Spectrometer based on a compact disordered multi-mode interferometer.

We present a compact, CMOS compatible, photonic integrated circuit (PIC) based spectrometer that combines a dispersive array element of SiO2-filled scattering holes within a multimode interferometer (MMI) fabricated on the silicon-on-insulator (SOI) platform. The spectrometer has a bandwidth of 67 nm, a lower bandwidth limit of 1 nm, and a peak-to-peak resolution of 3 nm for wavelengths around 1310 nm.

Ultrasmall porphyrin-silica core-shell dots for enhanced fluorescence imaging-guided cancer photodynamic therapy.

Clinically used small-molecular photosensitizers (PSs) for photodynamic therapy (PDT) share similar disadvantages, such as the lack of selectivity towards cancer cells, short blood circulation time, life-threatening phototoxicity, and low physiological solubility. To overcome such limitations, the present study capitalizes on the synthesis of ultra-small hydrophilic porphyrin-based silica nanoparticles (core-shell porphyrin-silica dots; PSDs) to enhance the treatment outcomes of cancer via PDT. These ultra-small PSDs, with a hydrodynamic diameter less than 7 nm, have an excellent aqueous solubility in water (porphyrin; TPPS3-NH2) and enhanced tumor accumulation therefore exhibiting enhanced fluorescence imaging-guided PDT in breast cancer cells. Besides ultra-small size, such PSDs also displayed an excellent biocompatibility and negligible dark cytotoxicity in vitro. Moreover, PSDs were also found to be stable in other physiological solutions as a function of time. The fluorescence imaging of porphyrin revealed a prolonged residence time of PSDs in tumor regions, reduced accumulation in vital organs, and rapid renal clearance upon intravenous injection. The in vivo study further revealed reduced tumor growth in 4T1 tumor-bearing bulb mice after laser irradiation explaining the excellent photodynamic therapeutic efficacy of ultra-small PSDs. Thus, ultrasmall hydrophilic PSDs combined with excellent imaging-guided therapeutic abilities and renal clearance behavior represent a promising platform for cancer imaging and therapy.

Suppression of neurotransmission on gonadotropin-releasing hormone neurons in letrozole-induced polycystic ovary syndrome: A mouse model.

Objective: Polycystic ovarian syndrome (PCOS) is a heterogeneous endocrine disorder in reproductive-age women, characterized by the accretion of small cystic follicles in the ovary associated with chronic anovulation and overproduction of androgens. Ovarian function in all mammals is controlled by gonadotropin-releasing hormone (GnRH) neurons, which are the central regulator of the hypothalamic-pituitary-gonadal (HPG) axis. However, the impact on the neurotransmitter system regulating GnRH neuronal function in the letrozole-induced PCOS mouse model remains unclear. Methods: In this study, we compared the response of various neurotransmitters and neurosteroids regulating GnRH neuronal activities between letrozole-induced PCOS and normal mice via electrophysiological techniques. Results: Response to neurotransmitter systems like GABAergic, glutamatergic and kisspeptinergic were suppressed in letrozole-fed compared to normal mice. In addition, neurosteroids tetrahydrodeoxycorticosterone (THDOC) and 4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridine-3-ol (THIP) mediated response on GnRH neurons were significantly smaller on letrozole-fed mice compared to normal mice. Furthermore, we also found that letrozole-fed mice showed irregularity in the estrous cycle, increased body weight, and anovulation in female mice. Conclusion: These findings suggest that PCOS is an endocrine disorder that may directly affect the neurotransmitter system regulating GnRH neuronal activity at the hypothalamic level and impact reproductive physiology.

Complementing Cancer Photodynamic Therapy with Ferroptosis through Iron Oxide Loaded Porphyrin-Grafted Lipid Nanoparticles.

