Glucosamine anchored cancer targeted nano-vesicular drug delivery system of doxorubicin

Background: Efficacy of an anticancer drug is challenged by severe adverse effects persuaded by the drug itself; hence designing a tumour targeted delivery system is chosen as an objective of this research work.

Purpose: We propose, glucose transporter targeting ligand, i.e. synthesised N-lauryl glucosamine (NLG) anchored doxorubicin (DOX) in niosomal formulation.

Methods: Synthesised NLG was incorporated into niosomal formulation of DOX using Span 60 as surfactant, cholesterol as membrane stabilizer and dicetyl phosphate (DCP) as stabilizer.

Results: The formulation was stable with particle size of 110?±?5?nm, zeta potential ?30?±?5?mV and entrapment efficiency approximately 95%. DSC and XRD pattern of freeze-dried formulation demonstrated encapsulation of DOX in niosomal formulation. Cytotoxicity of targeted niosomal formulation (IC₅₀?=?0.830?ppm) was higher than non-targeted niosomal formulation (IC₅₀?=?1.369?ppm) against B6F10 melanoma cell lines. In vitro cellular internalization revealed that targeted niosomal formulation was internalised more efficiently with higher cellular retention by cancer cells compared to the non-targeted niosomal formulation and free DOX. In vitro receptor binding and docking study of targeted niosomal formulation had shown the comparative association potential with glucose receptor.

Conclusion: NLG anchored niosomal formulation of DOX with enhanced cytotoxicity, internalization and receptor binding potential has implication in targeted cancer therapy.     

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.     

Targeted Delivery of Doxorubicin by HPMA Copolymer-Hyaluronan Bioconjugates

Purpose. Overexpression of hyaluronan (HA) receptors on cancer cells results in enhanced endocytotic uptake of the drug conjugate. An N-(2-hydroxypropyl)methacrylamide (HPMA)-HA polymeric drug delivery system was used for targeted delivery of doxorubicin to cancer cells. Methods. HA-doxorubicin (DOX) bioconjugates (HA-DOX), and HPMA copolymer-DOX conjugates containing HA as a side chain (HPMA-HA-DOX) were synthesized. The cytotoxicity of the polymer-drug conjugate was evaluated via in vitro cell culture. The internalization of the conjugate was visualized by fluorescence microscopy. Results. Cytotoxicity of HPMA-HA-DOX targeted bioconjugate was higher against human breast cancer (HBL-100), ovarian cancer (SKOV-3), and colon cancer (HCT-116) cells when compared to the non-targeted HPMA-DOX conjugate. Fluorescence confocal microscopy revealed that the targeted HPMA-HA-DOX conjugates were internalized more efficiently by cancer cells relative to the non-targeted HPMA-DOX conjugate. Both HPMA-DOX and HPMA-HA-DOX showed minimal cytotoxicity toward mouse fibroblast NIH 3T3 cells. The internalization of polymer conjugates was correlated with their cytotoxicity. Conclusions. Selective delivery of anti-cancer agents to cancer cells was achieved by biochemical targeting. The HA-modified HPMA copolymer showed improved toxicity due to receptor-mediated uptake of the macromolecular drug.     

Distribution,Metabolism and Tumoricidal Activity of Doxorubicin Administered in Sorbitan Monostearate (Span 60) Niosomes in the Mouse

