Prospects and challenges of the development of lipoprotein-based formulations for anti-cancer drugs

This review evaluates drug delivery systems that involve intact plasma lipoproteins or some of their components. These complex macromolecules transport highly water-insoluble compounds (cholesteryl esters and triacylglycerols) in their natural environment – a property that renders them ideal carriers of hydrophobic drugs. Particular emphasis is placed on the application of lipoproteins as drug delivery agents in cancer chemotherapy. The history and present activity regarding lipoprotein-based formulations are reviewed, with the primary focus on the smaller sized (low and high density) lipoprotein-based formulations and their potential clinical and commercial value. The use of both native and synthetic lipoproteins as drug delivery agents are discussed from the standpoint of therapeutic efficacy, as well as commercial feasibility. The advantages of lipoprotein-based drug delivery formulations are compared with other drug delivery models, with the primary focus on liposomal preparations. Finally, an expert opinion is provided, regarding the potential use of lipoprotein-based formulations in cancer treatment, taking into consideration the major advantages (biocompatibility, safety, drug solubility) and the barriers (manufacturing protein components, financial interest, investments) to their commercial development.     

纳米载体逆转肿瘤耐药的研究进展

联合化疗对恶性肿瘤患者有积极的意义,但肿瘤细胞产生的耐药性又是肿瘤化疗失败最常见而又最难解决的问题之一。肿瘤细胞产生耐药性是多方面的,其中以多药耐药性(Multidrug resistance,MDR)最为常见。MDR使药物从靶细胞中清除或阻断发挥药效的途径,是癌症治疗的重大障碍之一。纳米颗粒药物传递系统(DDS)是一种潜在的逆转MDR的工具,可以通过靶向针对多药耐药的肿瘤细胞本身或肿瘤的内皮细胞来实现功能。本文就逆转MDR中DDS的应用进行了综述。     

克服肿瘤多药耐药的药物共递送纳米载体的设计及研究新方向

多药耐药（multidrug resistance,MDR）是肿瘤治疗成功的主要障碍,药物共递送纳米载体因其肿瘤靶向、控制释放、一致的药动学曲线而被认为是克服MDR的有效策略。本综述总结了当前克服MDR的药物共递送纳米载体的设计思路,并分析了具有前景的研究方向,包括精确药物负载纳米载体、呈时序释放的纳米载体和对肿瘤微环境设计纳米载体,这些新兴策略为临床肿瘤治疗提供了新颖且更好的定制组合方案。     

Enhanced tolerance and antitumor efficacy by docetaxel-loaded albumin nanoparticles

Docetaxel is one of the most active chemotherapeutic agents for cancer treatment. The traditional docetaxel injection (TAXOTERE®) is currently formulated in the surfactant polysorbate 80, which has been associated with severe adverse reactions. To avoid the use of polysorbate 80 as well as to reduce the systemic toxicity of docetaxel, in this study, docetaxel-loaded albumin nanoparticles were fabricated by a novel simple self-assembly method. The resulting nanoparticles showed a mean diameter size of 150?nm. After being encapsulated into nanoparticles, docetaxel displayed similar cytotoxicity to traditional injection. Since polysorbate 80 was not involved in nanoparticles, the hemolysis was completely eliminated. The maximal tolerance dose of nanoparticles was also increased, which allowed a higher dose to be safely intravenously injected and produced ideal antitumor effects. The 150?nm diameter also allowed the nanoparticles to accumulate in tumor tissue via the enhanced permeability and retention effect. The passive targeting ability further caused the higher antitumor effects of nanoparticles than that of traditional injection at the same dose (7.5?mg/kg). Therefore, docetaxel-loaded albumin nanoparticles fabricated by our strategy showed higher promise in their safety and effectiveness than the traditional docetaxel injection.     

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.     