Nanomaterials that combine multimodality imaging and therapeutic functions within a single nanoplatform have drawn extensive attention for molecular medicines and biological applications. Herein, we report a theranostic nanoplatform based on a relatively smaller (<20 nm) iron oxide loaded porphyrin-grafted lipid nanoparticles (Fe3O4@PGL NPs). The amphiphilic PGL easily self-assembled on the hydrophobic exterior surface of ultrasmall Fe3O4 NPs, resulting in a final ultrasmall Fe3O4@PGL NPs with diameter of ∼10 nm. The excellent self-assembling nature of the as-synthesized PGL NPs facilitated a higher loading of porphyrins, showed a negligible dark toxicity, and demonstrated an excellent photodynamic effect against HT-29 cancer cells in vitro. The in vivo experimental results further confirmed that Fe3O4@PGL NPs were ideally qualified for both the fluorescence and magnetic resonance (MR) imaging guided nanoplatforms to track the biodistribution and therapeutic responses of NPs as well as to simultaneously trigger the generation of highly cytotoxic reactive oxygen species (ROS) necessary for excellent photodynamic therapy (PDT). After recording convincing therapeutic responses, we further evaluated the ability of Fe3O4@PGL NPs/Fe3O4@Lipid NPs for ferroptosis therapy (FT) via tumor microenvironment (TME) modulation for improved anticancer activity. We hypothesized that tumor-associated macrophages (TAMs) could significantly improve the efficacy of FT by accelerating the Fenton reaction in vitro. In our results, the Fe ions released in vitro directly contributed to the Fenton reaction, whereas the presence of RAW 264.7 macrophages further accelerated the ROS generation as observed by the fluorescence imaging. The significant increase in the ROS during the coincubation of NPs, endocytosed by HT-29 cells and RAW264.7 cells, further induced increased cellular toxicity of cancer cells.

Non-diffracting beam generated from a photonic integrated circuit based axicon-like lens.

We demonstrate an on-chip silicon-on-insulator (SOI) device to generate a non-diffracting beam of ≈850 µm length from a diffractive axicon-like lens etched using a low resolution (200 nm feature size, 250 nm gap) deep-ultraviolet lithographic fabrication. The device consists of circular gratings with seven stages of 1x2 multimode interferometers. We present a technique to apodize the gratings azimuthally by breaking up the circles into arcs which successfully increased the penetration depth in the gratings from ≈5 µm to ≈60 µm. We characterize the device's performance by coupling 1300±50 nm swept source laser in to the chip from the axicon and measuring the out-coupled light from a grating coupler. Further, we also present the implementation of balanced homodyne detection method for the spectral characterization of the device and show that the position of the output lobe of the axicon does not change significantly with wavelength.

Perfluorocarbon@Porphyrin Nanoparticles for Tumor Hypoxia Relief to Enhance Photodynamic Therapy against Liver Metastasis of Colon Cancer.

Photodynamic therapy (PDT) shows great promise for the treatment of colon cancer. However, practically, it is a great challenge to use a nanocarrier for the codelivery of both the photosensitizer and oxygen to improve PDT against PDT-induced hypoxia, which is closely related to tumor metastasis. Hence, an effective strategy was proposed to develop an oxygen self-supplemented PDT nanocarrier based on the ultrasonic dispersion of perfluorooctyl bromide (PFOB) liquid into the preformed porphyrin grafted lipid (PGL) nanoparticles (NPs) with high porphyrin loading content of 38.5%, followed by entrapping oxygen. Interestingly, the orderly arranging mode of porphyrins and alkyl chains in PGL NPs not only guarantees a high efficacy of singlet oxygen generation but also reduces fluorescence loss of porphyrins to enable PGL NPs to be highly fluorescent. More importantly, PFOB liquid was stabilized inside PGL NPs with an ultrahigh loading content of 98.15% due to the strong hydrophobic interaction between PGL and PFOB molecules, facilitating efficient oxygen delivery. Both in vitro and in vivo results demonstrated that the obtained O2@PFOB@PGL NPs could act as a prominent oxygen reservoir and effectively replenish oxygen into the hypoxic tumors with no need for external stimulation, conducive to augmented singlet oxygen generation, hypoxia relief, and subsequent downregulation of COX-2 expression. As a result, the use of O2@PFOB@PGL NPs for hypoxia relief dramatically inhibits tumor growth and liver metastasis in an HT-29 colon cancer mouse model. In addition, the O2@PFOB@PGL NPs could serve as a bimodal contrast agent to enhance fluorescence and CT imaging, visualizing nanoparticle accumulation to guide the subsequent laser irradiation for precise PDT.

