Engineering macrophage-derived exosomes for targeted paclitaxel delivery to pulmonary metastases: in vitro and in vivo evaluations

Exosomes have recently emerged as a promising drug delivery system with low immunogenicity, high biocompatibility, and high efficacy of delivery. We demonstrated earlier that macrophage-derived exosomes (exo) loaded with a potent anticancer agent paclitaxel (PTX) represent a novel nanoformulation (exoPTX) that shows high anticancer efficacy in a mouse model of pulmonary metastases. We now report the manufacture of targeted exosome-based formulations with superior structure and therapeutic indices for systemic administration. Herein, we developed and optimized a formulation of PTX-loaded exosomes with incorporated aminoethylanisamide-polyethylene glycol (AA-PEG) vector moiety to target the sigma receptor, which is overexpressed by lung cancer cells. The AA-PEG-vectorized exosomes loaded with PTX (AA-PEG-exoPTX) possessed a high loading capacity, profound ability to accumulate in cancer cells upon systemic administration, and improved therapeutic outcomes. The combination of targeting ability with the biocompatibility of exosome-based drug formulations offers a powerful and novel delivery platform for anticancer therapy.     

OncoGel (ReGel/paclitaxel) — Clinical applications for a novel paclitaxel delivery system

Cancer treatment regimens often include multiple anticancer agents targeting different cellular mechanisms in delicate balance with associated toxicity. Drug delivery systems offer a unique tool in the treatment of cancer, and applications in the local treatment of cancer have demonstrated utility in providing sustained high local concentrations at the tumor site while minimizing systemic drug levels. Treatment options for local cancer therapy are focused on indications where targeted activity may result in improved patient outcomes such as increased local control and decreased metastatic potential. Targeted therapies may also enhance response to combination anticancer regimens. OncoGel™, a controlled-release depot formulation of paclitaxel in ReGel™, has been evaluated in numerous nonclinical studies. Results from these studies demonstrated OncoGel's ability to physically target paclitaxel to the tumor site with very little reaching the circulation, resulting in an acceptable safety profile with dose-limiting toxicities being local in nature. In addition, OncoGel demonstrated efficacy as a stand-alone treatment and synergistic activity in combination therapies. Clinical studies in superficially-palpable tumors and esophageal carcinoma confirmed local paclitaxel release from OncoGel in patients. OncoGel's ability to improve current treatment options for esophageal and brain cancers is being further evaluated.     

透明质酸在紫杉醇新型给药系统中的应用

透明质酸是一种酸性黏多糖,其作为优良的药物载体,具有生物相容性良好,生物可降解的特性,同时可与肿瘤细胞表面富含的CD44、RHAMM等受体结合,目前已成为抗肿瘤药物递送载体研究的主要热点。本综述主要通过查阅近年文献,对透明质酸在紫杉醇新型给药系统中的应用进行综述。     

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.     

Improved anticancer delivery of paclitaxel by albumin surface modification of PLGA nanoparticles

Background

Nanoparticles (NPs) play an important role in anticancer delivery systems. Surface modified NPs with hydrophilic polymers such as human serum albumin (HSA) have long half-life in the blood circulation system.

Methods

The method of modified nanoprecipitation was utilized for encapsulation of paclitaxel (PTX) in poly (lactic-co-glycolic acid) (PLGA). Para-maleimide benzoic hydrazide was conjugated to PLGA for the surface modifications of PLGA NPs, and then HSA was attached on the surface of prepared NPs by maleimide attachment to thiol groups (cysteines) of albumin. The application of HSA provides for the longer blood circulation of stealth NPs due to their escape from reticuloendothelial system (RES). Then the physicochemical properties of NPs like surface morphology, size, zeta potential, and in-vitro drug release were analyzed.

Results

The particle size of NPs ranged from 170 to 190 nm and increased about 20–30 nm after HSA conjugation. The zeta potential was about -6 mV and it decreased further after HSA conjugation. The HSA conjugation in prepared NPs was proved by Fourier transform infrared (FT-IR) spectroscopy, faster degradation of HSA in Differential scanning calorimetry (DSC) characterization, and other evidences such as the increasing in size and the decreasing in zeta potential. The PTX released in a biphasic mode for all colloidal suspensions. A sustained release profile for approximately 33 days was detected after a burst effect of the loaded drug. The in vitro cytotoxicity evaluation also indicated that the HSA NPs are more cytotoxic than plain NPs.

Conclusions

HSA decoration of PLGA NPs may be a suitable method for longer blood circulation of NPs.     