Current trends in chemical modifications of magnetic nanoparticles for targeted drug delivery in cancer chemotherapy

Abstract

Nowadays, magnetic nanoparticles (MNPs) have been rapidly investigated and attracted worldwide attention due to their great potential as mediators of heat for treating hyperthermia and their possibility to deliver drugs at specific locations, which can thereby limit systematic effects. Cancer therapy via MNPs proposes novel properties rather than normal methods such as almost zero side effects and a high-efficiency rate of effectiveness. The key aim of targeted drug delivery is to reduce side effects of the main cancer treatment that other usual chemotherapies will attend to the body, and thus controlling the effectiveness of the drug on a specific location that tumoral tissue exist. Herein, the high potential of MNPs has been studied, and different examples of their effectiveness on drug delivery and hypothermia therapy have been provided.     

维拉帕米对胶质瘤细胞卡氮芥化疗敏感性的作用

目的探讨维拉帕米对不同胶质瘤细胞（U251、SHG-44）卡氮芥（BCNU）化疗敏感性的作用及其机制。方法通过免疫组化测定BCNU化疗前后肿瘤细胞中的耐药基因的表达;用MTT实验评估BCNU及维拉帕米作用前后化疗的细胞生长情况。结果 U251细胞中BCNU化疗前耐药基因LRP表达阳性,MRP阴性,P-gp阴性;化疗后LRP仍为阳性,MRP转变为阳性,P-gp为弱阳性,加入维拉帕米后细胞生长情况无明显差异（P〉0.05）;SHG-44细胞中,BCNU化疗前,LRP为阳性,P-gp和MRP1为阴性,化疗后上述基因表达无差异,加入维拉帕米后细胞生长受到明显抑制（P〈0.05）。结论维拉帕米对细胞化疗前后表达不同耐药基因的化疗敏感性具有不同的作用。     

多柔比星纳米载药系统逆转肿瘤多药耐药的研究进展

多柔比星是治疗乳腺癌、肺癌的1种有效的化疗药物。现存的主要问题是临床使用时肿瘤细胞产生多药耐药。为克服多药耐药,研究者们报道了一些利用纳米载药系统传递多柔比星的方法。纳米载药系统生物相容性好,稳定性高,具有药物控释和靶向性的优点,在药物传递中应用广泛。纳米载药系统可分为无机物纳米系统、基于脂质的纳米系统和聚合物纳米系统3种类型,在多柔比星载药中均有应用。综述近年来有关纳米载药系统最新研究文献,对其研究进展作了分析,并展望了其发展前景。     

Preparation of estradiol chitosan nanoparticles for improving nasal absorption and brain targeting

The aim of this study is to observe the synergistically enhanced percutaneous penetration and skin analgesia of tetracaine gel containing menthol and ethanol through experimental and clinical studies. Four anesthetic gels containing 4% tetracaine in carbomer vehicle named T-gel (containing no menthol or ethanol), 5%M/T-gel (containing 5% menthol), 70%E/T-gel (containing 70% ethanol, an optimal concentration for antiseptic), and 5%M+70%E/T-gel (containing both 5% menthol and 70% ethanol), respectively, were fabricated. The in vitro mouse skin permeation was investigated using a Franz diffusion cell. The mouse skin morphology was examined by a scanning electron microscope. The in vivo skin analgesic effect in mice was evaluated using the von Frey tests. To determine the efficacy of tetracaine gels for managing the pain in human volunteers, a paralleled, double-blinded, placebo-controlled, randomized controlled trial design combined with verbal pain scores (VPS) was performed. The combination of menthol and ethanol (5%M+70%E/T-gel) conferred significantly higher tetracaine diffusion across full-thickness mouse skin than 5%M/T-gel, 70%E/T-gel, and T-gel. The ultra structure changes of mouse skin stratum corneum treated with 5%M+70%E/T-gel were more marked compared with those of any other tetracaine gel. von Frey tests in mice showed a synergistically enhanced effect of menthol and ethanol on the analgesia of tetracaine gel. The mean VPS were significantly lower for volunteers treated with 5%M+70%E/T-gel than those receiving other gels or the EMLA cream. 5%M+70%E/T-gel possessed the shortest anesthesia onset time, the longest anesthesia duration and the strongest anesthesia efficacy. Seventy percent ethanol in 5%M+70%E/T-gel not only improved the analgesic efficacy of the tetracaine gel through synergistically enhanced percutaneous permeation with menthol but also served as an antiseptic agent keeping drug application site from infection. 5%M+70%E/T-gel is a potential topical anesthesia preparation for clinical use.     

