicity and improved bioavailability. Moreover, the NPs exhibited a significant extent of DOX accumulation in the tumors, thus suggesting that folate-targeted NPs could effectively transport into HeLa tumors with satisfying targeting.     

Folate-modified doxorubicin-loaded nanoparticles for tumor-targeted therapy

Context: Polymeric nanoparticles (NPs) have been used frequently as drug delivery vehicles. Surface modification of polymeric NPs with specific ligands defines a new biological identity, which assists in targeting of the nanocarriers to specific cancers cells.

Objective: The aim of this study is to develop a kind of modified vector which could target the cancer cells through receptor-mediated pathways to increase the uptake of doxorubicin (DOX).

Methods: Folate (FA)-conjugated PEG–PE (FA–PEG–PE) ligands were used to modify the polymeric NPs. The modification rate was optimized and the physical–chemical characteristics, in vitro release, and cytotoxicity of the vehicle were evaluated. The in vivo therapeutic effect of the vectors was evaluated in human nasopharyngeal carcinoma KB cells baring mice by giving each mouse 100?µl of 10?mg/kg different solutions.

Results: FA–PEG–PE-modified NPs/DOX (FA-NPs/DOX) have a particle size of 229?nm, and 86% of drug loading quantity. FA-NPs/DOX displayed remarkably higher cytotoxicity (812?mm³ tumor volume after 13?d of injection) than non-modified NPs/DOX (1290?mm³) and free DOX solution (1832?mm³) in vivo.

Conclusion: The results demonstrate that the modified drug delivery system (DDS) could function comprehensively to improve the efficacy of cancer therapy. Consequently, the system was shown to be a promising carrier for delivery of DOX, leading to the efficiency of antitumor therapy.     

Pharmacokinetics and analgesic effect of ketorolac floating delivery system

Abstract

Objectives: The efficacy of ketorolac tromethamine (KT) floating alginate beads as a drug delivery system for better control of KT release was investigated. The formulation with the highest drug loading, entrapment efficiency, swelling, buoyancy, and in vitro release would be selected for further in vivo analgesic effect in the mice and pharmacokinetics study in rats compared to the tablet dosage form.

Methods: KT floating alginate beads were prepared by extrusion congealing technique. KT in plasma samples was analyzed using a UPLC MS/MS assay.

Results: The percentage yield, drug loading and encapsulation efficiency were increased proportionally with the hydroxypropylmethyl cellulose (HPMC) polymer amount in the KT floating beads. A reverse relationship was observed between HPMC amount in the beads and the KT in vitro release rate. F3-floating beads were selected, due to its better in vitro results (continued floating for >8?h) than others. A longer analgesic effect was observed for F3 in fed mice as compared to the tablets. After F3 administration to rats, the C_max (2.2?±?0.3?µg/ml) was achieved at ～2?h and the decline in KT concentration was slower. F3 showed a significant increase in the AUC (1.89 fold) in rats as compared to the tablets.

Conclusion: KT was successfully formulated as floating beads with prolonged in vitro release extended to a better in vivo characteristic with higher bioavailability in rats. KT in floating beads shows a superior analgesic effect over tablets, especially in fed mice.     

In vitro cytotoxicity and bioavailability of solid lipid nanoparticles containing tamoxifen citrate

Abstract

The objective of this study was to evaluate the influence of solid lipid nanoparticles (SLN) loaded with the poorly water-soluble drug tamoxifen citrate (TC) on the in vitro antitumor activity and bioavailability of the drug. TC-loaded SLN were prepared by solvent injection method using glycerol monostearate (GMS) or stearic acid (SA) as lipid matrix. Poloxamer 188 or tween 80 were used as stabilizers. TC-loaded SLN (F3 and F4) prepared using GMS and stabilized by poloxamer 188 showed highest entrapment efficiency % (86.07?±?1.74 and 90.40?±?1.22%) and reasonable mean particle sizes (130.40?±?9.45 and 243.80?±?12.33?nm), respectively. The in vitro release of TC from F3 and F4 exhibited an initial burst effect followed by a sustained drug release. In vitro cytotoxicity of F3 against human breast cancer cell line MCF-7 showed comparable antitumor activity to free drug. Moreover, the results of bioavailability evaluation of TC-loaded SLN in rats compared to free TC indicated that 160.61% increase in the oral bioavailability of TC. The obtained results suggest that incorporation of the poorly water-soluble drug TC in SLN preserves the in vitro antitumor activity and significantly enhance oral bioavailability of TC in rats.     

Biodegradable Polymersomes as Nanocarriers for Doxorubicin Hydrochloride: Enhanced Cytotoxicity in MCF-7/ADR Cells and Prolonged Blood Circulation

Purpose

DOX is one of the most potent anticancer drugs. But its short half-life and the occurrence of multi-drug resistance (MDR) markedly limit its clinical application. To solve these problems, we develop DOX loaded polymersomes (DOX polymersomes).

Methods

An methoxy poly(ethylene glycol)-b-poly(epsilon-caprolactone) (mPEG-b-PCL) copolymer was synthesized and used to prepare DOX polymersomes. The pharmaceutical properties of DOX polymersomes were characterized. The in vitro release profile of DOX from polymersomes was investigated. The in vitro cytotoxicity and cell uptake studies were performed on MCF-7 and MCF-7/ADR cells. The in vivo pharmacokinetic profiles were investigated on Sprague–Dawley rats.

Results

DOX polymersomes had a nano-scale particle size of about 60 nm with a hydrophobic membrane about 10 nm in thickness. Release of DOX from the polymersomes took place in a sustained manner. Cell experiments showed DOX polymersomes enhanced the cytotoxicity and the intracellular accumulation of DOX in MCF-7/ADR cells, compared with free DOX. In vivo pharmacokinetic study showed the DOX polymersomes increased the bioavailability and prolonged the circulation time in rats.

Conclusions

The entrapment of DOX in biodegradable polymersomes could enhance cytotoxicity in MCF-7/ADR cells and improve its in vivo pharmacokinetic profile.