Optical imaging-guided cancer therapy with fluorescent nanoparticles

The diagnosis and treatment of cancer have been greatly improved with the recent developments in nanotechnology. One of the promising nanoscale tools for cancer diagnosis is fluorescent nanoparticles (NPs), such as organic dye-doped NPs, quantum dots and upconversion NPs that enable highly sensitive optical imaging of cancer at cellular and animal level. Furthermore, the emerging development of novel multi-functional NPs, which can be conjugated with several functional molecules simultaneously including targeting moieties, therapeutic agents and imaging probes, provides new potentials for clinical therapies and diagnostics and undoubtedly will play a critical role in cancer therapy. In this article, we review the types and characteristics of fluorescent NPs, in vitro and in vivo imaging of cancer using fluorescent NPs and multi-functional NPs for imaging-guided cancer therapy.     

Heavy-atomic construction of photosensitizer nanoparticles for enhanced photodynamic therapy of cancer

A new type of heavy-atom-affected Pluronic (F-127) nanoparticle (FIC NP) for photodynamic therapy (PDT) is reported. FIC NPs are formulated with biocompatible constituents, and contain densely integrated iodinated aromatic molecules that form a structurally rigid core matrix and stably encapsulate photosensitizers in a monomeric form. Tiny nanoparticles (≈10 nm) are prepared by aqueous dispersion of photosensitizer-embedded aromatic nanodomains, which self-assemble by phase separation from the Pluronic melt mixture. By using spectroscopic studies and cellular experiments, the following is demonstrated: 1) enhanced singlet-oxygen generation by means of the intraparticle heavy-atom effect on the embedded photosensitizer, 2) facilitated cell uptake due to the small nanoscopic size as well as the Pluronic surface characteristics, and thereby 3) actual enhancement of PDT efficacy for a human breast-cancer cell line (MDA-MB-231), which validates a photophysically motivated nanoformulation approach toward an advanced photosensitizing nanomedicine.     

Synthesis of superparamagnetic CaCO3 mesocrystals for multistage delivery in cancer therapy

To develop a new system for site-specific targeting, superparamagnetic CaCO(3) mesocrystals with the properties of biocompatibility and biodegradability are designed and synthesized. They serve as carriers for the co-delivery of drug and gene nanoparticles via a multistage method for cancer therapy. With a porous structure, the mesocrystalline CaCO(3) particles encapsulate doxorubicin (DOX), Au-DNA, and Fe(3)O(4)@silica nanoparticles for magnetic control and therapy. As stage 1 microparticles (S1MPs), the nanoparticles-CaCO(3) system is designed to protect functional sections from degradation and phagocytosis in blood circulation. After the particle margination in vascular walls, the Au-DNA nanoparticles (stage 2 nanoparticles, S2NPs) and DOX are gradually released from S1MPs by degradation towards targeted tissues for biomedical therapy. The nanoparticles-CaCO(3) system exhibits high efficiency of intracellular delivery, especially in nuclear invasion. The successful expression of reporter gene and intracellular transport of DOX in vitro suggest potential as a co-delivery system for drug and gene therapy. In a mouse tumor model, the system with particle margination and two-step strategy affords the protection of functional nanoparticles and drug from clearance and inactivation by enzymes and proteins in vivo. The targeted delivery of S2NPs into tumors by this system is tenfold more efficient than that of the nanoparticles themselves. The drug is observed to be widely distributed in tumor slices. Thus, this platform exhibits an efficient approach in the targeted delivery of therapeutic nanoparticles and molecules via a multistage strategy, and can be used as a potential system in co-delivery of multiple agents for biomedical imaging and therapy.     

Hyaluronic acid-coated,prodrug-based nanostructured lipid carriers for enhanced pancreatic cancer therapy

Abstract

Context: Gemcitabine (GEM) and Baicalein (BCL) are reported to have anti-tumor effects including pancreatic cancer. Hyaluronic acid (HA) can bind to over-expressed receptors in various kinds of cancer cells.

Objective: The aim of this study is to develop prodrugs containing HA, BCL and GEM, and construct nanomedicine incorporate GEM and BCL in the core and HA on the surface. This system could target the cancer cells and co-deliver the drugs.

Methods: GEM-stearic acid lipid prodrug (GEM-SA) and hyaluronic acid-amino acid-baicalein prodrug (HA-AA-BCL) were synthesized. Then, GEM and BCL prodrug-based targeted nanostructured lipid carriers (HA-GEM-BCL NLCs) were prepared by the nanoprecipitation technique. The in vitro cytotoxicity studies of the NLCs were evaluated on AsPC1 pancreatic cancer cell line. In vivo anti-tumor effects were observed on the murine-bearing pancreatic cancer model.