Enhancing cancer therapeutic efficacy through ultrasound-mediated micro-to-nano conversion.

Over the last century, significant progress has been made towards the development of microbubbles (MBs) as a contrast agent for imaging and as a carrier for the delivery of therapeutic moieties. The unparalleled ability of MBs to respond to ultrasound (US) render them advantageous for molecular imaging, and US-responsive targeted delivery. However, the use of MBs has broadened far beyond the imaging contrast agent or drug delivery system alone. Notably, there has been an enormous surge in the design and fabrication of multimodal MBs for cancer therapy. Furthermore, MBs in the presence of the US has unique ability to convert itself from the micro to nanoscale, which offers diagnostic and therapeutic ability in both dimensions. In this review, we summarize the design considerations of MBs, with particular emphasize on their size and composition. In addition, different MBs formulations are discussed in the context of their current progress as an imaging contrast agent and a vehicle for drug/gene delivery. We further highlight recent advancements in the micro-to-nano conversion of MBs and their potential application for cancer theranostics. This article is characterized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Harnessing platelets as functional vectors for contrast enhanced ultrasound imaging and fluorescence imaging.

The recent progress in the development of highly biocompatible nanoplatforms mostly encompasses the use of biological excipients such as red blood cells, cancer cell membranes, and also platelets. Such specialized vectors, if mimicked correctly, have intrinsic ability to navigate through the biological system and perform their intended action without eliciting any cascade of inflammatory processes. Naturally, platelets have been found to accumulate in the wound sites and also interact with circulating tumor cells (CTCs). Inspired by the targeting ability of platelets and the clinical success of ultrasound, herein we developed a novel ultrasound contrast agent (UCA) by backfilling of an insoluble gas into the platelets after lyophilization ex vivo. The as-prepared platelet-based ultrasound contrast agent (P-UCA) disguised the structural integrity of the natural platelets with an average diameter of 3.1 ± 0.4 µm, and could enhance the ultrasound signal both in vitro and in vivo. Besides, we further evaluated that such platelet particles could facilitate active loading of ICG molecules for prolonged in vivo fluorescence imaging compared to the free ICG. Taking all the results together, we established that biological structures such as platelets could be repurposed ex vivo as a"shell" to encapsulate gas and be further extended to load ICG for real-time ultrasound and fluorescence imaging respectively. This not only indicates many potential uses of these MBs in the diagnosis of platelet-related diseases, such as vascular damage, thrombosis, and atherosclerosis, but also serves as a powerful platform with multimodal theranostic capability after active loading of a variety of therapeutic and diagnostic agents.

Photothermal therapy and photoacoustic imaging via nanotheranostics in fighting cancer.

The nonradiative conversion of light energy into heat (photothermal therapy, PTT) or sound energy (photoacoustic imaging, PAI) has been intensively investigated for the treatment and diagnosis of cancer, respectively. By taking advantage of nanocarriers, both imaging and therapeutic functions together with enhanced tumour accumulation have been thoroughly studied to improve the pre-clinical efficiency of PAI and PTT. In this review, we first summarize the development of inorganic and organic nano photothermal transduction agents (PTAs) and strategies for improving the PTT outcomes, including applying appropriate laser dosage, guiding the treatment via imaging techniques, developing PTAs with absorption in the second NIR window, increasing photothermal conversion efficiency (PCE), and also increasing the accumulation of PTAs in tumours. Second, we introduce the advantages of combining PTT with other therapies in cancer treatment. Third, the emerging applications of PAI in cancer-related research are exemplified. Finally, the perspectives and challenges of PTT and PAI for combating cancer, especially regarding their clinical translation, are discussed. We believe that PTT and PAI having noteworthy features would become promising next-generation non-invasive cancer theranostic techniques and improve our ability to combat cancers.

