Development of Novel Tumor‐Targeted Theranostic Nanoparticles Activated by Membrane‐Type Matrix Metalloproteinases for Combined Cancer Magnetic Resonance Imaging and Therapy

A major drawback with current cancer therapy is the prevalence of unrequired dose‐limiting toxicity to non‐cancerous tissues and organs, which is further compounded by a limited ability to rapidly and easily monitor drug delivery, pharmacodynamics and therapeutic response. In this report, the design and characterization of novel multifunctional “theranostic” nanoparticles (TNPs) is described for enzyme‐specific drug activation at tumor sites and simultaneous in vivo magnetic resonance imaging (MRI) of drug delivery. TNPs are synthesized by conjugation of FDA‐approved iron oxide nanoparticles ferumoxytol to an MMP‐activatable peptide conjugate of azademethylcolchicine (ICT), creating CLIO‐ICTs (TNPs). Significant cell death is observed in TNP‐treated MMP‐14 positive MMTV‐PyMT breast cancer cells in vitro, but not MMP‐14 negative fibroblasts or cells treated with ferumoxytol alone. Intravenous administration of TNPs to MMTV‐PyMT tumor‐bearing mice and subsequent MRI demonstrates significant tumor selective accumulation of the TNP, an observation confirmed by histopathology. Treatment with CLIO‐ICTs induces a significant antitumor effect and tumor necrosis, a response not observed with ferumoxytol. Furthermore, no toxicity or cell death is observed in normal tissues following treatment with CLIO‐ICTs, ICT, or ferumoxytol. These findings demonstrate proof of concept for a new nanotemplate that integrates tumor specificity, drug delivery and in vivo imaging into a single TNP entity through attachment of enzyme‐activated prodrugs onto magnetic nanoparticles. This novel approach holds the potential to significantly improve targeted cancer therapies, and ultimately enable personalized therapy regimens.     

Delays and safety in airline maintenance

Airline maintenance operations affect the potential for flight delays and can also affect flight safety if signals of technical problems are missed or misinterpreted. In this paper, we use a probabilistic risk analysis model, represented by an influence diagram, to quantify the effect of an airline's maintenance policy on delays, cancellations and in-flight safety. The model represents the leading edge (LE) sub-system of a commercial passenger jet and consists of three tiers: (1) a set of management decision variables (e.g. the level of qualification of maintenance personnel); (2) a ground model linking policy decisions and flight delays; and (3) an in-flight model, linking policy decisions, maintenance quality and flight safety. To illustrate this model, we use data adapted (for confidentiality reasons) from a study of an existing airline. Clearly, the LE devices of an airplane are not among the most safety-critical and the risk of an accident due to poor maintenance is extremely small, but non-zero. The same model can be used for other, more critical parts of the aircraft to support maintenance policy decisions in which the trade-off between delays and safety may be more pronounced.     

Multi‐Reservoir Bioadhesive Microdevices for Independent Rate‐Controlled Delivery of Multiple Drugs

A variety of oral administrative systems such as enterically coated tablets, capsules, particles, and liposomes have been developed to improve oral bioavailability of drugs. However, they suffer from poor intestinal localization and therapeutic efficacy due to the various physiological conditions and high shear fluid flow. Fabrication of novel microdevices combined with the introduction of controlled release, improved adhesion, selective targeting, and tissue permeation may overcome these issues and potentially diminish the toxicity and high frequency of conventional oral administration. Herein, thin, asymmetric, poly(methyl methacrylate) (PMMA) microdevices are fabricated with multiple reservoirs using photolithography and reactive ion etching. They are loaded with different individual model drug in each reservoir. Enhanced bioadhesion of the microdevices is observed in the presence of a conjugated of targeting protein (tomato lectin) to the PMMA surface. As compared to drug encompassing hydrogels, an increase in drug permeation across the caco‐2 monolayer is noticed in the presence of a microdevice loaded with the same drug–hydrogel system. Also, the release of multiple drugs from their respective reservoirs is found to be independent from each other. The use of different hydrogel systems in each reservoir shows differences in the controlled release of the respective drugs over the same release period. These results suggest that, in the future, microfabricated unidirectional multi‐drug releasing devices will have an impact on the oral administration of a broad range of therapeutics.     

