Multifunctional Protein Hybrid Nanoplatform for Synergetic Photodynamic-Chemotherapy of Malignant Carcinoma by Homologous Targeting Combined with Oxygen Transport.

Photodynamic therapy (PDT) under hypoxic conditions and drug resistance in chemotherapy are perplexing problems in anti-tumor treatment. In addition, central nervous system neoplasm-targeted nanoplatforms are urgently required. To address these issues, a new multi-functional protein hybrid nanoplatform is designed, consisting of transferrin (TFR) as the multicategory solid tumor recognizer and hemoglobin for oxygen supply (ODP-TH). This protein hybrid framework encapsulates the photosensitizer protoporphyrin IX (PpIX) and chemotherapeutic agent doxorubicin (Dox), which are attached by a glutathione-responsive disulfide bond. Mechanistically, ODP-TH crosses the blood-brain barrier (BBB) and specifically aggregated in hypoxic tumors via protein homology recognition. Oxygen and encapsulated drugs ultimately promote a therapeutic effect by down-regulating the abundance of multidrug resistance gene 1 (MDR1) and hypoxia-inducible factor-1-α (HIF-1α). The results reveal that ODP-TH achieves oxygen transport and protein homology recognition in the hypoxic tumor occupation. Indeed, compared with traditional photodynamic chemotherapy, ODP-TH achieves a more efficient tumor-inhibiting effect. This study not only overcomes the hypoxia-related inhibition in combination therapy by targeted oxygen transport but also achieves an effective treatment of multiple tumors, such as breast cancer and glioma, providing a new concept for the construction of a promising multi-functional targeted and intensive anti-tumor nanoplatform.

Triple-Configurational Magnetic Robot for Targeted Drug Delivery and Sustained Release.

Active targeted therapy for bowel cancer using untethered microrobots has attracted extensive attention. However, traditional microrobots face challenges, such as issues of mobility, biocompatibility, drug loading, sustained-release capabilities, and targeting accuracy. Here, we propose an untethered triple-configurational magnetic robot (TCMR) that is composed of three geometrically nested parts: actuation and guarding, anchoring and seeding, and drug release part. A targeting magnetic driving system actuates the TCMR along the predetermined trajectory to the target position. The pH-sensitive actuation and guarding part formed by electrodeposition is degraded in the intestinal environment and separates from the two other parts. A majority of magnetic nanoparticles encapsulated in this part are retrieved. The anchoring and seeding part anchors the lesion area and seeds the drug release part in the gaps of intestinal villi by hydrolysis. Ultimately, the drug release part containing the therapeutic completes the sustained release to prolong the duration of the therapeutic agent. Cytotoxicity and therapeutic tests reveal that TCMRs are biocompatible and suitable for targeted therapy and have good therapeutic performance. The newly designed TCMR will provide new ideas for targeted therapy, thus expanding the application scope of robotics technology in the biomedical field.

Near-Infrared-Light Remote-Controlled Activation of Cancer Immunotherapy Using Photothermal Conjugated Polymer Nanoparticles.

Remote control of the therapeutic process is an ideal strategy for maximizing efficacy and avoiding side effects, especially for cancer immunotherapy. Herein, a conjugated polymer nanoparticles (CPNs)-mediated optogenetic system for in situ activation of immunotherapy under near-infrared laser irradiation is reported. This system is composed of photothermal CPNs and interferon-gamma (IFN-γ) plasmid driven by heat shock promoter HSP70. The photothermally responsive CPNs serve as a photo-heat nanotransducer to trigger the gene transcription of IFN-γ cytokine. The secreted IFN-γ from cancer cells can sufficiently elicit surrounding tumor-associated macrophages activation through IFN-γ-JAK-STAT1 transcription-factor signaling pathway and finally induce cancer cell killing by immunotherapy. Therefore, this synergetic optogenetic system provides a promising approach to remotely control the process of cancer immunotherapy.

Targeting Brain Cancer Cells by Nanorobot, a Promising Nanovehicle: New Challenges and Future Perspectives.