Purpose. Encapsulation of doxorubicin in niosomes was sought as a route to tumour targeting and improved tumoricidal through the alteration of doxorubicin pharmacokinetics and metabolism. Methods. Doxorubicin niosomes (10 mg kg^–l doxorubicin) prepared from sorbitan monostearate (Span 60), cholesterol and choleth-24 (a 24 oxyethylene cholesteryl ether) in the molar ratio 45:45:10 were administered intravenously to female NMRI mice bearing the MAC 15A subcutaneously implanted tumour. Plasma doxorubicin was fractionated by gel filtration and quantified by HPLC with fluorometric detection as niosome-associated doxorubicin and released doxorubicin. Tumoricidal activity of the formulation was assessed by the intravenous injection of 5 mg kg^–1 and 10 mg kg^–1 doxorubicin niosomes to male NMRI mice bearing a 6 day old MAC 15A tumour. Results. At least 90% of the plasma doxorubicin was associated with the niosome fraction 4 h after dosing, and 50% was still associated after 24 h. The clearance of doxorubicin released from the niosomes was about 10 fold greater than the clearance of niosomal doxorubicin (176.5 mL h^–l and 16.2 mL h^–1, respectively). The area under the plasma level-time curve increased 6 fold when doxorubicin was administered in niosomes, compared to doxorubicin solution (66.0 µg.h mL^–l and 10.3 µg.h mL^–1, respectively). The area under the tumour level time curve was increased by over 50% by the administration of doxorubicin in niosomes when compared to the drug administered in solution (58.6 µg.h mL^–l and 34.3 µg.h mL^–1, respectively). There was no statistically significant difference between levels of the drug in the heart when niosomal doxorubicin or doxorubicin solution were administered. Doxorubicin metabolites, namely doxorubicinol and the aglycones doxorubicinone, doxorubicinolone and 7-deoxydoxorubicinone, were found associated with the niosomes in the plasma, possibly due to their adsorption to the vesicle surface once formed outside the niosome. Overall metabolite levels in the liver were increased when doxorubicin niosomes were administered compared to the drug in solution. A 5 mg kg^–1 injection of doxorubicin niosomes produced a terminal mean tumour weight that was similar to that obtained from animals administered 10 mg kg^–1 doxorubicin solution. Conclusions. Modest tumour targeting was achieved by the delivery of doxorubicin in sorbitan monostearate niosomes, increasing the tumour to heart AUC^0–24 ratio from 0.27 to 0.36 and a doubling of tumoricidal activity. The overall level of doxorubicin metabolites was also increased.     

Cytotoxicity and apoptotic gene expression in an in vitro model of the blood–brain barrier following exposure to poly(butylcyanoacrylate) nanoparticles

Background Poly(butylcyanoacrylate) (PBCA) nanoparticles (NPs) loaded with doxorubicin (DOX) and coated with polysorbate 80 (PS80) have shown efficacy in the treatment of rat glioblastoma. However, cytotoxicity of this treatment remains unclear.

Purpose The purpose of this study was to investigate cytotoxicity and apoptotic gene expression using a proven in vitro co-culture model of the blood–brain barrier.

Methods The co-cultures were exposed to uncoated PBCA NPs, PBCA-PS80 NPs or PBCA-PS80-DOX NPs at varying concentrations and evaluated using a resazurin-based cytotoxicity assay and an 84-gene apoptosis RT-PCR array.

Results The cytotoxicity assays showed PBCA-PS80-DOX NPs exhibited a decrease in metabolic function at lower concentrations than uncoated PBCA NPs and PBCA-PS80 NPs. The apoptosis arrays showed differential expression of 18 genes in PBCA-PS80-DOX treated cells compared to the untreated control.

Discussion As expected, the cytotoxicity assays demonstrated enhanced dose-dependent toxicity in the DOX loaded NPs. The differentially expressed apoptotic genes participate in both the tumor necrosis factor receptor-1 and mitochondria-associated apoptotic pathways implicated in current DOX chemotherapeutic toxicity.

Conclusion The following data suggest that the cytotoxic effect may be attributed to DOX and not the NPs themselves, further supporting the use of PBCA-PS80 NPs as an effective drug delivery vehicle for treating central nervous system conditions.     

Cytotoxic enhancement of hexapeptide-conjugated micelles in EGFR high-expressed cancer cells

Objectives: The aim of this study was to develop the hexapeptide-conjugated active targeting micelles for delivery of doxorubicin (DOX) and paclitaxel (PTX) to EGFR high-expressed cancer cells.

Methods: A hexapeptide, which mimicked the EGFR, was applied as a targeting ligand. The active targeting micelles were prepared using the synthesized poly(D,L-lactide-co-glycolide)–PEG copolymer conjugated with the hexapeptide. The micelles were used for encapsulating DOX and/or PTX, and the cellular uptake, in vitro drug release and cellular viability of drug-loaded peptide-conjugated and peptide-free micelles were investigated.

Results: The particle size of drug-loaded peptide-conjugated and peptide-free micelles was < 150 nm with narrow size distribution. The uptake of peptide-conjugated micelles was more efficient in EGFR high-expressed MDA-MB-468 and SKOV3 cells than in EGFR low-expressed HepG2 cells. The in vitro release of DOX and PTX was faster in pH 4.0 (500 U lipase) than in pH 7.4 release medium. The cytotoxicity in terms of IC₅₀ of DOX/PTX-loaded peptide-conjugated micelles was 4.8-folds lower than that of peptide-free micelles and 18.2-folds lower than DOX/PTX drug solution in SOKV3 cells.

