Review: doxorubicin delivery systems based on chitosan for cancer therapy

Objectives This review sheds insight into an increasingly popular polymer that has been widely explored as a potential drug delivery system. The abundant, biodegradable and biocompatible polysaccharide chitosan, with many other favourable properties, has been favoured as a drug delivery system for the purposes of encapsulating and delivery of doxorubicin with reduced side‐effects. Key findings Doxorubicin is frequently used as a frontline chemotherapeutic agent against a variety of cancers. It has largely been able to demonstrate anti‐tumour effects, though there are major shortfalls of doxorubicin, which include serious side‐effects such as cardiomyopathy and myelosuppression, and also an ever‐present danger of extravasation during drug administration. In view of this, drug delivery systems are currently being explored as alternative methods of drug delivery in a bid to more effectively direct doxorubicin to the specific lesion site and reduce its systemic side‐effects. Liposomes and dendrimers have been tested as potential carriers for doxorubicin; however they are not the focus of this review. Summary Recent advancements in doxorubicin and chitosan technology have shown some preliminary though promising results for cancer therapy.     

Smart albumin-loaded Rose Bengal and doxorubicin nanoparticles for breast cancer therapy

Abstract

Objective: To synthesise HSA-RB-DOX nanoparticles, measure its characteristics and preliminarily evaluate its anti-cancer effects.

Methods: Doxorubicin (DOX) and Rose Bengal (RB) were co-delivered using albumin as a carrier. HSA-RB-DOX nanoparticles were prepared by RB-induced self-assembly of albumin. Its characteristics were measured and anti-cancer effects were tested in MCF-7 cells and tumour-bearing mice.

Results: HSA-RB-DOX nanoparticle with a mean size of 42?nm was stable in different medium and behaved controlled release characteristic. It was well took in MCF-7 cells and inhibited MCF-7 cells proliferation by inducing reactive oxygen species (ROS) production. It retained a much higher blood concentration up to 12?h and accumulated more in tumour tissues. In tumour-bearing mice, HSA-RB-DOX nanoparticles inhibited tumour growth and even decreased its volume from 100 to 50?mm³, with barely no influence on body weight.

Conclusions: HSA-RB-DOX nanoparticles may be potentially used for enhanced treatment of breast cancer.     

黄芪多糖对阿霉素治疗小鼠乳腺癌的增效减毒机制研究

目的：探讨黄芪多糖对阿霉素治疗乳腺癌的增效减毒作用机制,为乳腺癌的治疗提供帮助。方法：建立小鼠乳腺癌皮下移植肿瘤模型,44只荷瘤小鼠随机平分为4组,即对照组（生理盐水治疗）、DOX组（阿霉素治疗）、APS组（黄芪多糖治疗）和APS+DOX组（黄芪多糖和阿霉素联合治疗）;观察治疗后荷瘤小鼠肿瘤体积大小、体质量变化以及平均存活时间、各器官组织学变化;检测荷瘤小鼠治疗前后T淋巴细胞、应激反应因子以及肝肾功能变化。结果：经过联合治疗后,APS+DOX组荷瘤小鼠肿瘤体积比显著低于对照组、APS组和DOX组;同时APS+DOX组荷瘤小鼠平均存活时间明显长于对照组、APS组和DOX组;HE染色表明荷瘤小鼠经过黄芪多糖和阿霉素联合治疗后,各器官损伤程度低于DOX组和对照组;治疗后APS+DOX组荷瘤小鼠肝功能和肾功能各指标、GSH、SOD以及T淋巴细胞（CD3⁺、CD4⁺、CD4⁺/CD8⁺和NK）水平显著高于DOX组但显著低于APS组和对照组,APS+DOX组CD8⁺、MDA水平显著低于DOX组但显著高于APS组、对照组,数据比较差异存在统计学意义（P<0.05）。结论：黄芪多糖能够有效促进阿霉素对乳腺癌皮下移植肿瘤小鼠的治疗和平均存活时间的延长,同时能够提高荷瘤小鼠免疫功能、抑制氧化应激反应和改善荷瘤小鼠的肝肾功能,有利于促进乳腺癌的治疗。     