Results: HA-GEM-BCL NLCs were effective in entering pancreatic cancer cells over-expressing HA receptors, and showed cytotoxicity of tumor cells in vitro. In vivo study revealed significant tumor growth inhibition ability of HA-GEM-BCL NLCs in murine pancreatic cancer model.

Conclusion: It could be concluded that HA-GEM-BCL NLCs could be featured as promising co-delivery, tumor-targeted nanomedicine for the treatment of cancers.     

Synthesis of protein nano-conjugates for cancer therapy

A eukaryotic cell contains thousands of proteins that regulate its cellular function; delivering functional proteins into cells to rectify cellular functions holds great promise for treatment of various diseases, especially cancers. In this context, ribonuclease (RNase), an enzyme that breaks down ribonucleic acid (RNA), has great potential for cancer therapy. However, its therapeutic application is hampered by poor intracellular delivery efficiency and inhibition by ubiquitous intracellular RNase inhibitors. In this work, by designing and synthesizing RNase nano-conjugates by in situ atom transfer radical polymerization (ATRP), we demonstrate a simple solution to address both challenges. Compared with native RNase, nano-conjugates exhibit significantly enhanced intracellular delivery efficiency, inhibitor resistance, and a near five-fold increase in cytotoxicity. This work provides a novel platform for delivery of therapeutic proteins for cancer therapy and other applications.     

Synthesis,self-assembly,and characterization of PEG-coated iron oxide nanoparticles as potential MRI contrast agent

Aim: Investigated the self-assembly and characterization of novel antifouling polyethylene glycol (PEG)-coated iron oxide nanoparticles as nanoprobes for magnetic resonance imaging (MRI) contrast agent. Method: Monodisperse oleic acid-coated superparamagnetic iron oxide cores are synthesized by thermal decomposition of iron oleate. The self-assembly behavior between iron oxide cores and PEG-lipid conjugates in water and their characteristics are confirmed by transmission electron microscope, X-ray diffraction, thermogravimetric analysis, Fourier transform infrared spectroscopy, and vibrating sample magnetometer. Result: Dynamic light scattering shows superparamagnetic iron oxide nanoparticles coated with PEG are stable in water for pH of 3–10 and ionic strengths up to 0.3 M NaCl, and are protein resistant in physiological conditions. Additionally, in vitro MRI study demonstrates the efficient magnetic resonance imaging contrast characteristics of the iron oxide nanoparticles. Conclusion: The result indicates that the novel antifouling PEG-coated superparamagnetic iron oxide nanoparticles could potentially be used in a wide range of applications such as biotechnology, MRI, and magnetic fluid hyperthermia.     

A new era for cancer treatment: gold-nanoparticle-mediated thermal therapies

Nanotechnology-based cancer treatment approaches potentially provide localized, targeted therapies that aim to enhance efficacy, reduce side effects, and improve patient quality of life. Gold-nanoparticle-mediated hyperthermia shows particular promise in animal studies, and early clinical testing is currently underway. In this article, the rapidly evolving field of gold nanoparticle thermal therapy is reviewed, highlighting recent literature and describing current challenges to clinical translation of the technology.     

Engineering nanocomposite materials for cancer therapy

Cancer accounted for 13% of all deaths worldwide in 2005. Although early detection is critical for the successful treatment of many cancers, there are sensitivity limitations associated with current detection methodologies. Furthermore, many traditional anticancer drug treatments exhibit limited efficacy and cause high morbidity. The unique physical properties of nanoscale materials can be utilized to produce novel and effective sensors for cancer diagnosis, agents for tumor imaging, and therapeutics for cancer treatment. Functionalizing inorganic nanoparticles with biocompatible polymers and natural or rationally designed biomolecules offers a route towards engineering responsive and multifunctional composite systems. Although only a few such innovations have reached human clinical trial to date, nanocomposite materials based on functionalized metal and semiconductor nanoparticles promise to transform the way cancer is diagnosed and treated. This review summarizes the current state-of-the-art in the development of inorganic nanocomposites for cancer-related applications.     