Conclusion: The peptide-conjugated micelles acted as a nanocarrier to increase intracellular accumulation of anticancer drugs in EGFR high-expressed SKOV3 cancer cells to enhance cell cytotoxicity.     

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.     

Drug distribution and a pulmonary adverse effect of intraperitoneally administered doxorubicin niosomes in the mouse

Niosomes (non-ionic surfactant vesicles) prepared from C₁₆G₂ (a hexadecyl-diglycerol ether), and loaded with doxorubicin, were administered intraperitoneally to male AKR mice at dose levels of 0, 2.5, 5.0, and 10.0 mg kg^?1. Free drug was given at 10.0 mg kg^?1 by the intraperitoneal route. At a dose level of 10.0 mg kg^?1, peak doxorubicin levels in the central compartment were attained faster with the free drug than with the niosome formulation. However, the peak plasma levels were similar for the free drug and the niosome preparation at the 10 mg kg^?1 dose level. With doxorubicin administered as the niosome preparation by the intraperitoneal route at 2.5, 5.0, and 10.0 mg kg^?1, mean peak plasma concentrations of the drug showed a tendency to be dose-related although the differences were not significant. Over the 24 h period of the experiment, with doxorubicin at 10 mg kg^?1, the niosome formulation delivered significantly more drug to the plasma compartment than the free drug (p <0.05). When doxorubicin was given in niosomes at 2.5, 5.0 and 10.0 mg kg^?1 by the intraperitoneal route, the resulting levels of doxorubicin in cardiac tissue were not dose related and the differences not significant and, although the mean peak cardiac-tissue concentration was higher in animals receiving the free drug at 10.0 mg kg^?1 intraperitoneally than in mice given intaperitoneal doxorubicin niosomes at this dose level, the differences were again not significant. There were clinical signs of toxicity in mice given doxorubicin-containing niosomes intraperitoneally at 5.0 and 10.0 mg kg^?1, and at post-mortem an accumulation of fluid in the pleural cavity was evident. These changes were not seen in mice dosed intraperitoneally with free drug at 10 mg kg^?1, or in animals given doxorubicin niosomes intraperitoneally at 2.5 mg kg^?1. In mice dosed intraperitoneally with doxorubicin niosomes at 12.0 mg kg^?1 and at a dose volume of 0.2–0.4 mL, histological examination of the lungs demonstrated a congestion of the alveolar capillaries, and an increased number of acute inflammatory cells in the alveolar walls. There was no histological evidence of lung toxicity in mice dosed with doxorubicin niosomes at 12.0 mg kg^?1 when the formulation was administered with the higher dose volume of 1.8–2.0 mL. Importantly there was no histological evidence of lung toxicity in mice dosed with empty niosomes intraperitoneally or with doxorubicin niosomes given itravenously at 12.0 mg kg^?1.     

The use of single chain Fv as targeting agents for immunoliposomes: an update on immunoliposomal drugs for cancer treatment

Importance of the field: Targeted liposomal drugs represent the next evolution of liposomal drug delivery in cancer treatment. In various preclinical cancer models, antibody-targeted PEGylated liposomal drugs have demonstrated superior therapeutic effects over their non-targeted counterparts. Single chain Fv (scFv) has gained popularity in recent years as the targeting agent of choice over traditional targeting agents such as monoclonal antibodies (mAb) and antibody fragments (e.g., Fab′).

Areas covered in this review: This review is focused mainly on advances in scFv-targeted liposomal drug delivery for the treatment of cancers, based on a survey of the recent literature, and on experiments done in a murine model of human B-lymphoma, using anti-CD19 targeted liposomes targeted with whole mAb, Fab′ fragments and scFv fragments.

What the reader will gain: This review examines the recent advances in PEGylated immunoliposomal drug delivery, focusing on scFv fragments as targeting agents, in comparison with Fab′ and mAb.

Take home message: For clinical development, scFv are potentially preferred targeting agents for PEGylated liposomes over mAb and Fab′, owing to factors such as decreased immunogenicity, and pharmacokinetics/biodistribution profiles that are similar to non-targeted PEGylated (Stealth^®) liposomes.     