内分泌联合唑来膦酸治疗晚期前列腺癌临床对照研究

目的：评价内分泌联合唑来膦酸治疗晚期前列腺癌的疗效及安全性。方法：回顾分析40例晚期前列腺癌患者,给予内分泌治疗并检测血清ALP值的临床资料。结果：与基础值相比,治疗组第3、6、9、12个月血清ALP值分别减少79.3%（P=0.017）、84.7%（P=0.015）、82.9%（P=0.017）、82.5%（P=0.020）;对照组分别减少45.9%（P=0.13）、35.2%（P=0.21）、30.3%（P=0.26）、20.2%（P=0.45）。治疗组血清ALP水平显著低于对照组（P〈0.01）。结论：唑来膦酸可降低合并骨转移前列腺癌患者的骨代谢水平,防治肿瘤细胞及内分泌治疗引起的骨质疏松。     

对前列腺癌的基因放射联合疗法的生物学效应观察

目的：探讨基因治疗和放射治疗联合应用于前列腺癌的治疗效果和安全性。方法：应用单纯自杀基因，射线照射及联合方法分别处理2种前列腺癌细胞．alamarBlue还原法观察细胞生长情况，绘制细胞生长曲线。结果：由细胞生长曲线可以看出较低浓度的基因转染和低剂量的照射联合应用，获得了比常规剂量的单纯治疗更好的治疗效果。结论：联合治疗中两种治疗可以相互促进，低剂量的联合应用就可以达到甚至超过常规剂量的单纯治疗，同时剂量的降低也提高了治疗的安全性，为进一步研究和临床应用提供了实验基础。     

Star polyester-based folate acid-targeting nanoparticles for doxorubicin and curcumin co-delivery to combat multidrug-resistant breast cancer

Chemotherapeutic treatments are indispensable in the treatment of breast cancer. However, the emergence of multidrug-resistance, strong cell toxicity, and poor targeting selection has inhibited their clinical application. In this study, two synergistic drugs, doxorubicin (DOX) and curcumin (CUR), were co-administered to overcome multidrug resistance (MDR). Based on the characteristics of the tumor microenvironment, we developed folic acid-modified nanoparticles ((DOX + CUR)-FA-NPs) based on a star-shaped polyester (FA-TRI-CL) to enhance the tumor targeting selectivity and drug loading (DL) capacity. The (DOX + CUR)-FA-NPs displayed a characteristic spheroid morphology with an ideal diameter (186.52 nm), polydispersity index (0.024), zeta potential (–18.87 mV), and good entrapment efficiency (97.64%/78.13%, DOX/CUR) and DL (20.27%/11.29%, DOX/CUR) values. In vitro pharmacokinetic and pharmacodynamic experiments demonstrated that the (DOX + CUR)-FA-NPs were gradually released, and they displayed the highest cell apoptosis and cellular uptake in MCF-7/ADR cells. Additionally, in vivo results illustrated that (DOX + CUR)-FA-NPs not only displayed significant tumor targeting and anticancer efficacy, but also induced less pathological damage to the normal tissue. In summary, co-administered DOX and CUR appeared to reverse MDR, and this targeted combinational nanoscale delivery system could thus be a promising carrier for tumor therapies in the future.     

Cell-derived biomimetic nanocarriers for targeted cancer therapy: cell membranes and extracellular vesicles

Nanotechnology provides synthetic carriers for cancer drug delivery that protect cargos from degradation, control drug release and increase local accumulation at tumors. However, these non-natural vehicles display poor tumor targeting and potential toxicity and are eliminated by the immune system. Recently, biomimetic nanocarriers have been widely developed based on the concept of ‘mimicking nature.’ Among them, cell-derived biomimetic vehicles have become the focus of bionics research because of their multiple natural functions, such as low immunogenicity, long circulation time and targeting ability. Cell membrane-coated carriers and extracellular vesicles are two widely used cell-based biomimetic materials. Here, this review summarizes the latest progress in the application of these two biomimetic carriers in targeted cancer therapy. Their properties and performance are compared, and their future challenges and development prospects are discussed.     

Myocet (liposome-encapsulated doxorubicin citrate): a new approach in breast cancer therapy

Doxorubicin, either as a single agent or in combination regimens, is considered to be one of the most active chemotherapeutic agents in the treatment of metastatic breast cancer. However, its clinical utility is limited by a cumulative, dose-dependent cardiac myopathy that can lead to potentially fatal congestive heart failure. Considerable research has gone into improving the therapeutic index of doxorubicin-based regimens. A new liposomal formulation of doxorubicin (Myocet?, Elan Pharmaceuticals) has a significantly improved therapeutic index compared with conventional doxorubicin. The development of Myocet, a less cardiotoxic, better tolerated and equally efficacious doxorubicin, extends the therapeutic options in the overall management of breast cancer.     