Advances in the field of nanotechnology and nanomedicine have resulted in the development of novel diagnosis and potential treatment for different types of diseases, including brain cancer. Nanomaterials are smaller in size, having a higher area to volume ratio, and can be conjugated with other molecules. Nanomaterials are excellent transport vehicles that can easily cross the extracellular matrix, cell membrane, and by crossing the blood-brain barrier, they can deliver the drugs to the remote and inaccessible internal parts of the brain. A nanorobot is a device that ranges in size from 0.1-10 micrometer and resembles in size to a red blood cell. Nanorobot is a smart robot that can patrol the bloodstream, recognize the specific target, and can release a tiny but deadly cargo of drugs or nanoparticles to kill the cancer cells. With the multidisciplinary approach of biotechnology, molecular biology, electronics, bioinformatics-based computer simulation, and molecular medicine, a self-sufficient nanodevice can be developed for brain tumor diagnosis and treatment. This review article discusses the current applications and future promises of nanorobots in brain cancer therapy.

Dual Size/Charge-Switchable Nanocatalytic Medicine for Deep Tumor Therapy.

Elevating intratumoral levels of highly toxic reactive oxygen species (ROS) by nanocatalytic medicine for tumor-specific therapy without using conventional toxic chemodrugs is recently of considerable interest, which, however, still suffers from less satisfactory therapeutic efficacy due to the relatively poor accumulation at the tumor site and largely blocked intratumoral infiltration of nanomedicines. Herein, an ultrasound (US)-triggered dual size/charge-switchable nanocatalytic medicine, designated as Cu-LDH/HMME@Lips, is constructed for deep solid tumor therapy via catalytic ROS generations. The negatively charged liposome outer-layer of the nanomedicine enables much-prolonged blood circulation for significantly enhanced tumoral accumulation, while the positively charged Fenton-like catalyst Cu-LDH released from the liposome under the US stimulation demonstrates much enhanced intratumoral penetration via transcytosis. In the meantime, the co-released sonosensitizer hematoporphyrin monomethyl ether (HMME) catalyze the singlet oxygen (1O2) generation upon the US irradiation, and deep-tumoral infiltrated Cu-LDH catalyzes the H2O2 decomposition to produce highly toxic hydroxyl radical (·OH) specifically within the mildly acidic tumor microenvironment (TME). The efficient intratumoral accumulation and penetration via the dual size/charge switching mechanism, and the ROS generations by both sonosensitization and Fenton-like reactions, ensures the high therapeutic efficacy for the deep tumor therapy by the nanocatalytic medicine.

NIR-Responsive Spatiotemporally Controlled Cyanobacteria Micro-Nanodevice for Intensity-Modulated Chemotherapeutics in Rheumatoid Arthritis.

The expression of hypoxia-inducible factor-1α (HIF-1α) is upregulated in hypoxic environments at the lesions of rheumatoid arthritis (RA), which promoted the polarization of proinflammatory M1 macrophages and inhibited the differentiation of anti-inflammatory M2 to deteriorate synovial inflammation. Since oxygen scarcity at the joints causes an imbalance of macrophages M1 and M2, herein, we designed a cyanobacteria micro-nanodevice that can be spatiotemporally controlled in vivo to continuously producing oxygen in the RA joints for the downregulation of the expression of HIF-1α, thereby reducing the amounts of M1 macrophages and inducing the polarization of M2 macrophages for chemically sensitized RA treatment. The forthputting of temperature-sensitive hydrogel guaranteed the safety of cyanobacteria micro-nanodevice in vivo. Furthermore, the oxygen produced by cyanobacteria micro-nanodevice in a sustained manner enhanced the therapeutic effect of the antirheumatic drug methotrexate (MTX) and discouraged inflammation and bone erosion at RA. This study provided a new approach for the RA treatment of spatiotemporal-controlled release of oxygen in vitro.

Therapeutic strategies of iron-based nanomaterials for cancer therapy.

Iron-based nanomaterials have appeared in various cancer treatments owing to their promising functions and safety. Various sophisticated iron-based nanomaterials have been designed to exhibit great therapeutic effects through different strategies. Given the rapid progression, there is a great need to integrate the recent advances to learn about the latest innovation in this field. In this review, we classified the strategies of iron-based nanomaterials for cancer treatment into the following categories: immunotherapy, ferroptosis, magnetic hyperthermia and magneto-mechanical destruction. On the one hand, we discussed the underlining mechanism of iron-based nanomaterials in these therapies and applications; on the other hand, we analyzed the feasible combination of these applications and other therapies. Finally, the current challenges and expectation of iron-based nanomaterials in this field were highlighted.