Self-assembly of porphyrin-grafted lipid into nanoparticles encapsulating doxorubicin for synergistic chemo-photodynamic therapy and fluorescence imaging.

The limited clinical efficacy of monotherapies in the clinic has urged the development of novel combination platforms. Taking advantage of light-triggered photodynamic treatment combined together with the controlled release of nanomedicine, it has been possible to treat cancer without eliciting any adverse effects. However, the challenges imposed by limited drug loading capacity and complex synthesis process of organic nanoparticles (NPs) have seriously impeded advances in chemo-photodynamic combination therapy. In this experiment, we utilize our previously synthesized porphyrin-grafted lipid (PGL) NPs to load highly effective chemotherapeutic drug, doxorubicin (DOX) for synergistic chemo-photodynamic therapy. Methods: A relatively simple and inexpensive rapid injection method was used to prepare porphyrin-grafted lipid (PGL) NPs. The self-assembled PGL NPs were used further to encapsulate DOX via a pH-gradient loading protocol. The self-assembled liposome-like PGL NPs having a hydrophilic core were optimized to load DOX at an encapsulation efficiency (EE) of ~99%. The resultant PGL-DOX NPs were intact, highly stable and importantly these NPs successfully escaped from the endo-lysosomal compartment after laser irradiation to release DOX in the cytosol. The therapeutic efficacy of the aforementioned formulation was validated both in vitro and in vivo. Results: PGL-DOX NPs demonstrated excellent cellular uptake, chemo-photodynamic response, and fluorescence imaging ability in different cell lines. Under laser irradiation, cells treated with a low molar concentration of PGL-DOX NPs reduced cell viability significantly. Moreover, in vivo experiments conducted in a xenograft mouse model further demonstrated the excellent tumor accumulation capability of PGL-DOX NPs driven by the enhanced permeability and retention (EPR) effect. Through fluorescence imaging, the biodistribution of PGL-DOX NPs in tumor and major organs was also easily monitored in real time in vivo. The inherent ability of porphyrin to generate ROS under laser irradiation combined with the cytotoxic effect of the anticancer drug DOX significantly suppressed tumor growth in vivo. Conclusion: In summary, the PGL-DOX NPs combined chemo-photodynamic nanoplatform may serve as a potential candidate for cancer theranostics.

Amphiphilic Drug Conjugates as Nanomedicines for Combined Cancer Therapy.

Chemotherapy suffers from some limitations such as poor bioavailability, rapid clearance from blood, poor cellular uptake, low tumor accumulation, severe side effects on healthy tissues and most importantly multidrug resistance (MDR) in cancer cells. Nowadays, a series of smart drug delivery system (DDS) based on amphiphilic drug conjugates (ADCs) has been developed to solve these issues, including polymer-drug conjugate (PDC), phospholipid-mimicking prodrugs, peptide-drug conjugates (PepDCs), pure nanodrug (PND), amphiphilic drug-drug conjugate (ADDC), and Janus drug-drug conjugate (JDDC). These ADCs can self-assemble into nanoparticles (NPs) or microbubbles (MBs) for targeted drug delivery by minimizing the net amount of excipients, realizing great goals, such as stealth behavior and physical integrity, high drug loading content, no premature leakage, long blood circulation time, fixed drug combination, and controlled drug-release kinetics. Besides, these self-assembled systems can be further used to load additional therapeutic agents and imaging contrast agents for combined therapy, personalized monitoring of in vivo tumor targeting, and the pharmacokinetics of drugs for predicting the therapeutic outcome. In this review, we will summarize the latest progress in the development of ADCs based combination chemotherapy and discuss the important roles for overcoming the tumor MDR.

Cerasomes and Bicelles: Hybrid Bilayered Nanostructures With Silica-Like Surface in Cancer Theranostics.