Androgen deprivation therapy with Leuprolide acetate for treatment of advanced prostate cancer

Introduction: Hormone sensitive advanced prostate cancer (PCa) is an incurable disease that is treated with a variety of hormonal therapies targeting the androgen/androgen receptor signaling axis. For decades androgen deprivation therapy (ADT) by surgical or chemical castration is the gold standard for the treatment of advanced PCa.

Areas covered: This review discusses the pharmacological features of Leuprolide, a luteinizing hormone-releasing hormone (LHRH) agonists/analog and the most commonly used drug in ADT.

Expert opinion: Although Leuprolide has been on the market for more than 30 years it is still the leading option for ADT and serves as a basis for most multimodal therapy concepts. The fact that with the onset of castration-resistance in late stage metastatic disease, a prolongation of ADT in combination with a second line hormonal manipulation is recommended supports the importance of the compound for daily clinical practice.     

Combination therapy of cRGD-DOX self-assembled nanoparticles and bevacizumab for breast cancer

The interplay among diverse cell populations in the tumor microenvironment contributes to tumor progression. Targeting to different cell populations might result in improved therapeutic effects on malignant tumors. Integrins high express on many kinds of tumor cells, and VEGF has a strong effect on tumor angiogenesis. Therefore, based on tumor cells and angiogenesis, we fabricated integrin-targeting cRGD-DOX nanoparticles and combined them with the anti-VEGF antibody bevacizumab. We evaluated the antitumor effect of this combination therapy in an integrin-overexpressing MDA-MB-231 tumor model. The cRGD-DOX nanoparticles were effectively uptake by MDA-MB-231 cells and the uptake was related to the expression of integrinin; cRGD-DOX nanoparticles showed less cytotoxic than free DOX; Bevacizumab did not show significant cytotoxicity against MDA-MB-231 cells at concentrations less than 1 mg/mL. The in vivo results showed that bevacizumab could reduce tumor interstitial fluid pressure; the combination of bevacizumab and cRGD-DOX nanoparticles showed enhanced antitumor effects compared with the corresponding single-agent treatments. These findings suggested the combination of angiogenesis antibody and integrin-targeting nanoparticle loaded with a cytotoxic drug was a promising cancer treatment regimen.     

Precise engineering of cetuximab encapsulated gadollium nanoassemblies: in vitro ultrasound diagnosis and in vivo thyroid cancer therapy

We report the formulation of nanoassemblies (NAs) comprising C225 conjugates Gd-PFH-NAs (C-Gd-PFH-NAs) for low-intensity focused ultrasound diagnosis ablation of thyroid cancer. C-Gd-PFH-NAs showed excellent stability in water, phosphate-buffered saline (PBS), and 20% rat serum. Transmission electron microscopy (TEM) images also revealed the effective construction of C-Gd-PFH-NAs as common spherical assemblies. The incubation of C625 thyroid carcinoma with C-Gd-PFH-NAs triggers apoptosis, as confirmed by flow cytometry analysis. The C-Gd-PFH-NAs exhibited antitumor efficacy in human thyroid carcinoma xenografts, where histopathological results further confirmed these outcomes. Furthermore, we were able to use low-intensity focused ultrasound diagnosis imaging (LIFUS) to examine the efficiency of C-Gd-PFH-NAs in thyroid carcinoma in vivo. These findings clearly show that the use of LIFUS agents with high performance imaging in different therapeutic settings will have extensive potential for future biomedical applications.     

Carbopol emulgel loaded with ebastine for urticaria: development,characterization, in vitro and in vivo evaluation

Urticaria affects all age groups of a population. It is triggered by allergens in foods, insect bites, medications, and environmental conditions. Urticaria is characterized by itching, a burning sensation, wheals and flares, erythema, and localized edema. The aim of this study was to develop a polymeric dosage form of ebastine using Carbopol 940 and mixture of span and tween. The emulsion was prepared, the gelling agent was added and the desired emulgel loaded with active drug was formulated. The formulations were subjected to physical stability, pH, viscosity, spreadability, drug content analysis, thermal analysis, in vitro drug release, and in vivo anti-allergic activity in animal model. The formulated emulgel exhibited good physical stability. The pH of the formulation was in the range of 5.2 ± 0.17 to 5.5 ± 0.20 which is suitable for topical application. Insignificant changes (p > .05) were observed in viscosity and spreadability of stored emulgels. The drug content was in the official limit of Pharmacopeia (i.e. 100 ± 10%). DSC measurements predicted that there is no interaction between the active moiety and excipients in emulgel formulation. The optimized formulation (ES3) released 74.25 ± 1.8% of ebastine after 12 h. The ebastine emulgel showed significant (p < .05; ANOVA) in vivo anti-allergic activity as compared to commercial product Benadryl^® in histamine-induced allergy in rabbits. This study concluded that a topical drug delivery of ebastine-loaded emulgel could be well tolerated and safe for the treatment of urticaria/hives.     