New insight into the synthesis, morphological architectures and biomedical applications of elemental selenium nanostructures.

Selenium nanoparticles have been shown to be versatile in their applications by being used in catalysis, solar cells, electronic devices and especially in medical applications such as antiviral, anticancer, antitumor and antibacterial agents in different concentrations. They have also shown enhanced drug and gene delivery by conjugating with drug molecules and showing high synergistic effects. After realising their usefulness in the biomedical field, we have made a sincere effort to correlate and consolidate the recent developments made in their synthesis methods, structural features and biological applications. This review paper highlights the three preparation methods, being the chemical, physical and biological approaches. The variation in the different techniques employed for synthesis and the different parameters and process conditions dictating the size and morphology are discussed. The importance and influence of various reducing agents used in the chemical method, pulsed laser ablation technique in the physical method and green plant extract microorganism in the biological approach have been explored. The detailed structural features of trigonal crystalline structures, with different nanoscaled morphologies such as nano spheres, rods, wires, tubes and belts have also been explored. An overview of selenium nanoparticle activity in various biomedical applications such as anticancer, antioxidant, antiviral, antibacterial, antifungal, antiparasitic, and antidiabetics is discussed.

Graphene-semiconductor nanocomposites for cancer phototherapy.

Being a carbon-based hybrid, graphene-semiconductor composites have attracted considerable attention in recent decades owing to their potential features such as high photosensitivity, extended light absorption, and effective separation of charge carriers, thus have been regarded as a promising platform for environmental and biomedical applications, respectively. In this mini-review, we first summarized the recent advancements in the development of graphene-based semiconductor nanocomposites via sol-gel, solution mixing, in situ growth, hydrothermal, and solvothermal approaches, and then comprehensively reviewed their potential light activated cancer phototherapeutic applications. Finally, we rationally analyze the current challenges and new perspectives for the future development of more effective phototherapeutic nanoagents. We hope to offer enriched information to harvest the utmost fascinating properties of graphene as a platform to construct efficient graphene/semiconductor hybrids for cancer phototherapy.

Ultrasound activated nanosensitizers for sonodynamic therapy and theranostics.

Sonodynamic therapy (SDT) is a promising non-invasive therapeutic modality with an extensive application prospect. Due to the engineerable nature of nanotechnology, nanosensitizers with predominant advantages of increased SDT efficacy and targeting specificity have attracted more and more research recently. In this review, we introduce the current investigations of nanosonosensitizers and focus on the potential strategies on nanoparticles-assisted sonosensitizers to enhance SDT efficacy. We extensively discuss the biomedical applications of ultrasound activated nanosonosensitizers in SDT and theranostics.

Recent Advances in Microfluidics for the Preparation of Drug and Gene Delivery Systems.

Drug delivery systems (DDSs) have great potential for improving the treatment of several diseases, especially microbial infections and cancers. However, the formulation procedures of DDSs remain challenging, especially at the nanoscale. Reducing batch-to-batch variation and enhancing production rate are some of the essential requirements for accelerating the translation of DDSs from a small scale to an industrial level. Microfluidic technologies have emerged as an alternative to the conventional bench methods to address these issues. By providing precise control over the fluid flows and rapid mixing, microfluidic systems can be used to fabricate and engineer different types of DDSs with specific properties for efficient delivery of a wide range of drugs and genetic materials. This review discusses the principles of controlled rapid mixing that have been employed in different microfluidic strategies for producing DDSs. Moreover, the impact of the microfluidic device design and parameters on the type and properties of DDS formulations was assessed, and recent applications in drug and gene delivery were also considered.

Pharmacophore hybridisation and nanoscale assembly to discover self-delivering lysosomotropic new-chemical entities for cancer therapy.

Integration of the unique advantages of the fields of drug discovery and drug delivery is invaluable for the advancement of drug development. Here we propose a self-delivering one-component new-chemical-entity nanomedicine (ONN) strategy to improve cancer therapy through incorporation of the self-assembly principle into drug design. A lysosomotropic detergent (MSDH) and an autophagy inhibitor (Lys05) are hybridised to develop bisaminoquinoline derivatives that can intrinsically form nanoassemblies. The selected BAQ12 and BAQ13 ONNs are highly effective in inducing lysosomal disruption, lysosomal dysfunction and autophagy blockade and exhibit 30-fold higher antiproliferative activity than hydroxychloroquine used in clinical trials. These single-drug nanoparticles demonstrate excellent pharmacokinetic and toxicological profiles and dramatic antitumour efficacy in vivo. In addition, they are able to encapsulate and deliver additional drugs to tumour sites and are thus promising agents for autophagy inhibition-based combination therapy. Given their transdisciplinary advantages, these BAQ ONNs have enormous potential to improve cancer therapy.