RETRACTED ARTICLE: Preparation and characterization of novel lipid nanocapsules of ropivacaine for transdermal delivery

Abstract

Ropivacaine, a novel long-acting local anesthetic, has been proved to own superior advantage. However, the application form used in clinic, ropivacaine hydrochloride (Naropin® Injection), which should be administed intravenously, is causing poor patient convenience. The purpose of this study was to formulate ropivacaine (RPV) in lipid nanocapsules (LNCs) and character the potential of LNCs in delivering RPV transdermally to exploit novel external preparation. The RPV-LNCs were successfully prepared by phase inversion technique and the formulation was characterized in terms of size, zeta potential, ex vivo permeation study, and pharmacodynamics. The prepared RPV-LNCs displayed a typical core-shell structure with a narrow size distribution of 62.1?±?1.7?nm and drug loading of 1.35?±?0.20%. The results of differential scanning calorimetry (DSC) analysis and X-ray diffraction showed that RPV was in amorphous crystalline state when encapsulated into LNCs. Furthermore, the results of ex vivo permeation study displayed that RPV-LNCs had an improved permeability (349.0?±?11.5?μg?cm^?2 versus 161.0?±?1.3?μg?cm^?2) compared with free RPV. The results of histopathology study showed that interaction between LNCs and skin could break the close conjugation of corneocyte layers. In the mice writhing test, RPV-LNCs exhibited obvious analgesic effect by both prolonging pain latency and reducing the writhing response with an inhibition rate of 91.3% compared to the control group. In conclusion, RPV-LNCs could be a promising delivery system to encapsulate RPV and deliver RPV for transdermal administration.     

Applications of innovative technologies to the delivery of antipsychotics

Psychosis is a high-incidence pathology associated with a profound alteration in the perception of reality. The limitations of drugs available on the market have stimulated the search for alternative solutions to achieve effective antipsychotic therapies. In this review, we evaluate innovative formulations of antipsychotic drugs developed through the application of modern pharmaceutical technologies, including classes of micro and nanocarriers, such as lipid formulations, polymeric nanoparticles (NPs), solid dispersions, and cyclodextrins (CDs). We also consider alternative routes of administration to the oral and parenteral ones currently used. Improved solubility, stability of preparations, and pharmacokinetic (PK) and pharmacodynamic (PD) parameters confirm the potential of these new formulations in the treatment of psychotic disorders.     

Localized delivery of paclitaxel using elastic liposomes: Formulation development and evaluation

In the present study an elastic liposomes-based paclitaxel formulation was developed with the objective to remove Cremophor EL. Cremophor EL is currently used for solubilizing paclitaxel in the marketed formulation and is known to produce toxic effects. Elastic liposomal paclitaxel formulation was extensively characterized in vitro, ex-vivo, and in vivo. The results obtained were compared against the marketed paclitaxel formulation. The maximum amount of paclitaxel loaded in the elastic liposomal formulation was found to be 6.0?mg/ml, which is similar to the commercial strength of marketed paclitaxel formulation. In vitro skin permeation and deposition studies showed 10.8-fold enhanced steady state transdermal flux and 15.0-fold enhanced drug deposition in comparison to drug solution. These results further confirmed with the vesicle–skin interaction study using FTIR technique. Results of the hemolytic toxicity assay indicate that elastic liposomal formulation induced only 11.2?±?0.2% hemolysis in comparison to the commercial formulation which showed 38?±?3.0%. Further, results of the Draize test showed no skin irritation of paclitaxel elastic liposomal formulation. Findings of the study demonstrate that elastic liposomes as a carrier is an attractive approach for localized delivery of paclitaxel.     

Advances in the formulation and delivery technology of paclitaxel for injection

Paclitaxel is a promising antineoplastic agent against a variety of human solid tumors, such as ovary, breast, lung, head and neck tumors, and melanoma. Owing to its poor solubility, the first available formulation of paclitaxel (Taxol^®) exists as a non-aqueous concentrate composed of Cremophor EL (polyethoxylated castor oil) and ethanol. It must be diluted to a suitable aqueous solution prior to long time intravenous infusion. Based on the components and usage, Taxol^® has serious adverse effects and is inconvenient for clinical use. To address these problems, the development of a less-toxic, better-tolerated, Cremophor EL-free formulation of paclitaxel has been attempted. In recent years, new drug delivery systems (DDS) including albumin-based nanoparticles, micelles, liposomes, etc. have been investigated. In this review, we present the formulations and delivery technologies of paclitaxel for injection and focus on some of preclinical and clinical experience on the formulations which are already on the market or under clinical stages. Finally, possible nanotechnology advantages, existing challenges and future perspectives of paclitaxel delivery are highlighted.     