Construction and research on size and phase ‘fixed-point remodelling’ intelligent drug delivery system

Abstract

It is important to enhance penetration depth of nanomedicine and realise rapid drug release simultaneously at targeted tumour for improving anti-tumour efficiency of chemotherapeutic drugs. This project employed sodium alginate (Alg) as matrix material, to establish tumour-responsive nanogels with particle size conversion and drug controlled release functions. Specifically, tumour-targeting peptide CRGDK was conjugated with Alg first (CRGDK-Alg). Then, doxorubicin (DOX) was efficiently encapsulated in CRGDK-FeAlg nanogel during the cross-linking process (CRGDK-FeAlg/DOX). This system was closed during circulation. Once reaching tumour, the particle size of nanogels was reduced to ～25?nm, which facilitated deep penetration of DOX in tumour tissues. After entering tumour cells, the size of nanogels was further reduced to ～10?nm and DOX was released simultaneously. Meanwhile, FeAlg efficiently catalysed H₂O₂ to produce ?OH by Fenton reaction, achieving local chemodynamic therapy without O₂ mediation. Results showed CRGDK-FeAlg/DOX significantly inhibited tumour proliferation in vivo with V/V0 of 1.13 after treatment, significantly lower than that of control group with V/V0 of 4.79.     

Comparison of predictability for human pharmacokinetics parameters among monkeys,rats, and chimeric mice with humanised liver

1.?The aim of the present study was to evaluate the usefulness of chimeric mice with humanised liver (PXB mice) for the prediction of clearance (CL_t) and volume of distribution at steady state (Vd_ss), in comparison with monkeys, which have been reported as a reliable model for human pharmacokinetics (PK) prediction, and with rats, as a conventional PK model.

2.?CL_t and Vd_ss values in PXB mice, monkeys and rats were determined following intravenous administration of 30 compounds known to be mainly eliminated in humans via the hepatic metabolism by various drug-metabolising enzymes. Using single-species allometric scaling, human CL_t and Vd_ss values were predicted from the three animal models.

3.?Predicted CL_t values from PXB mice exhibited the highest predictability: 25 for PXB mice, 21 for monkeys and 14 for rats were predicted within a three-fold range of actual values among 30 compounds. For predicted human Vd_ss values, the number of compounds falling within a three-fold range was 23 for PXB mice, 24 for monkeys, and 16 for rats among 29 compounds. PXB mice indicated a higher predictability for CL_t and Vd_ss values than the other animal models.

4.?These results demonstrate the utility of PXB mice in predicting human PK parameters.     

Development of biodegradable polymeric implants of RGD-modified PEG-PAMAM-DOX conjugates for long-term intratumoral release

Abstract

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.     

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。     

Breast cancer targeted chemotherapy based on doxorubicin-loaded bombesin peptide modified nanocarriers

Context: Breast cancer is the most common cancer in female population. Breast cancer chemotherapy using doxorubicin (DOX) is well illustrated. However, a significant obstacle for successful chemotherapy with DOX is multidrug resistant (MDR) in breast cancer cells. Targeted nanocarriers have emerged as frontier research for the improvement of cancer chemotherapy.

Objective: Bombesin (Bn)-modified, DOX-loaded solid lipid nanoparticles (Bn-DOX/SLNs) were constructed. Doxorubicin-resistant MCF-7/MDR human breast cancer cells and the cancer animal models were applied for the evaluation of the in vitro and in vivo anti-tumor effect of Bn-DOX/SLNs.

Methods: Bn-conjugated lipids were synthesized. DOX was then loaded into Bn-modified SLNs. The physicochemical properties of the Bn-DOX/SLNs were investigated by particle size and zeta potential measurement, drug loading and drug-entrapment efficiency, and in vitro drug release behavior. In vitro cytotoxicity against MCF-7/MDR cells was investigated, and in vivo anti-tumor of SLNs was evaluated in human breast cancer mice models.

Results: Bn-DOX/SLNs showed an excellent in vitro cytotoxicity and in vivo anti-tumor effect both in MCF-7/MDR breast cancer cells and breast cancer animal model.