Comparative enhancement of curcumin cytotoxic photodynamic activity by nanoliposomes and gold nanoparticles with pharmacological appraisal in HepG2 cancer cells and Erlich solid tumor model

Curcumin is a natural pigment that generates singlet oxygen upon light excitation, hence it can be used as a photosensitizer in photodynamic therapy. The extremely low water solubility and poor systemic bioavailability make curcumin a challenging molecule to be used clinically. In this study, two nanocarrier systems for curcumin were prepared and characterized; nanoliposomes and polyvinyl pyrrolidone-capped gold nanoparticles. The dark and photocytotoxicity were investigated as a function of light fluence rate (100 and 200?mW/cm²) on HepG2 cancer cells. In vivo Erlich tumor model was developed and comparison of the tumor volume, survival rate, and histopathological alterations was made for the two nanocarriers. Results showed that both curcumin nanocarriers were successfully prepared and characterized. Light irradiation was able to augment the cytotoxicity of both curcumin liposomes and gold nanoparticles, with the former being superior in cytotoxicity compared to the latter. The tumor size was almost diminished 1 month post-photodynamic treatment for both systems with regression in the number of tumor cells upon histopathological evaluation, with curcumin liposomes producing better tumor regression than gold nanoparticles with comparable survival rate. Liposomes were confirmed to be superior to gold nanoparticles as a photodynamic treatment modality for cancer.     

超小型超顺磁性氧化铁磁共振对比剂的制备及性能研究

制备了一种性能良好的超小型超顺磁性氧化铁磁共振对比剂。我们通过透射电镜、振动样品磁强计和红外光谱仪等测量手段研究了样品的形貌、粒径、磁学性能和表面包覆情况,并进行了磁共振成像动物实验,同时将我们的样品和哈佛医学院分子影像研究中心同类样品进行了比较。结果表明,我们所制备样品分散均匀,粒径在10nm以下,具有良好的超顺磁性,动物成像实验中成像效果优于哈佛医学院分子影像研究中心同类样品,表明我们所制备样品可以作为一种有前途的磁共振成像对比剂。     

Toxicity Evaluation for Safe Use of Nanomaterials: Recent Achievements and Technical Challenges

Recent developments in the field of nanotechnology involving the synthesis of novel nanomaterials (NM) have attracted the attention of numerous scientists owing to the possibility of degradative perturbations in human health. This Review evaluates previous investigations related to NM toxicity studies using biological models and describes the limitations that often prevent toxicologists from identifying whether NM pose a real hazard to human health. One major limitation to assess toxicity is the characterization of the NM prior to and after exposure to living cells or animals. The most relevant physicochemical characteristics of NM are: size, surface chemistry, crystallinity, morphology, solubility, aggregation tendency, homogeneity of dispersions, and turbidity. All of these properties need to be assessed in order to determine their contribution to toxicity. Due to the lack of appropriate methods to determine the physicochemical nature of nanoparticles in biological systems, the exact nature of NM toxicity is not fully described or understood at this time. This Review emphasizes the need for state‐of‐the‐art physicochemical characterization, the determination of appropriate exposure protocols and reliable methods for assessing NM internalization and their kinetics in living organisms. Once these issues are addressed, optimal experimental conditions could be established in order to identify if NM pose a threat to human health. Multidisciplinary research between materials scientists and life scientists should overcome these limitations in identifying the true hazards of NM.     

Inverse problem in the hyperthermia therapy of cancer with laser heating and plasmonic nanoparticles

In this paper, laser-induced hyperthermia therapy of cancer is treated as a state estimation problem and solved with a particle filter method, namely the Auxiliary Sampling Importance Resampling algorithm. In state estimation problems, the available measured data are used together with prior knowledge about the physical phenomena, in order to sequentially produce estimates of the desired dynamic variables. Although the hyperthermia treatment of cancer has been addressed in the literature by different computational methods, these usually involved deterministic analyses. On the other hand, state space representation of the problem in a Bayesian framework allows for the analyses of uncertainties present in the mathematical formulation of the problem, as well as in the measured data of observable variables that might be eventually available. Two physical problems are considered in this paper, involving the irradiation with a laser in the near infrared range of a non-homogeneous cylindrical medium representing either a soft-tissue phantom or a skin model, both containing a tumour. The region representing the tumour is assumed to be loaded with nanoparticles in order to enhance the hyperthermia effects and to limit such effects to the tumour. The light propagation problem is coupled with the bioheat transfer equation in the present study. Simulated transient temperature measurements are used in the inverse analysis.     