Tailoring combinatorial lipid nanoparticles for intracellular delivery of nucleic acids,proteins, and drugs

Lipid nanoparticle (LNP)-based drug delivery systems have become the most clinically advanced non-viral delivery technology. LNPs can encapsulate and deliver a wide variety of bioactive agents, including the small molecule drugs, proteins and peptides, and nucleic acids. However, as the physicochemical properties of small- and macromolecular cargos can vary drastically, every LNP carrier system needs to be carefully tailored in order to deliver the cargo molecules in a safe and efficient manner. Our group applied the combinatorial library synthesis approach and in vitro and in vivo screening strategy for the development of LNP delivery systems for drug delivery. In this Review, we highlight our recent progress in the design, synthesis, characterization, evaluation, and optimization of combinatorial LNPs with novel structures and properties for the delivery of small- and macromolecular therapeutics both in vitro and in vivo. These delivery systems have enormous potentials for cancer therapy, antimicrobial applications, gene silencing, genome editing, and more. We also discuss the key challenges to the mechanistic study and clinical translation of new LNP-enabled therapeutics.     

Targeted delivery of nanoparticles for the treatment of lung diseases

Targeted delivery of drug molecules to organs or special sites is one of the most challenging research areas in pharmaceutical sciences. By developing colloidal delivery systems such as liposomes, micelles and nanoparticles a new frontier was opened for improving drug delivery. Nanoparticles with their special characteristics such as small particle size, large surface area and the capability of changing their surface properties have numerous advantages compared with other delivery systems. Targeted nanoparticle delivery to the lungs is an emerging area of interest. This article reviews research performed over the last decades on the application of nanoparticles administered via different routes of administration for treatment or diagnostic purposes. Nanotoxicological aspects of pulmonary delivery are also discussed.     

PEGylated poly(trimethylene carbonate) nanoparticles loaded with paclitaxel for the treatment of advanced glioma: in vitro and in vivo evaluation

The aim of this study was to investigate the antitumor effect of paclitaxel (PTX)-loaded poly(ethylene glycol)-poly(trimethylene carbonate) (MPEG-PTMC) nanoparticles (NP) against gioblastoma multiforme (GMB). PTX-loaded NP (NP/PTX) were prepared with synthesized MPEG-PTMC by the emulsion/solvent evaporation technique. In vitro physiochemical characterization of those NP/PTX showed satisfactory encapsulation efficiency and loading capacity and size distribution. Cytotoxicity assay revealed that encapsulation in nanoparticles did not compromise the antitumor efficacy of PTX against U87MG cells. Pharmacokinetic study in rats demonstrated that the polymer micellar nanoparticles significantly enhanced the bioavailability of PTX than Taxol. In intracranial xenograft tumor-bearing mice, the accumulation of nanoparticles in tumor tissues increased distinctly after 12 h post i.v. More importantly, in vivo anti-tumor effect exhibited the median survival time of NP/PTX treated mice (27 days) was significantly longer than those of mice treated with Taxol (24 days), physiological saline (21 days) and blank MPEG-PTMC NP (21 days). Therefore, our results suggested that PTX-loaded MPEG-PTMC nanoparticles significantly enhanced the anti-glioblastoma activity of PTX and may be a potential vehicle in the treatment of high-grade glioma.     

Redispersible spray-dried lipid-core nanocapsules intended for oral delivery: the influence of the particle number on redispersibility

Abstract

This study proposes a new approach to produce easily redispersible spray-dried lipid-core nanocapsules (LNC) intended for oral administration, evaluating the influence of the particle number density of the fed sample. The proposed approach to develop redispersible spray-dried LNC formulations intended for oral route is innovative, evidencing the needing of an optimization of the initial particle number density in the liquid suspension of nanocapsules. A mixture of maltodextrin and L-leucine (90:10 w/w) was used as drying adjuvant. Dynamic light scattering, turbidimetry, determination of surface area and pore size distribution, electron microscopy and confocal Raman microscopy (CRM) were used to characterize the proposed system and to better understand the differences in the redispersion behavior. An easily aqueous redispersion of the spray-dried powder composed of maltodextrin and L-leucine (90:10 w/w) was obtained, depending on the particle number density. Their surface area decreased in the presence of LNC. CRM enabled the visualization of the spatial distribution of the different compounds in the powders affording to better understand the influence of the particle number density of the fed sample on their redispersion behavior. This study shows the need for optimizing initial particle number density in the liquid formulation to develop redispersible spray-dried LNC powders.     

Spotlight on the delivery of photosensitizers: different approaches for photodynamic-based therapies

Introduction: Nanomedicine development allowed the discovery of new photosensitizers (PS) and drug delivery systems (DDS) to overcome current issues on phototherapy. Nano-engineered materials have the potential to improve the solubility of PS, control drug pharmacokinetics, decreasing side effects, increasing bioavailability, and overcoming multidrug resistance. A recent approach is the co-delivery of PS with other therapeutic agents in a multimodal platform for synergic and improved results.