Conclusion: The results demonstrated that Bn-DOX/SLNs reversed the resistance of doxorubicin, suggesting that chemotherapy using this kind of targeted nanocarriers may benefit human breast MDR cancer therapy.     

Dioscorea bulbifera L. delays the excretion of doxorubicin and aggravates doxorubicin-induced cardiotoxicity and nephrotoxicity by inhibiting the expression of P-glycoprotein in mice liver and kidney

1. We aimed to investigate the drug–drug interaction (DDI) between doxorubicin (DOX) and Dioscorea bulbifera L. (DB) solution in mice, and to explore the effect of P-glycoprotein (P-gp) on this type of DDI.

2. The toxicity of DOX in the liver, kidneys, and heart was assessed with alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cr), urea nitrogen (BUN), creatine kinase MB (CK-MB), creatine kinase (CK) and histopathology. High-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) was used to determine the concentrations of DOX in the serum, liver, kidneys and heart. Immunohistochemistry and western blots were used to determine the expression levels of P-gp in these tissues.

3. Our results demonstrated that, after co-administration of DOX and DB, survival was significantly decreased compared with either administration of DOX or DB alone, or water. Co-administration of DOX and DB induced elevated levels of toxicity in the heart and kidneys, but not the liver, compared with DOX alone.

4. We conclude that concurrent treatment with DOX and DB results in increased levels of toxicity due to the accumulation of DOX in the body. Delayed excretion of DOX is associated with inhibition of P-gp in liver and kidneys.

     

The effective combination therapy against human osteosarcoma: doxorubicin plus curcumin co-encapsulated lipid-coated polymeric nanoparticulate drug delivery system

Objective: To overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure incurred from multidrug resistant (MDR) in osteosarcoma (OS), biodegradable lipid-coated polymeric nanoparticles (LPNs) were explored for the loading of doxorubicin (DOX) and curcumin (CUR).

Methods: DOX plus CUR co-encapsulated LPNs (DOX?+?CUR LPNs) of mixed lipid monolayer shell and biodegradable polymer core were prepared. The cytotoxicity effect of DOX?+?CUR LPNs, single drug loaded LPNs, and free drug solutions were evaluated on human OS cell line KHOS cells and mice KHOS cells xenograft in vivo.

Results: DOX?+?CUR LPNs displayed a curative effect on OS cell lines than the free drug counterparts. Also, best anti-OS effects were observed on the animal model compared with other groups tested.

Conclusion: This promising dual drugs co-encapsulated lipid-coated polymeric nanoparticulate drug delivery system enhanced the cell delivery and activity of drugs against human OS cancer cell lines and in cancer bearing mice. This research may offer new options for the treatment of OS.     

Which one performs better for targeted lung cancer combination therapy: pre- or post-bombesin-decorated nanostructured lipid carriers?

Abstract

Purpose: The co-delivery of gene and drugs has the potential to treat cancer. The aim of this study was to compare post-bombesin decorated nanostructured lipid carriers (NLC) carrying both doxorubicin (DOX) and DNA with pre-bombesin decorated NLC for lung cancer therapy.

Methods: Post-bombesin decorated NLC were prepared by two steps. First, DOX and DNA-loaded NLC (DOX-DNA-NLC) was prepared. Second, Bombesin-NH₂ (BN-NH₂) was added into DOX-DNA-NLC to react with stearic acid-polyethylene glycol-COOH (SA-PEG-COOH) loaded in NLC. Pre-bombesin decorated NLC were prepared by two steps. First, Bombesin (BN)-conjugated ligands were synthesized. Second, DOX and DNA were loaded into BN decorated NLC. Their average size, zeta potential, drug and gene loading were evaluated. NCl-H460 human non-small lung cancer cells (NCl-H460 cells) were used for the testing of in vitro transfection efficiency and in vitro cytotoxicity. In vivo transfection efficiency and anti-tumor effect of NLC were evaluated on mice bearing NCl-H460 cells model.

Results: Post-bombesin decorated NLC has a particle size of 128?nm, DOX encapsulation efficiency (EE) of 85% and DNA EE of 91%. Pre-bombesin decorated NLC has a particle size of 101?nm, DOX EE of 86% and DNA EE of 92%. Post-bombesin decorated NLC displayed more stable and remarkably higher transfection efficiency and better anti-tumor ability than pre-bombesin decorated NLC both in vitro and in vivo.