Polydopamine and peptide decorated doxorubicin-loaded mesoporous silica nanoparticles as a targeted drug delivery system for bladder cancer therapy

We reported a simple polydopamine (PDA)-based surface modification method to prepare novel targeted doxorubicin-loaded mesoporous silica nanoparticles and peptide CSNRDARRC conjugation (DOX-loaded MSNs@PDA-PEP) for enhancing the therapeutic effects on bladder cancer. Drug-loaded NPs were characterized in terms of size, size distribution, zeta potential, transmission electron microscopy (TEM), Brunauer–Emmett–Teller (BET) surface area and drug loading content. In vitro drug release indicated that DOX-loaded MSNs@PDA and MSNs@PDA-PEP had similar release kinetic profiles of DOX. The PDA coating well controlled DOX release and was highly sensitive to pH value. Confocal laser scanning microscopy (CLSM) showed that drug-loaded MSNs could be internalized by human bladder cancer cell line HT-1376, and DOX-loaded MSNs@PDA-PEP had the highest cellular uptake efficiency due to ligand–receptor recognition. The antitumor effects of DOX-loaded nanoparticles were evaluated by the MTT assay in vitro and by a xenograft tumor model in vivo, demonstrating that targeted nanocarriers DOX-loaded MSNs@PDA-PEP were significantly superior to free DOX and DOX-loaded MSNs@PDA. The novel DOX-loaded MSNs@PDA-PEP, which specifically recognized HT-1376 cells, can be used as a potential targeted drug delivery system for bladder cancer therapy.     

Lipid bubbles combined with low-intensity ultrasound enhance the intratumoral accumulation and antitumor effect of pegylated liposomal doxorubicin in vivo

Pegylated liposomal doxorubicin (PLD) is a representative nanomedicine that has improved tumor selectivity and safety profile. However, the therapeutic superiority of PLD over conventional doxorubicin has been reported to be insignificant in clinical medicine. Combination treatment with microbubbles and ultrasound (US) is a promising strategy for enhancing the antitumor effects of chemotherapeutics by improving drug delivery. Recently, several preclinical studies have shown the drug delivery potential of lipid bubbles (LBs), newly developed monolayer microbubbles, in combination with low-intensity US (LIUS). This study aimed to elucidate whether the combined use of LBs and LIUS enhanced the intratumoral accumulation and antitumor effect of PLD in syngeneic mouse tumor models. Contrast-enhanced US imaging using LBs showed a significant decrease in contrast enhancement after LIUS, indicating that LIUS exposure induced the destruction of LBs in the tumor tissue. A quantitative evaluation revealed that the combined use of LBs and LIUS improved the intratumoral accumulation of PLD. Furthermore, tumor growth was inhibited by combined treatment with PLD, LBs, and LIUS. Therefore, the combined use of LBs and LIUS enhanced the antitumor effect of PLD by increasing its accumulation in the tumor tissue. In conclusion, the present study provides important evidence that the combination of LBs and LIUS is an effective method for enhancing the intratumoral delivery and antitumor effect of PLD in vivo.     

Kallikrein-related peptidases targeted therapies in prostate cancer: perspectives and challenges

Introduction: Despite the emergence of several new effective treatments for metastatic castration-resistant prostate cancer patients, disease progression inevitably occurs, leading scientific community to carefully look for novel therapeutic targets of prostate cancer. Kallikrein (KLK)-related peptidases have been demonstrated to facilitate prostate tumorigenesis and disease progression through the development of an oncogenic microenvironment for prostate cells.

Areas covered: This review first summarizes the large amount of preclinical data showing the involvement of KLKs in prostate cancer pathobiology. In the second part, the authors assess the current status and future directions for KLK-targeted therapy and briefly describe the advances and challenges implicated in the design of effective manufactured drugs. The authors then focus on the preclinical data and on Phase I/II studies of the most promising KLK-targeted agents in prostate cancer. The drugs discussed here are divided on the basis of their mechanism of action: KLK-engineered inhibitors; KLK-activated pro-drugs; KLK-targeted microRNAs and small interfering RNAs^-/small hairpin RNAs; KLK vaccines and antibodies.