Poly(lactide-co-glycolide) nanoparticles as carriers for norcantharidin

Norcantharidin (NCTD) is one of the new chemotherapy agents that have anti-tumor activity. However, the clinical potential of NCTD is limited by its high systemic toxicity, poor solubility in physiological environment and short half-life. In this paper, NCTD loaded poly(lactide-co-glycolide) (PLGA) nanoparticles for controlled delivery were prepared by using an interfacial deposition method. The resulting particles were characterized for their size, morphology, drug loading capacity, entrapment efficiency and in vitro drug release over an extended period of 12 days. The interfacial deposition technique succeeded in building a spherical, monodisperse nanoparticulate delivery system with high entrapment efficiency. The in vitro release lasts for more than 10 days showed a biphasic profile with an initial burst. The in vitro anti-tumor activity of NCTD-PLGA nanocapsules was assessed using the Human Hepatocellular Carcinoma cells SMMC-7721 by the MTT test. Ascites hepatoma (H-22H) and pulmonary adenocarcinoma (LA795) mice models were used to study the in vivo tumoricidal efficacy of NCTD delivery from the PLGA nanoparticles. The results demonstrate that i.v. or i.p. administration of this controlled release system could be of high clinical significance in cancer chemotherapy.     

Efficient nanoparticle mediated sustained RNA interference in human primary endothelial cells

Endothelium forms an important target for drug and/or gene therapy since endothelial cells play critical roles in angiogenesis and vascular functions and are associated with various pathophysiological conditions. RNA mediated gene silencing presents a new therapeutic approach to overcome many such diseases, but the major challenge of such an approach is to ensure minimal toxicity and effective transfection efficiency of short hairpin RNA (shRNA) to primary endothelial cells. In the present study, we formulated shAnnexin A2 loaded poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles which produced intracellular small interfering RNA (siRNA) against Annexin A2 and brought about the downregulation of Annexin A2. The per cent encapsulation of the plasmid within the nanoparticle was found to be 57.65%. We compared our nanoparticle based transfections with Lipofectamine mediated transfection, and our studies show that nanoparticle based transfection efficiency is very high (~97%) and is more sustained compared to conventional Lipofectamine mediated transfections in primary retinal microvascular endothelial cells and human cancer cell lines. Our findings also show that the shAnnexin A2 loaded PLGA nanoparticles had minimal toxicity with almost 95% of cells being viable 24 h post-transfection while Lipofectamine based transfections resulted in only 30% viable cells. Therefore, PLGA nanoparticle based transfection may be used for efficient siRNA transfection to human primary endothelial and cancer cells. This may serve as a potential adjuvant treatment option for diseases such as diabetic retinopathy, retinopathy of prematurity and age related macular degeneration besides various cancers.     

Acid-degradable gadolinium-based nanoscale coordination polymer: A potential platform for targeted drug delivery and potential magnetic resonance imaging

Nano Research - During conventional chemotherapy for cancer, nonspecific drug distribution, which causes serious side effects in normal tissues, is a serious limitation. Thus, it is desirable to...     

pH‐Responsive PEG‐Shedding and Targeting Peptide‐Modified Nanoparticles for Dual‐Delivery of Irinotecan and microRNA to Enhance Tumor‐Specific Therapy

Irinotecan is one of the main chemotherapeutic agents for colorectal cancer (CRC). MicroRNA‐200 (miR‐200) has been reported to inhibit metastasis in cancer cells. Herein, pH‐sensitive and peptide‐modified liposomes and solid lipid nanoparticles (SLN) are designed for encapsulation of irinotecan and miR‐200, respectively. These peptides include one cell‐penetrating peptide, one ligand targeted to tumor neovasculature undergoing angiogenesis, and one mitochondria‐targeting peptide. The peptide‐modified nanoparticles are further coated with a pH‐sensitive PEG‐lipid derivative with an imine bond. These specially‐designed nanoparticles exhibit pH‐responsive release, internalization, and intracellular distribution in acidic pH of colon cancer HCT116 cells. These nanoparticles display low toxicity to blood and noncancerous intestinal cells. Delivery of miR‐200 by SLN further increases the cytotoxicity of irinotecan‐loaded liposomes against CRC cells by triggering apoptosis and suppressing RAS/β‐catenin/ZEB/multiple drug resistance (MDR) pathways. Using CRC‐bearing mice, the in vivo results further indicate that irinotecan and miR‐200 in pH‐responsive targeting nanoparticles exhibit positive therapeutic outcomes by inhibiting colorectal tumor growth and reducing systemic toxicity. Overall, successful delivery of miR and chemotherapy by multifunctional nanoparticles may modulate β‐catenin/MDR/apoptosis/metastasis signaling pathways and induce programmed cancer cell death. Thus, these pH‐responsive targeting nanoparticles may provide a potential regimen for effective treatment of colorectal cancer.     