Over years, theranostic nanoplatforms have provided a new avenue for the diagnosis and treatment of various cancer types. To this end, a myriad of nanocarriers such as polymeric micelles, liposomes, and inorganic nanoparticles (NPs) with distinct physiochemical and biological properties are routinely investigated for preclinical and clinical studies. So far, liposomes have received great attention for various biomedical applications, however, it still suffers from insufficient morphological stability. On the other hand, inorganic NPs depicting excellent therapeutic ability have failed to address biocompatibility issues. This has raised a serious concern about the clinical approval of multifunctional organic or inorganic-based theranostic agents. Recently, partially silica coated nanohybrids such as cerasomes and bicelles demonstrating both diagnostic and therapeutic ability in a single system, have drawn profound attention as a fascinating novel drug delivery system. Compared with traditional liposomal or inorganic-based nanoformulations, this new and highly stable nanocarriers integrates the functional attributes of biomimetic liposomes and silica NPs, therefore, synergize strengths and functions, or even surpass weaknesses of individual components. This review at its best enlightens the emerging concept of such partially silica coated nanohybrids, fabrication strategies, and theranostic opportunities to combat cancer and related diseases.

Nanotherapeutic approaches targeting angiogenesis and immune dysfunction in tumor microenvironment.

Tumor microenvironment (TME) comprising cellular and non-cellular components is a major source of cancer hallmarks. Notably, angiogenesis responsible for normal physiological remodeling process can otherwise harness vessel abnormalities during tumorigenesis eliciting severe therapeutic inefficiency. Currently, FDA approved antiangiogenic drugs have only shown modest clinical success owing to tumor hypoxia, antiangiogenic therapeutic resistance, and limited knowledge in understanding TME. In order to overcome these limitations, targeting angiogenesis combined with immunosuppressive TME could offer potential therapeutic opportunities. Indeed, these therapeutic approaches can be further revisited with the advent of nanotechnology that can target the key cellular components of TME and tumor cells more precisely. Synergetic targeting without eliciting systemic toxicity achieved by integration of antiangiogenic and immunotherapy in a single nanoplatform is vital for therapeutic success. In this review, we will discuss the most promising nanotechnological advancements oriented to modulate the immunosuppressive TME in association with antiangiogenic therapy that has gained immense popularity in cancer treatment.

Recent advances in anti-angiogenic nanomedicines for cancer therapy.

Angiogenesis is a normal physiological remodeling process initiated at the time of embryonic development and lessened with the progress of time. Nevertheless, continuous activation of stringent signaling pathways and proangiogenic factors during tumorigenesis (a pathological condition) instigates serious vessel abnormalities eliciting severe therapeutic inefficiency. In principle, systemic delivery of robust antiangiogenic drugs often fails to reach these abnormal tumor vessels depicting poor pharmacokinetics, biodistribution profiles and adverse side effects in vivo. Recently, the advent of nanotechnology has offered numerous advantages encompassing high drug payloads, increased blood half-life and reduced toxicity; likewise, such nanomedicines can also target the key components of the tumor microenvironment and tumor cells effectively. Synergistic targeting of malignant cells and vessel abnormalities via integration of antiangiogenic and other potent combinational regimens in a single nanoplatform can revitalize therapeutic success. In this review, we will discuss the most promising nanotechnological advancements rehabilitating angiogenesis, and emerging nanocarriers comprehending gene delivery, stem cell therapies and dynamic combinational strategies for effective anticancer therapy.

Cyanine based Nanoprobes for Cancer Theranostics.

Cyanine dyes are greatly accredited in the development of non-invasive therapy that can "see" and "treat" tumor cells via imaging, photothermal and photodynamic treatment. However, these dyes suffer from poor pharmacokinetics inducing severe toxicity to normal cells, insufficient accumulation in tumor regions and rapid photobleaching when delivered in free forms. Nanoparticles engineered to encapsulate these compounds and delivering them into tumor regions have increased rapidly, however, so far, these nanoparticles (NPs) have not proved to be so effective to circumvent existing challenges. Newly designed multifunctional smart nanocarriers that can improve phototherapeutic properties of these dyes, co-encapsulate multiple potent therapeutic compounds, and simultaneously overcome limitations related to tumor recurrence, metastases, limited intracellular uptake, and tumor hypoxia have potential to revolutionize modern paradigm of cancer therapy. Such cyanine based multifunctional nanocarriers integrating imaging and therapy in a single platform can effectively produce better clinical outcomes in cancer treatment. This review briefly summarizes recent advancements of cyanine nanoprobes that are currently used as imaging/phototherapeutic agents in unimodal/bimodal/trimodal cancer theranostics. Finally, we conclude this review by addressing challenges of pre-existing therapeutic systems and designs adopted to overcome them with a brief insight assimilating future perspective of emerging cyanine-based NPs in cancer theranostics.