Expert opinion: Targeting KLK expression and/or activity could be a promising direction in prostate cancer treatment. Future human clinical trials will help us to evaluate the real benefits, toxicities and the consequent optimal use of KLK-targeted drugs, as mono-therapy or in combination regimens.     

氟他胺联合注射用醋酸亮丙瑞林微球间歇性治疗手术去势后前列腺癌的临床分析

目的分析手术去势后间歇性内分泌治疗晚期前列腺癌的临床疗效。方法选取2007年1月-2010年1月晚期前列腺癌患者62例,睾丸去势手术后分别采用间歇性、持续性内分泌治疗。结果两组患者平均随访时间（30．0±7．2）个月,两组患者血清前列腺特异性抗原（PSA）值、临床症状差异较治疗前均取得明显改善。间歇组生存率为90．3％（27／31）,显著优于持续组。结论相比较持续性内分泌治疗,间歇性内分泌治疗可延缓前列腺癌患者病程进展,缓解病痛,是晚期前列腺癌治疗的有效方法。     

Precise engineering of hybrid molecules-loaded macromolecular nanoparticles shows in vitro and in vivo antitumor efficacy toward the treatment of nasopharyngeal cancer cells

Cancers continue to be the second leading cause of death worldwide. Despite the development and improvement of surgery, chemotherapy, and radiotherapy in cancer management, effective tumor ablation strategies are still in need due to high cancer patient mortality. Hence, we have established a new approach to achieve treatment-actuated modifications in a tumor microenvironment by using synergistic activity between two potential anticancer drugs. Dual drug delivery of gemcitabine (GEM) and cisplatin (PT) exhibits a great anticancer potential, as GEM enhances the effect of PT treatment of human cells by providing stability of the microenvironment. However, encapsulation of GEM and PT fanatical by methoxypoly(ethylene glycol)-block-poly(D, L-lactic acid) (PEG-PLA in termed as NPs) is incompetent owing to unsuitability between the binary Free GEM and PT core and the macromolecular system. Now, we display that PT can be prepared by hydrophobic coating of the dual drug centers with dioleoylphosphatidic acid (DOPA). The DOPA-covered PT can be co-encapsulated in PLGA NPs alongside GEM to stimulate excellent anticancer property. The occurrence of the PT suggestively enhanced the encapsulations of GEM into PLGA NPs (GEM-PT NPs). Further, the morphology of GEM NPs, PT NPs, and GEM-PT NPs and nanoparticle size was examined by transmission microscopy (TEM), respectively. Furthermore GEM-PT NPs induced significant apoptosis in human nasopharyngeal carcinoma CNE2 and SUNE1 cancer cells by in vitro. The morphological observation and apoptosis were confirmed by the various biochemical assays (AO-EB, nuclear staining, and annexin V-FITC). In a xenograft model of nasopharyngeal cancer, this nanotherapy shows a durable inhibition of tumor progression upon the administration of a tolerable dose. Our results suggest that a macromolecular hydrophobic and highly toxic drug can be rationally converted into a pharmacologically efficient and self-deliverable of nanotherapy.     

β2 微球蛋白在内分泌治疗前列腺癌根治术后患者体内表达与预后关系研究

目的观察β2微球蛋白在内分泌治疗前列腺癌根治术后患者体内表达情况及其与患者预后关系。方法选取我院行前列腺根治术联合内分泌治疗病例30例,术后3周服用氟他胺（250mg,3次/天）。分别在治疗前、治疗后3月、6月、12月收集患者血清,采用放射免疫法检测血清β2微球蛋白的表达。分析患者β2微球蛋白表达水平与患者Gleason评分以及PSA的关系。结果治疗后β2微球蛋白以及PSA水平均显著降低,差异有统计学意义（P〈0.05）。Pearson相关性分析显示,β2微球蛋白以及PSA水平有相关性（r1=0.693,r2=0.627,P〈0.05）,Gleason评分与β2微球蛋白以及PSA表达水平呈正相关（r=0.857,P〈0.05;r=0.793,P〈0.05）。结论血清β2微球蛋白是诊断以及检测肿瘤治疗预后的有效指标,与PSA协同观察可以提高临床诊断以及治疗水平。