Near‐Infrared Upconversion Mesoporous Cerium Oxide Hollow Biophotocatalyst for Concurrent pH‐/H2O2‐Responsive O2‐Evolving Synergetic Cancer Therapy

Tumor hypoxia is typically presented in the central region of solid tumors, which is mainly caused by an inadequate blood flow and oxygen supply. In the conventional treatment of hypoxic human tumors, not only the oxygen‐dependent photodynamic therapy (PDT), but also antitumor drug‐based chemotherapy, is considerably limited. The use of direct oxygen delivering approach with oxygen‐dependent PDT or chemotherapy may potentiate the reactive oxygen species (ROS)‐mediated cytotoxicity of the drug toward normal tissues. Herein, a synergetic one‐for‐all mesoporous cerium oxide upconversion biophotocatalyst is developed to achieve intratumorally endogenous H₂O₂‐responsive self‐sufficiency of O₂ and near‐infrared light controlled PDT simultaneously for overcoming hypoxia cancer. Furthermore, the sufficient O₂ plays an important role in overcoming the chemotherapeutic drug‐resistant cancer caused by hypoxia, therefore inducing tumor cell apoptosis significantly.     

Biopolymers for Antitumor Implantable Drug Delivery Systems: Recent Advances and Future Outlook

In spite of remarkable improvements in cancer treatments and survivorship, cancer still remains as one of the major causes of death worldwide. Although current standards of care provide encouraging results, they still cause severe systemic toxicity and also fail in preventing recurrence of the disease. In order to address these issues, biomaterial‐based implantable drug delivery systems (DDSs) have emerged as promising therapeutic platforms, which allow local administration of drugs directly to the tumor site. Owing to the unique properties of biopolymers, they have been used in a variety of ways to institute biodegradable implantable DDSs that exert precise spatiotemporal control over the release of therapeutic drug. Here, the most recent advances in biopolymer‐based DDSs for suppressing tumor growth and preventing tumor recurrence are reviewed. Novel emerging biopolymers as well as cutting‐edge polymeric microdevices deployed as implantable antitumor DDSs are discussed. Finally, a review of a new therapeutic modality within the field, which is based on implantable biopolymeric DDSs, is given.     

Biodegradable Microalgae‐Based Carriers for Targeted Delivery and Imaging‐Guided Therapy toward Lung Metastasis of Breast Cancer

High delivery efficiency, prolonged drug release, and low systemic toxicity are effective weapons for drug delivery systems to win the battle against metastatic breast cancer. Herein, it is shown that Spirulina platensis (S. platensis) can be used as natural carriers to construct a drug‐loaded system for targeted delivery and fluorescence imaging‐guided chemotherapy on lung metastasis of breast cancer. The chemotherapeutic doxorubicin (DOX) is loaded into S. platensis (SP) via only one facile step to fabricate the DOX‐loaded SP (SP@DOX), which exhibits ultrahigh drug loading efficiency and PH‐responsive drug sustained release. The rich chlorophyll endows SP@DOX excellent fluorescence imaging capability for noninvasive tracking and real‐time monitoring in vivo. Moreover, the micrometer‐sized and spiral‐shaped SP carriers enable the as‐prepared SP@DOX to passively target the lungs and result in a significantly enhanced therapeutic efficacy on lung metastasis of 4T1 breast cancer. Finally, the undelivered carriers can be biodegraded through renal clearance without notable toxicity. The SP@DOX described here presents a novel biohybrid strategy for targeted drug delivery and effective treatment on cancer metastasis.     