A Novel Cyanine and Porphyrin Based Theranostic Nanoagent for Near-Infrared Fluorescence Imaging Guided Synergistic Phototherapy.

Design and synthesis of multifunctional organic nanoparticles (NPs) for non-invasive diagnosis and phototherapy of cancer are widely acknowledged. However, limited drug loading of NPs are major limitations for attaining synergistic effect in most of the combination therapies. Herein, a novel cyanine-porphyrin combined NPs (PGL-DiR) was fabricated in a simple and inexpensive way for the treatment of prostate cancer. A most commonly used near-infrared fluorescent (NIRF) cyanine dye, DiR was chosen as a photothermal agent to encapsulate in a porphyrin grafted lipid (PGL) (PGL-DiR) NPs of average size 156.25±31.31 nm. Unlike conventional liposomes, the self-assembled PGL morphology revealed encapsulation efficiency of DiR higher than 98%. However, as observed in vitro, DiR loading contents could trigger obvious quenching of singlet oxygen (1O2) by PGL thereby reducing the efficiency of PDT. Nevertheless, after successful photobleaching of DiR, as prepared PGL-DiR NP could facilitate enhanced synergistic photothermal and photodynamic (PTT-PDT) therapy both in vitro and in vivo. After intravenous administration of PGL-DiR NPs in a PC3 tumor xenograft mice, a high accumulation in tumor until 24 hrs was clearly evident via NIRF imaging. With the successive laser irradiation, these NPs effectively suppressed the tumor growth synergistically as PTT < PDT < PTT + PDT while compared to monotherapies such as PTT or PDT alone. These results demonstrated that as prepared PGL-NPs could serve as an excellent theranostic agent both in vitro and in vivo for combined therapy of prostate cancer.

Non-genomic action of vitamin D3 on N-methyl-D-aspartate and kainate receptor-mediated actions in juvenile gonadotrophin-releasing hormone neurons.

Vitamin D is a versatile signalling molecule that plays a critical role in calcium homeostasis. There are several studies showing the genomic action of vitamin D in the control of reproduction; however, the quick non-genomic action of vitamin D at the hypothalamic level is not well understood. Therefore, to investigate the effect of vitamin D on juvenile gonadotrophin-releasing hormone (GnRH) neurons, excitatory neurotransmitter receptor agonists N-methyl-D-aspartate (NMDA, 30µM) and kainate (10µM) were applied in the absence or in the presence of vitamin D3 (VitaD3, 10nM). The NMDA-mediated responses were decreased by VitaD3 in the absence and in the presence of tetrodotoxin (TTX), a sodium-channel blocker, with the mean relative inward current being 0.56±0.07 and 0.66±0.07 (P<0.05), respectively. In addition, VitaD3 induced a decrease in the frequency of gamma-aminobutyric acid mediated (GABAergic) spontaneous postsynaptic currents and spontaneous postsynaptic currents induced by NMDA application with a mean relative frequency of 0.595±0.07 and 0.56±0.09, respectively. Further, VitaD3 decreased the kainate-induced inward currents in the absence and in the presence of TTX with a relative inward current of 0.64±0.06 and 0.68±0.06, respectively (P<0.05). These results suggest that VitaD3 has a non-genomic action and partially inhibits the NMDA and kainate receptor-mediated actions of GnRH neurons, suggesting that VitaD3 may regulate the hypothalamic-pituitary-gonadal (HPG) axis at the time of pubertal development.