Using microfluidics for scalable manufacturing of nanomedicines from bench to GMP: A case study using protein-loaded liposomes.

Nanomedicines are well recognised for their ability to improve therapeutic outcomes. Yet, due to their complexity, nanomedicines are challenging and costly to produce using traditional manufacturing methods. For nanomedicines to be widely exploited, new manufacturing technologies must be adopted to reduce development costs and provide a consistent product. Within this study, we investigate microfluidic manufacture of nanomedicines. Using protein-loaded liposomes as a case study, we manufacture liposomes with tightly defined physico-chemical attributes (size, PDI, protein loading and release) from small-scale (1 mL) through to GMP volume production (200 mL/min). To achieve this, we investigate two different laminar flow microfluidic cartridge designs (based on a staggered herringbone design and a novel toroidal mixer design); for the first time we demonstrate the use of a new microfluidic cartridge design which delivers seamless scale-up production from bench-scale (12 mL/min) through GMP production requirements of over 20 L/h using the same standardised normal operating parameters. We also outline the application of tangential flow filtration for down-stream processing and high product yield. This work confirms that defined liposome products can be manufactured rapidly and reproducibly using a scale-independent production process, thereby de-risking the journey from bench to approved product.

Lab-On-A-Chip for the Development of Pro-/Anti-Angiogenic Nanomedicines to Treat Brain Diseases.

There is a huge demand for pro-/anti-angiogenic nanomedicines to treat conditions such as ischemic strokes, brain tumors, and neurodegenerative diseases such as Alzheimer's and Parkinson's. Nanomedicines are therapeutic particles in the size range of 10-1000 nm, where the drug is encapsulated into nano-capsules or adsorbed onto nano-scaffolds. They have good blood-brain barrier permeability, stability and shelf life, and able to rapidly target different sites in the brain. However, the relationship between the nanomedicines' physical and chemical properties and its ability to travel across the brain remains incompletely understood. The main challenge is the lack of a reliable drug testing model for brain angiogenesis. Recently, microfluidic platforms (known as "lab-on-a-chip" or LOCs) have been developed to mimic the brain micro-vasculature related events, such as vasculogenesis, angiogenesis, inflammation, etc. The LOCs are able to closely replicate the dynamic conditions of the human brain and could be reliable platforms for drug screening applications. There are still many technical difficulties in establishing uniform and reproducible conditions, mainly due to the extreme complexity of the human brain. In this paper, we review the prospective of LOCs in the development of nanomedicines for brain angiogenesis-related conditions.

Advances in refunctionalization of erythrocyte-based nanomedicine for enhancing cancer-targeted drug delivery.

Cancer remains a daunting and cureless disease, which is responsible for one-sixth of human deaths worldwide. These mortality rates have been expected to rise in the future due to the side effects of conventional treatments (chemotherapy, radiotherapy, and surgery), which can be addressed by applying nanomedicine. In order to escape from biological barriers, such nanomedicine should be mimicked and designed to be stealthy while navigating in the bloodstream. To achieve this, scientists take advantage of erythrocytes (red blood cells; RBCs) as drug carriers and develop RBC membrane (RBCm) coating nanotechnology. Thanks to the significant advances in nanoengineering, various facile surface functionalization methods can be applied to arm RBCm with not only targeting moieties, but also imaging agents, therapeutic agents, and nanoparticles, which are useful for theranostic nanomedicine. This review focuses on refunctionalization of erythrocyte-based nanomedicine for enhancing cancer-targeted drug delivery.

A DNA Nanodevice Simultaneously Activating the EGFR and Integrin for Enhancing Cytoskeletal Activity and Cancer Cell Treatment.