Dual‐Action Cancer Therapy with Targeted Porous Silicon Nanovectors

There is a pressing need to develop more effective therapeutics to fight cancer. An idyllic chemotherapeutic is expected to overcome drug resistance of tumors and minimize harmful side effects to healthy tissues. Antibody‐functionalized porous silicon nanoparticles loaded with a combination of chemotherapy drug and gold nanoclusters (AuNCs) are developed. These nanocarriers are observed to selectively deliver both payloads, the chemotherapy drug and AuNCs, to human B cells. The accumulation of AuNCs to target cells and subsequent exposure to an external electromagnetic field in the microwave region render them more susceptible to the codelivered drug. This approach represents a targeted two‐stage delivery nanocarrier that benefits from a dual therapeutic action that results in enhanced cytotoxicity.     

Hypnosis regulation in propofol anaesthesia employing super‐twisting sliding mode control to compensate variability dynamics

Regulation of hypnosis level on bi‐spectral index monitor (BIS) during a surgical procedure in propofol anaesthesia administration is a challenging task for an anaesthesiologist in multi‐tasking environment of the operation theater. Automation in anaesthesia has the potential to solve issues arising from manual administration. Automation in anaesthesia is based on developing the three‐compartmental model including pharmacokinetics and pharmacodynamic of the silico patients. This study focuses on regulation of the hypnosis level in the presence of surgical stimulus including skin incision, surgical diathermy and laryngoscopy as well as inter‐patient variability by designing super‐twisting sliding mode control (STSMC). The depth of the hypnosis level is maintained to 50 on the BIS level in the maintenance phase after improving the induction phase to 60 s using the conventional sliding mode control and 30 s with STSMC. The proposed scheme also compensates the inter‐patient variability dynamics including height, age and weight of the different silico patients. Moreover, the surgical stimuli direct the hypnosis level towards the state of consciousness and stimulate the controller to provide continuous drug infusion during the interval 80–90 s. Simulation results witness that the oscillatory behaviour is observed in drug infusion to ensure the moderate level of hypnosis (40–60) for general surgery.Inspec keywords: surgery, patient treatment, patient monitoring, drugs, drug delivery systems, variable structure systems, medical control systems, perturbation techniquesOther keywords: hypnosis regulation, hypnosis level, bi‐spectral index monitor, surgical procedure, propofol anaesthesia administration, multitasking environment, manual administration, three‐compartmental model, surgical diathermy, laryngoscopy, BIS level, silico patients, surgical stimuli direct, moderate level, pharmacokinetics, interpatient variability dynamics, surgical stimulus, skin incision, time 60.0 s, time 80.0 s to 90.0 s, time 30.0 s     

光响应多功能药物载体的制备及其对宫颈癌细胞的抑制作用

细胞因子的过量分泌有可能造成癌细胞的耐药性,导致癌细胞的增殖和迁移。为了清除相关细胞因子,同时抑制癌细胞生长,本实验合成了一种在紫外光/暗室处理下可同时控制释放抗癌药物多烯紫杉醇和智能吸附宫颈癌细胞分泌的血管内皮细胞生长因子的磁性靶向多功能药物载体。宫颈癌细胞的增殖抑制实验结果表明,多功能药物载体控释药物的化疗作用联合血管内皮细胞生长因子清除作用,对癌细胞的抑制效果明显优于单纯药物化疗结果。因此,该多功能药物载体在癌症的临床化疗中具有极大的应用潜力。     

Controlled Drug Release and Chemotherapy Response in a Novel Acoustofluidic 3D Tumor Platform

Overcoming transport barriers to delivery of therapeutic agents in tumors remains a major challenge. Focused ultrasound (FUS), in combination with modern nanomedicine drug formulations, offers the ability to maximize drug transport to tumor tissue while minimizing toxicity to normal tissue. This potential remains unfulfilled due to the limitations of current approaches in accurately assessing and quantifying how FUS modulates drug transport in solid tumors. A novel acoustofluidic platform is developed by integrating a physiologically relevant 3D microfluidic device and a FUS system with a closed‐loop controller to study drug transport and assess the response of cancer cells to chemotherapy in real time using live cell microscopy. FUS‐induced heating triggers local release of the chemotherapeutic agent doxorubicin from a liposomal carrier and results in higher cellular drug uptake in the FUS focal region. This differential drug uptake induces locally confined DNA damage and glioblastoma cell death in the 3D environment. The capabilities of acoustofluidics for accurate control of drug release and monitoring of localized cell response are demonstrated in a 3D in vitro tumor mode. This has important implications for developing novel strategies to deliver therapeutic agents directly to the tumor tissue while sparing healthy tissue.     