Conclusion: Post-bombesin decorated NLC could function as better carriers to improve the cell targeting and nuclear targeting ability. The resulting nanomedicine could be a promising active targeting drug/gene therapeutic system for lung cancer therapy.     

负载阿霉素的黄芩苷纳米粒的制备及其体外性能评价

目的 制备负载阿霉素的黄芩苷纳米粒（DOX/SA-SS-BAI NPs）,并评价其体外性能。方法 构建以胱胺为连接臂的海藻酸钠–黄芩苷聚合物,并负载阿霉素,得到DOX/SA-SS-BAI NPs。对DOX/SA-SS-BAI NPs的理化性质进行表征;采用HepG2细胞进行MTT实验验证其细胞毒性。结果 DOX/SA-SS-BAI NPs粒径为（158.2±2.8）nm,PDI为（0.241±0.008）,Zeta电位为（-24.1±0.3）m V,包封率为（64.34±0.25）%,载药量为（16.22±0.06）%。体外释放显示载药纳米粒具有良好的还原响应性;MTT实验证明DOX/SA-SS-BAINPs对HepG2细胞具有良好的抑制作用;细胞摄取实验表明DOX/SA-SS-BAI NPs在HepG2细胞内较快地释放阿霉素。结论 制备的DOX/SA-SS-BAI NPs具有较好的理化性质和体外抗癌作用。     

Copolymers of poly(lactic acid) and d-α-tocopheryl polyethylene glycol 1000 succinate-based nanomedicines: versatile multifunctional platforms for cancer diagnosis and therapy

Introduction: The major drawbacks associated with most of the anti-cancer drugs are their potential adverse effects. Distribution of these drugs throughout the body causes untoward adverse effects and less accumulation of drug at the site of tumors also causes decrease in therapeutic efficacy. Targeted nanomedicines are the emerging systems to improve the targetability of drug to the tumor site and to reduce the toxicity with maximum efficacy. Copolymers of poly-lactic acid (PLA) and d-α-tocopheryl polyethylene glycol 1000 succinate (Vitamin-E TPGS or TPGS) are innovative materials being actively investigated for the fabrication of non-targeted and targeted nanomedicines for diagnosis and therapy of cancer.

Areas covered: In this review, different nanomedicines of copolymers such as poly-lactic acid – polyoxyethylene sorbitan monooleate (PLA – Tween® 80), poly-lactic acid – poly-ethyleneglycol (PLA-PEG), poly-lactic acid-d-α-tocopheryl polyethylene glycol 1000 succinate (PLA-TPGS) and TPGS-based nanomedicines (i.e., TPGS emulsified polymeric nanoparticles, TPGS prodrugs, TPGS liposomes, and TPGS micelles) for the diagnosis and therapy of cancer have been discussed.

Expert opinion: PLA, PLA-Tween® 80, PLA-PEG, PLA-TPGS, and TPGS are the promising polymeric biomaterials well studied as cancer nanomedicines. These biomaterials have proved that they could be applied in the fabrication of multifunctional nanomedicines for the future needs in simultaneous diagnosis of cancer as well as targeted chemotherapy.     

Nanodiamond-mediated drug delivery and imaging: challenges and opportunities

Introduction: The field of nanoparticle-based therapeutic systems is rapidly expanding encompassing a wide variety of practices ranging from detection to diagnosis to treatment. Recently a great potential of nanodiamond (ND) particles as a multimodal imaging/therapy platform has been demonstrated.

Areas covered: This review describes a unique set of properties of ND particles attractive for drug delivery and imaging applications and highlights the most recent ND-based multimodal imaging/therapy approaches and related biocompatibility studies. The spectrum of major advancements includes marked improvements in tumor treatment efficacy and safety based on integration of ND with doxorubicin (DOX). Recent progress of ND-mediated drug delivery in orthopedic, dental and ophthalmic applications is also discussed.

Expert opinion: ND particles possess a unique set of properties attractive for drug delivery applications, including exceptional biocompatibility, large carrier capacity and versatile surface chemistry properties, which enhance drug binding and provide sustainable drug release. Other unique attributes of NDs embrace bright stable fluorescence based on crystallographic defects. A roadmap toward a clinical translation comprises identification of ND-therapeutic compounds that display marked improvements over clinical standards with respects to efficacy, safety and cost.