Enhancement of cellular uptake and cytotoxicity of curcumin-loaded PLGA nanoparticles by conjugation with anti-P-glycoprotein in drug resistance cancer cells

Aim:

To compare the anti-cancer activity and cellular uptake of curcumin (Cur) delivered by targeted and non-targeted drug delivery systems in multidrug-resistant cervical cancer cells.

Methods:

Cur was entrapped into poly (DL-lactide-co-glycolide) (PLGA) nanoparticles (Cur-NPs) in the presence of modified-pluronic F127 stabilizer using nano-precipitation technique. On the surface of Cur-NPs, the carboxy-terminal of modified pluronic F127 was conjugated to the amino-terminal of anti-P-glycoprotein (P-gp) (Cur-NPs-APgp). The physical properties of the Cur-NPs, including particle size, zeta potential, particle morphology and Cur release kinetics, were investigated. Cellular uptake and specificity of the Cur-NPs and Cur-NPs-APgp were detected in cervical cancer cell lines KB-V1 (higher expression of P-gp) and KB-3-1 (lower expression of P-gp) using fluorescence microscope and flow cytometry, respectively. Cytotoxicity of the Cur-NPs and Cur-NPs-APgp was determined using MTT assay.

Results:

The particle size of Cur-NPs and Cur-NPs-APgp was 127 and 132 nm, respectively. The entrapment efficiency and actual loading of Cur-NPs-APgp (60% and 5 μg Cur/mg NP) were lower than those of Cur-NPs (99% and 7 μg Cur/mg NP). The specific binding of Cur-NPs-APgp to KB-V1 cells was significantly higher than that to KB-3-1 cells. Cellular uptake of Cur-NPs-APgp into KB-V1 cells was higher, as compared to KB-3-1 cells. However, the cellular uptake of Cur-NPs and Cur-NPs-IgG did not differ between the two types of cells. Besides, the cytotoxicity of Cur-NPs-APgp in KB-V1 cells was higher than those of Cur and Cur-NPs.

Conclusion:

The results demonstrate that Cur-NPs-APgp targeted to P-gp on the cell surface membrane of KB-V1 cells, thus enhancing the cellular uptake and cytotoxicity of Cur.     

Lipid nanoparticles for parenteral delivery of actives

The present review compiles the applications of lipid nanoparticles mainly solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC) and lipid drug conjugates (LDC) in parenteral delivery of pharmaceutical actives. The attempts to incorporate anticancer agents, imaging agents, antiparasitics, antiarthritics, genes for transfection, agents for liver, cardiovascular and central nervous system targeting have been summarized. The utility of lipid nanoparticles as adjuvant has been discussed separately. A special focus of this review is on toxicity caused by these kinds of lipid nanoparticles with a glance on the fate of lipid nanoparticles after their parenteral delivery in vivo viz the protein adsorption patterns.     

Solid lipid nanoparticles,an effective carrier for classical antifungal drugs

Solid-lipid nanoparticles (SLNs) are an innovative group of nanosystems used to deliver medicine to their respective targets with better efficiency and bioavailability in contrast to classical formulations. SLNs are less noxious, have fewer adverse effects, have more biocompatibility, and have easy biodegradability. Lipophilic, hydrophilic and hydrophobic drugs can be loaded into SLNs, to enhance their physical and chemical stability in critical environments. Certain antifungal agents used in different treatments are poorly soluble medications, biologicals, proteins etc. incorporated in SLNs to enhance their therapeutic outcome, increase their bioavailability and target specificity. SLNs-based antifungal agents are currently helpful against vicious drug-resistant fungal infections. This review covers the importance of SLNs in drug delivery of classical antifungal drugs, historical background, preparation, physicochemical characteristic, structure and sizes of SLNs, composition, drug entrapment efficacy, clinical evaluations and uses, challenges, antifungal drug resistance, strategies to overcome limitations, novel antifungal agents currently in clinical trials with special emphasis on fungal infections.     

Advances in mesoporous silica nanoparticles for targeted stimuli-responsive drug delivery: an update

Introduction: Mesoporous silica nanoparticles (MSNs) are outstanding nanoplatforms for drug delivery. Herein, the most recent advances to turn MSN-based carriers into minimal side effect drug delivery agents are covered.