Targeted Theranostic Nano Vehicle Endorsed with Self‐Destruction and Immunostimulatory Features to Circumvent Drug Resistance and Wipe‐Out Tumor Reinitiating Cancer Stem Cells

The downsides of conventional cancer monotherapies are profound and enormously consequential, as drug‐resistant cancer cells and cancer stem cells (CSC) are typically not eliminated. Here, a targeted theranostic nano vehicle (TTNV) is designed using manganese‐doped mesoporous silica nanoparticle with an ideal surface area and pore volume for co‐loading an optimized ratio of antineoplastic doxorubicin and a drug efflux inhibitor tariquidar. This strategically framed TTNV is chemically conjugated with folic acid and hyaluronic acid as a dual‐targeting entity to promote folate receptor (FR) mediated cancer cells and CD44 mediated CSC uptake, respectively. Interestingly, surface‐enhanced Raman spectroscopy is exploited to evaluate the molecular changes associated with therapeutic progression. Tumor microenvironment selective biodegradation and immunostimulatory potential of the MSN‐Mn core are safeguarded with a chitosan coating which modulates the premature cargo release and accords biocompatibility. The superior antitumor response in FR‐positive syngeneic and CSC‐rich human xenograft murine models is associated with a tumor‐targeted biodistribution, favorable pharmacokinetics, and an appealing bioelimination pattern of the TTNV with no palpable signs of toxicity. This dual drug‐loaded nano vehicle offers a feasible approach for efficient cancer therapy by on demand cargo release in order to execute complete wipe‐out of tumor reinitiating cancer stem cells.     

Monitoring drug efflux from sensitive and multidrug-resistant single cancer cells with microvoltammetry.

Multidrug resistance (MDR) is the eventual cross-resistance of certain cancer cells to a series of chemically unrelated drugs. It is attributed to a number of possible biophysical processes, one of them being increased drug efflux from resistant cells which leads to a decreased intracellular drug accumulation and retention. In this work, a carbon fiber microdisk electrode was used to monitor directly doxorubicin efflux from single preloaded cancer cells. Electrochemical cleaning, adsorptive preconcentration, and an electrocatalytic effect due to ambient oxygen made it possible to detect eventually very low drug concentrations (down to 1 nM) at good temporal resolution (down to 30 s/measurement) very close (< or = 1 micron) to single cancer cells for the first time. The results from a sensitive (AUXB1) and a drug-resistant (CHRC5) version of Chinese hamster ovarian cancer cells show that resistant cells exhibit a much higher initial efflux rate and shorter efflux time constant when both cell lines are preloaded up to the same intracellular drug concentration. These observations are consistent with results obtained from populations of the same cells by conventional techniques, proving that microvoltammetry can be used to monitor doxorubicin efflux at the single-cell level. Compared with existing methodologies, however, whose data represent only average cell behavior at typically low temporal resolution, the technique described here can provide information on the microheterogeneity of cancer cell populations in terms of drug efflux at high temporal resolution. The actual driving force of efflux is obtained since concentrations are measured directly at individual cells. This approach may lead to important new information on the mechanisms and prospective treatments of MDR.     

Neoadjuvant Chemotherapy Based on Abraxane/Human Neutrophils Cytopharmaceuticals with Radiotherapy for Gastric Cancer