Areas covered: This paper discusses the delivery of PS-nanostructured platforms for conventional, photothermal, and antimicrobial photodynamic therapies, as well as in a recent therapeutic modality for photobiomodulation, covering applications of cancer diagnosis, targeting to skin pathogens, photoregeneration and wound healing. The focus of the present review is to describe the use of different DDS to enhance the therapeutic outcomes triggered by the combination of delivered PS, light, and oxygen.

Expert opinion: Nanotechnology allowed the development of site-specific delivery of PS molecules, expanding possibilities poorly explored before to enhance photodynamic efficacy and extrapolate the concept to other treatment protocols. Research in this area embraces potential and pitfalls of PS delivery, allowing new clinical phase outcomes and long-term issues to be established, which will impact on several biomedical applications.     

脂质类纳米载体在难溶性药物递送中的应用

随着新技术在药物研发中的广泛应用,大量有活性的难溶性候选药物涌现出来,但水溶性差的问题又严重制约了此类药物的开发。目前纳米载体作为难溶性药物递送系统的研究日益增多。本文综述了微乳、脂肪乳、脂质体、固体脂质纳米粒、纳米脂质载体、脂质纳米混悬剂和仿生载体等脂质类纳米载体在难溶性药物递送中的应用,旨在为产品的开发提供新策略。     

The adaptation of lipid nanocapsule formulations for blood administration in animals

In many cell-culture and animal models, the therapeutic effects of the entrapped drugs in lipid nanocapsules (LNCs) were preserved with low toxicity. These results allow foreseeing further preclinical efficiency and toxicity studies in animals. In this article, preliminary studies were performed to check the genetically modified organism (GMO) status of the LNCs components and to determine the effects of the acidity of the LNCs dispersions in acid–base balance in rats. Then, several freezing protocols to store paclitaxel-loaded LNCs dispersions for a 6-month period were compared. Results indicate that the Lipoïd^® S75-3 could not be certified GMO-free. The same soya bean lecithin certified to be GMO-free permitted to produce LNCs with expected characteristics. The blood administration of blank LNCs dispersions in rats induced no modifications of blood acidity, but a significant decrease of the base excess was observed. Injections of LNCs dispersions in animals might induce iatrogenic acidosis. We finally demonstrated that the best protocol to store LNCs dispersion for a 6-month period is by freezing in liquid nitrogen. This protocol minimized the characteristics modifications and interrupted the drug-release phenomenon. These original data are expected to prepare of LNCs dispersions well adapted for i.v. administration in animals.     

SMART drug delivery systems: Back to the future vs. clinical reality

Recent advances in nanotechnology and material science have re-ignited interest in drug delivery research. Arguably, however, hardly any of the systems developed and strategies proposed are really relevant for shaping the future (clinical) face of the nanomedicine field. Consequently, as outlined in this commentary, instead of making ever more carrier materials, and making nanomedicine both science-fiction and fiction-science, we should try to come up with rational and realistic concepts to make nanomedicines work, in particular in patients.     

联合递送IDO抑制剂和紫杉醇用于癌症治疗

为实现化学疗法与免疫疗法的联合应用,本研究合成了具有还原响应性的紫杉醇(Paclitaxel,PTX)前药PEG-SS-PTX,并以此为载体包载吲哚胺2,3-双加氧酶(Indoleamine 2,3-dioxygenase,IDO)抑制剂CY-1-4制备PEG-SS-PTX/CY-1-4 NPs.通过细胞毒作用、免疫原...     

阳离子聚合物在基因传递系统中的应用阳离子聚合物在基因传递系统中的应用

随着近代生物技术的发展与人类基因库的不断完善 ,各种与人类疾病相关基因逐步被揭晓 ,使人类从分子水平上认识某些疾病根源已逐步成为可能 ,为基因治疗提供了理论基础。基因治疗即ＤＮＡ给药系统 ,属于靶向给药系统 ,它不同于一般靶向药物作用于机体的某器官或某组织 ,它是细胞与分子水平上的靶向作用。基因治疗从 1980年第 1篇哺乳类基因转移公开报告[1]到 1994年 30 0余人接受临床基因治疗试验 ,整整花了 15年时间 ,1994年美国重组ＤＮＡ咨询委员会(ＲＡＣ)批准了人基因治疗方案。此后 ,许多分子疾病 (ｍｏｌｅｃｕｌａｒｄｉｓｅａｓｅ)…     

缓释型肺吸入制剂的研究进展

近年来,肺吸入制剂因为直接将药物递送至患病部位、无首过效应、患者依从性大等优点,成为研究热点。但肺吸入制剂仍然存在许多问题如药物消除迅速、给药次数频繁、存在临床用药安全性隐患。本文将从肺部主要的消除机制入手,对目前缓释肺吸入制剂进行综述,为今后肺吸入的临床应用提供思路。