Cell-surface receptors (e.g., EGFR and integrin) and their interactions play determining roles in signal transduction and cytoskeletal activation, which affect cell attachment/detachment, invasion, motility, metastasis (intracellular), and cell-cell signaling. For instance, the interactions between the EGFR and integrin (α6ß4) may cause increased mechanical force and shear stress via enhanced cytoskeleton activation. Here, we design a DNA nanodevice (DNA-ND) that can simultaneously target the EGFR and integrin receptors on the caveolae. The piconewton (pN) forces in response to the EGFR-integrin coactivation can be sensed upon the unfolding of the DNA hairpin structure on the side arm of the device via changes of the fluorescence and plasmonic signals. We find that simultaneous activation of EGFR-integrin receptors causes enhanced signal transduction, contractions of the cells, and initiation of the biochemical pathways, thus resulting in a change of the cell division and endocytosis/exocytosis processes that affect the cell proliferation/apoptosis. The DNA-ND further enables us to visualize the cointernalization and degradation of the receptors by lysosomes, providing a novel approach toward bioimaging and mechano-pharmacology.

Multidimensional (0D-3D) nanostructures for lung cancer biomarker analysis: Comprehensive assessment on current diagnostics.

The pragmatic outcome of a lung cancer diagnosis is closely interrelated in reducing the number of fatal death caused by the world's top cancerous disease. Regardless of the advancement made in understanding lung tumor, and its multimodal treatment, in general the percentage of survival remain low. Late diagnosis of a cancerous cell in patients is the major hurdle for the above circumstances. In the new era of a lung cancer diagnosis with low cost, portable and non-invasive clinical sampling, nanotechnology is at its inflection point where current researches focus on the implementation of biosensor conjugated nanomaterials for the generation of the ideal sensing. The present review encloses the superiority of nanomaterials from zero to three-dimensional nanostructures in its discrete and nanocomposites nanotopography on sensing lung cancer biomarkers. Recent researches conducted on definitive nanomaterials and nanocomposites at multiple dimension with distinctive physiochemical property were focused to subside the cases associated with lung cancer through the development of novel biosensors. The hurdles encountered in the recent research and future preference with prognostic clinical lung cancer diagnosis using multidimensional nanomaterials and its composites are presented.

Design of nanorobots for exposing cancer cells.

We discuss in detail, the design of a nanorobot that can navigate, detect cancer cells in the blood and actuate the exposure of drugs. The nanorobot is designed with blood energy harvesting capability and the accumulation of electricity in a capacitor, which forms the main body of the nanorobot. Glucose hunger-based cancer detectors immobilized on a carbon nanotube sensor, reduces its electrical resistance when attached to a cancer cell. This mechanism in turn allows electric current to activate a nano-electrical-mechanical relay (mechanical transistor) to break the chamber ceiling exposing a drug identified by the immune system for cell elimination. This concept is in line with the effort to design an autonomous computational nanorobot for in vivo medical diagnosis and treatment. We present this facile approach to design a collective system to visualize the programmability in nanorobots. The calculations and simulation results provide a proof-of-concept towards a plausible implementation. Through this work, we present an overall picture towards an inorganic autonomous computational nanorobot for cancer diagnosis and treatment.

Nanomedicines for developing cancer nanotherapeutics: from benchtop to bedside and beyond.

Cancer is a devastating disease and remains a significant cause of mortality and morbidity in both developed and developing countries. Although there are large number of drugs that can be used for the treatment of cancer, the problem is selective and specific killing of cancerous cells without harming the normal cells. There are some biological barriers to potential drug delivery in cancer cells like hepatic, renal, abnormal vasculature, dense extracellular matrix, and high interstitial fluid pressure. The physicochemical characteristics of nanoparticles (NPs) such as size, shape, and surface charge may also have significant effects on tumor penetration. NPs coated with drug can be used to overcome these biological barriers to enhance targeted delivery. This literature survey encompasses the biological barriers to potential drug delivery in cancer cells, elaborate on designing strategies to enhance NPs penetration and distribution inside the tumor interstitium. Scientists are now doing great efforts to design next-generation of nanomedicines (NMs) that need to be better targeted with high specificity and efficacy to kill cancer cells. These challenges need to be overcome through collaborations among academia, pharmaceutical industries, and regulatory agencies to eradicate this global menace. Furthermore, this review article has critically discussed the recent developments, controversies, challenges, emerging concepts, and future perspectives in cancer NMs.

The future of robotic surgery.

How robotics could help shape the future of surgical care.