Gastric cancer remains one of the most lethal cancers with high incidence and mortality worldwide. The majority of gastric cancer patients are those who have first been diagnosed in advanced stage, in which the standard chemo‐radiotherapy produces limited benefit along with severe general toxicity, thus the demand for improved therapeutic efficacy and decreased side effects drives the development of novel therapeutic strategies. Here, a neoadjuvant chemotherapy based on Abraxane/human neutrophils (NEs) cytopharmaceuticals with radiotherapy is presented for effective cancer treatment. Human NEs, the most abundant white blood cells in peripheral blood, are developed to carry Abraxane, the commercial albumin‐bound paclitaxel nanoparticle, to form cytopharmaceuticals (Abraxane/NEs) which have been confirmed to maintain the intrinsic functions of human NEs. The modest radiation is applied not only to exert tumor disruption, but also to increase the release of inflammatory factors which guide the NEs homing to the tumoral sites. These amplified inflammatory factors at tumor sites excessively activate Abraxane/NEs to form neutrophil extracellular traps, along with a burst release of Abraxane to induce superior tumor suppression. This adjuvant chemo‐radiotherapy based on cytopharmaceuticals may provide new opportunities for advanced cancer treatment, which reveals the huge clinical potential of human neutrophils as drug delivery vectors.     

Somatostatin Receptor‐Mediated Tumor‐Targeting Nanocarriers Based on Octreotide‐PEG Conjugated Nanographene Oxide for Combined Chemo and Photothermal Therapy

Nano‐sized in vivo active targeting drug delivery systems have been developed to a high anti‐tumor efficacy strategy against certain cancer‐cells‐specific. Graphene based nanocarriers with unique physical and chemical properties have shown significant potentials in this aspect. Here, octreotide (OCT), an efficient biotarget molecule, is conjugated to PEGylated nanographene oxide (NGO) drug carriers for the first time. The obtained NGO‐PEG‐OCT complex shows low toxicity and excellent stability in vivo and is able to achieve somatostatin receptor‐mediated tumor‐specific targeting delivery. Owing to the high loading efficiency and accurate targeting delivery of anti‐cancer drug doxorubicin (DOX), our DOX loaded NGO‐PEG‐OCT complex offers a remarkably improved cancer‐cell‐specific cellular uptake, chemo‐cytotoxicity, and decreased systemic toxicity compared to free DOX or NGO‐PEG. More importantly, due to its strong near‐infrared absorption, the NGO‐PEG‐OCT complex further enhances efficient photothermal ablation of tumors, delivering combined chemo and photothermal therapeutic effect against cancer cells.     

Energy‐Converting Nanomedicine

Serious side effects to surrounding normal tissues and unsatisfactory therapeutic efficacy hamper the further clinic applications of conventional cancer‐therapeutic strategies, such as chemotherapy and surgery. The fast development of nanotechnology provides unprecedented superiorities for cancer therapeutics. Externally activatable therapeutic modalities mediated by nanomaterials, relying on highly effective energy transformation to release therapeutic elements/effects (cytotoxic reactive oxygen species, thermal effect, photoelectric effect, Compton effect, cavitation effect, mechanical effect or chemotherapeutic drug) for cancer therapies, categorized and termed as “energy‐converting nanomedicine,” have arouse considerable concern due to their noninvasiveness, desirable tissue‐penetration depth, and accurate modulation of therapeutic dose. This review summarizes the recent advances in the engineering of intelligent functional nanotherapeutics for energy‐converting nanomedicine, including photo‐based, radiation‐based, ultrasound‐based, magnetic field‐based, microwave‐based, electric field‐based, and radiofrequency‐based nanomedicines, which are enabled by external stimuli (light, radiation, ultrasound, magnetic field, microwave, electric field, and radiofrequency). Furthermore, biosafety issues of energy‐converting nanomedicine related to future clinical translation are also addressed. Finally, the potential challenges and prospects of energy‐converting nanomedicine for future clinical translation are discussed.     

Swelling and diffusion of PNIPA-based gels for localized chemotherapy and hyperthermia

This paper presents the results of an experimental study of the swelling and diffusion of poly(N-iso-propyl-acrylamide) PNIPA-based gels with the potential for applications in bio-micro-electro-mechanical systems (BioMEMS) for localized cancer treatment that involves both chemotherapy and hyperthermia. The swelling due to the uptake of water, rhodamine dye and the cancer drug, paclitaxel, are studied using weight gain experiments that are conducted over a range of temperatures in which hyperthermia can occur during drug delivery. The release of rhodamine dye and paclitaxel is also elucidated by considering their diffusion through the gels. The underlying mechanisms of diffusion and swelling are discussed over a temperature range in which synergistic cancer treatment can be effected by the combined use of hyperthermia and chemotherapy.