Gold nanoparticles loaded into niosomes: A novel approach for enhanced antitumor activity against human ovarian cancer

In the current study, gold nanoparticles (AuNPs) were prepared using the green synthesis method using Artemisia annua extract, loaded into niosomes, and investigated their cytotoxicity and apoptotic effects. To optimize the niosomal formulation containing AuNPs, the effects of surfactants: cholesterol molar ratio, Span 60: Tween 60 M ratio, and AuNP concentration (µg/mL) were investigated. After examining the drug release profile, mathematical models were assessed to predict release kinetic. The cytotoxicity of noisome encapsulated AuNPs and free AuNPs was evaluated against human ovarian cancer cell line (A2780) by MTT assay. The apoptotic/necrosis ratio was studied using flow cytometry as well as Real-Time PCR was used for the Bax and Bcl-2 apoptosis gene expression. The results showed that the entrapment efficiency and particle size of optimized niosomal formulation encapsulated AuNPs were 34.49%±0.84 and 153.6 ± 4.62 nm with a regular spherical shape, respectively. The release profile of AuNPs from niosomal formulation was 59%±1.0 after 8 h suggesting the controlled release profile. This formulation exerted dose-dependent cytotoxicity against the A2780 cells via induction of apoptosis and significant upregulation of mRNA expression of Bax gene; while expression of anti-apoptotic gene Bcl-2 was down-regulated. Thus, the findings suggest that AuNP-loaded niosomal formulation is considered a promising and suitable targeted system for improving anti-tumor activity against A2780 cells.     

具有自组装纳米结构的AIE光敏剂用于增强光动力治疗（英文）

基于具有聚集诱导发光(AIE)性质的2,3-双(4’-(二苯基)-[1,1’-联苯]-4-基]富甲腈(BDBF)分子,制备了三种纳米结构并用于图像引导光动力学治疗(PDT).普兰尼克F127可包封BDBF形成常见的球形纳米粒子(F127@BDBF NPs),该纳米粒子可发射红色荧光,荧光量子效率(FQY)为9.8%.此外, BDBF也可在水中自组装成纳米棒(BDBF NRs).与F127@BDBF NPs相比, BDBF NRs呈现出较强的橙色荧光,具有较高的荧光量子产率(23.3%),以及基本相同的单线态氧(1O2)产生能力.利用F127对BDBF NRs进行进一步修饰可得到BDBF@F127 NRs,该纳米粒子仍然保持了棒状形貌和较好的1O2产生能力.同时,与溶解态的BDBF相比,三种纳米结构的单线态氧产生效率增强.这些纳米结构在水溶液和生理条件下具有良好的稳定性.细胞的光毒性实验表明,三种纳米结构均能有效抑制肿瘤细胞增殖.因此,通过简单的自组装方法制备高荧光量子效率和较强单线态氧产生能力的纳米结构可作为一种有效的途径来增强光动力.     

Iridium(III) Complex–Derived Polymeric Micelles with Low Dark Toxicity and Strong NIR Excitation for Phototherapy and Chemotherapy

Iridium(III) complexes are potent candidates for photodynamic therapy. However, their clinical usage is impeded by their poor water solubility, high dark toxicity, and negligible absorption in near‐infrared region (NIR region). Here, it is proposed to solve these challenges by developing an iridium(III) complexe‐based polymeric micelle system. This system is self‐assembled using an iridium(III) complex‐containing amphiphilic block polymer. The upconversion nanoparticles are included in the polymeric micelles to permit NIR excitation. Compared with the nonformulated iridium(III) complexes, under NIR stimulation, this polymeric micelle system exhibits higher ¹O₂ generation efficiency, negligible dark toxicity, excellent tumor‐targeting ability, and synergistic phototherapy–chemotherapy effect both in vitro and in vivo.     

光触发增强葡萄糖氧化酶催化活性的等离子体囊泡用于程序化光热-饥饿疗法

在肿瘤的饥饿治疗及协同治疗中,基于葡萄糖氧化酶(GOx)的纳米诊疗剂展现出具大的应用前景.自组装等离子体金囊泡(GV),由于具有独特的光学性能、巨大空腔和强局域表面等离子体共振等特性,可作为协同治疗的多功能纳米载体.本文中,我们开发了一种装载GOx的GV(GV-GOx)用于光触发释放GOx,同时增强GOx的催化活性,从而实现程序化光热-饥饿治疗.在近红外激光照射下,由于GV具有等离子体耦合效应, GV-GOx可以产生很强的局部高热,引起封装的GOx释放,同时高热可提高GOx催化活性,从而增强肿瘤的饥饿效应.此外,高光热效应可促进细胞对GV-GOx的摄取,并可通过活体光声/光热双模态成像对协同治疗进行有效监测.令人印象深刻的是,协同光热/饥饿疗法能完全消融4T1荷瘤小鼠的肿瘤,抗肿瘤效果明显优于单一疗法,且没有明显的系统毒性.本工作展示了一种光触发的纳米平台,可用于癌症协同治疗.