Areas covered: This review summarizes the scientific advances dealing with MSNs for targeted and stimuli-responsive drug delivery since 2015. Delivery aspects to diseased tissues together with approaches to obtain smart MSNs able to respond to internal or external stimuli and their applications are here described. Special emphasis is done on the combination of two or more stimuli on the same nanoplatform and on combined drug therapy.

Expert opinion: The use of MSNs in nanomedicine is a promising research field because they are outstanding platforms for treating different pathologies. This is possible thanks to their structural, chemical, physical and biological properties. However, there are certain issues that should be overcome to improve the suitability of MSNs for clinical applications. All materials must be properly characterized prior to their in vivo evaluation; furthermore, preclinical in vivo studies need to be standardized to demonstrate the MSNs clinical translation potential.     

Biodegradable polymers for targeted delivery of anti-cancer drugs

ABSTRACT

Introduction: Biodegradable polymers have been used for more than three decades in cancer treatment and have received increased interest in recent years. A range of biodegradable polymeric drug delivery systems designed for localized and systemic administration of therapeutic agents as well as tumor-targeting macromolecules has entered into the clinical phase of development, indicating the significance of biodegradable polymers in cancer therapy.

Areas covered: This review elaborates upon applications of biodegradable polymers in the delivery and targeting of anti-cancer agents. Design of various drug delivery systems based on biodegradable polymers has been described. Moreover, the indication of polymers in the targeted delivery of chemotherapeutic drugs via passive, active targeting, and localized drug delivery are also covered.

Expert opinion: Biodegradable polymer-based drug delivery systems have the potential to deliver the payload to the target and can enhance drug availability at desired sites. Systemic toxicity and serious side effects observed with conventional cancer therapeutics can be significantly reduced with targeted polymeric systems. Still, there are many challenges that need to be met with respect to the degradation kinetics of the system, diffusion of drug payload within solid tumors, targeting tumoral tissue and tumor heterogeneity.     

Nano-drug co-delivery system of natural active ingredients and chemotherapy drugs for cancer treatment: a review

Chemotherapy drugs have been used for a long time in the treatment of cancer, but serious side effects are caused by the inability of the drug to be solely delivered to the tumor when treating cancer with chemotherapy. Natural products have attracted more and more attention due to the antitumor effect in multiple ways, abundant resources and less side effects. Therefore, the combination of natural active ingredients and chemotherapy drugs may be an effective antitumor strategy, which can inhibit the growth of tumor and multidrug resistance, reduce side effects of chemotherapy drugs. Nano-drug co-delivery system (NDCDS) can play an important role in the combination of natural active ingredients and chemotherapy drugs. This review provides a comprehensive summary of the research status and application prospect of nano-delivery strategies for the combination of natural active ingredients and chemotherapy drugs, aiming to provide a basis for the development of anti-tumor drugs.     

叶酸靶向聚合物纳米粒共传输紫杉醇和吉西他滨用于乳腺癌的治疗（英文）

针对肿瘤细胞不同信号通路的多药递药系统具有协同治疗的作用。本文中,我们开发了一种由聚-L-赖氨酸(PLL)和负载有紫杉醇/吉西他滨的聚谷氨酸(PGA-PTX和PGA-GEM)组装的叶酸(FA)修饰的聚合物多药纳米粒(FA-PMDNPs),用于FA受体靶向的乳腺癌协同治疗。PGA富含大量的羧基,为药物负载提供了充足的反应位点和负电荷。透射电子显微镜(TEM)结果表明制备的FA-PMDNPs粒径均一,为球形。溶血实验表明FA-PMDNP具有良好的生物相容性。由于乳腺癌细胞(4T1)的FA受体(FR)高表达,体外细胞活性和体内疗效结果表明FA-PMDNP比单药能够更有效地抑制乳腺癌细胞(4T1)的增殖。与单药相比,FA-PMDNPs可以有效地靶向癌细胞。因此,FA受体靶向双重载药递药系统是一种具有潜力的肿瘤纳米治疗平台。