A Dual Concentration-Tailored Cytokine-Chemo Nanosystem to Alleviate Multidrug Resistance and Redirect Balance of Cancer Proliferation and Apoptosis.

Background: Cancer multidrug resistance (MDR) is an important factor that severely affects the chemotherapeutic efficacy. Among various methods to bypass MDR, usage of cytokines, such as tumor necrosis factor alpha (TNFα) is attractive, which exerts antitumor effects of immunotherapeutic response and apoptotic/proinflammatory pathways. Nevertheless, the challenges remain how to implement targeted delivery of TNFα to reduce toxicity and manifest the involved signaling mechanism that subdues MDR. Methods: We synthesized a multifunctional nanosytem, in which TNFα covalently bound to doxorubicin (Dox)-loaded pH-responsive mesoporous silica nanoparticles (MSN) through bi-functional polyethylene glycol (TNFα-PEG-MSN-Hydrazone-Dox) as a robust design to overcome MDR. Results: The salient features of this nanoplatform are: 1) by judicious tailoring of TNFα concentration conjugated on MSN, we observed it could lead to a contrary effect of either proliferation or suppression of tumor growth; 2) the MSN-TNFα at higher concentration serves multiple functions, besides tumor targeting and inducer of apoptosis through extrinsic pathway, it inhibits the expression level of p-glycoprotein (P-gp), a cell membrane protein that functions as a drug efflux pump; 3) the enormous surface area of MSN provides for TNFα functionalization, and the nanochannels accommodate chemotherapeutics, Dox; 4) targeted intracellular release of Dox through the pH-dependent cleavage of hydrazone bonds induces apoptosis by the specific intrinsic pathway; and 5) TNFα-PEG-MSN-Hydrazone-Dox (MSN-Dox-TNFα) could infiltrate deep into the 3D spheroid tumor model through disintegration of tight junction proteins. When administered intratumorally in a Dox-resistant mouse tumor model, MSN-Dox-TNFα exhibited a synergistic therapeutic effect through the collective performances of TNFα and Dox. Conclusion: We hereby develop and demonstrate a multifunctional MSN-Dox-TNFα system with concentration-tailored TNFα that can abrogate the drug resistance mechanism, and significantly inhibit the tumor growth through both intrinsic and extrinsic apoptosis pathways, thus making it a highly potential nanomedicine translated in the treatment of MDR tumors.

Illuminating and Radiosensitizing Tumors with 2DG-Bound Gold-Based Nanomedicine for Targeted CT Imaging and Therapy.

Although radiotherapy is one of the most important curative treatments for cancer, its clinical application is associated with undesired therapeutic effects on normal or healthy tissues. The use of targeted agents that can simultaneously achieve therapeutic and imaging functions could constitute a potential solution. Herein, we developed 2-deoxy-d-glucose (2DG)-labeled poly(ethylene glycol) (PEG) gold nanodots (2DG-PEG-AuD) as a tumor-targeted computed tomography (CT) contrast agent and radiosensitizer. The key advantages of the design are its biocompatibility and targeted AuD with excellent sensitivity in tumor detection via avid glucose metabolism. As a consequence, CT imaging with enhanced sensitivity and remarkable radiotherapeutic efficacy could be attained. Our synthesized AuD displayed linear enhancement of CT contrast as a function of its concentration. In addition, 2DG-PEG-AuD successfully demonstrated significant augmentation of CT contrast in both in vitro cell studies and in vivo tumor-bearing mouse models. In tumor-bearing mice, 2DG-PEG-AuD showed excellent radiosensitizing functions after intravenous injection. Results from this work indicate that 2DG-PEG-AuD could greatly potentiate theranostic capabilities by providing high-resolution anatomical and functional images in a single CT scan and therapeutic capability.

Personalized Cancer Therapeutics Using Photoacoustic Imaging-Guided Sonodynamic Therapy.

Sonodynamic therapy (SDT) is a promising approach for cancer treatment that uses sonosensitizers (SNSs) to generate reactive oxygen species (ROS) in the presence of ultrasound (US). However, SDT is oxygen-dependent and requires an imaging tool to monitor the tumor microenvironment and guide treatment. Photoacoustic imaging (PAI) is a noninvasive and powerful imaging tool that offers high spatial resolution and deep tissue penetration. PAI can quantitatively assess tumor oxygen saturation (sO2) and guide SDT by monitoring time-dependent sO2 changes in the tumor microenvironment. Here, we discuss recent advances in PAI-guided SDT for cancer therapy. We discuss various exogenous contrast agents and nanomaterial-based SNSs developed for PAI-guided SDT. Additionally, combining SDT with other therapies, including photothermal (PTT) therapy, can enhance its therapeutic effect. However, the application of nanomaterial-based contrast agents in PAI-guided SDT for cancer therapy remains challenging due to the lack of simple designs, the need for extensive pharmacokinetic studies, and high production costs. Integrated efforts from researchers, clinicians, and industry consortia are necessary for the successful clinical translation of these agents and SDT for personalized cancer therapy. PAI-guided SDT shows the potential to revolutionize cancer therapy and improve patient outcomes, but further research is necessary to realize its full potential.

Industrialization's eye view on theranostic nanomedicine.

The emergence of nanomedicines (NMs) in the healthcare industry will bring about groundbreaking improvements to the current therapeutic and diagnostic scenario. However, only a few NMs have been developed into clinical applications due to a lack of regulatory experience with them. In this article, we introduce the types of NM that have the potential for clinical translation, including theranostics, multistep NMs, multitherapy NMs, and nanoclusters. We then present the clinical translational challenges associated with NM from the pharmaceutical industry's perspective, such as NMs' intrinsic physiochemical properties, safety, scale-up, lack of regulatory experience and standard characterization methods, and cost-effectiveness compared with their traditional counterparts. Overall, NMs face a difficult task to overcome these challenges for their transition from bench to clinical use.

Multimodal Magnetic Resonance and Photoacoustic Imaging of Tumor-Specific Enzyme-Responsive Hybrid Nanoparticles for Oxygen Modulation.

Multimodal imaging contrast agents for cancer that can not only perform diagnostic functions but also serve as tumor microenvironment-responsive biomaterials are encouraging. In this study, we report the design and fabrication of a novel enzyme-responsive T1 magnetic resonance imaging (MRI) contrast agent that can modulate oxygen in the tumor microenvironment via the catalytic conversion of H2O2 to O2. The T1 contrast agent is a core-shell nanoparticle that consists of manganese oxide and hyaluronic acid (HA)-conjugated mesoporous silica nanoparticle (HA-MnO@MSN). The salient features of the nanoparticle developed in this study are as follows: 1) HA serves as a targeting ligand for CD44-expressing cancer cells; 2) HA allows controlled access of water molecules to the MnO core via the digestion of enzyme hyaluronidase; 3) the generation of O2 bubbles in the tumor by consuming H2O2; and 4) the capability to increase the oxygen tension in the tumor. The r 1 relaxivity of HA-MnO@MSN was measured to be 1.29 mM-1s-1 at a magnetic field strength of 9.4 T. In vitro results demonstrated the ability of continuous oxygen evolution by HA-MnO@MSN. After intratumoral administration of HA-MnO@MSN to an HCT116 xenograft mouse model, T1 weighted MRI contrast was observed after 5 h postinjection and retained up to 48 h. In addition, in vivo photoacoustic imaging of HA-MnO@MSN demonstrated an increase in the tumor oxygen saturation over time after i. t. administration. Thus, the core-shell nanoparticles developed in this study could be helpful in tumor-targeted T1 MR imaging and oxygen modulation.

Assessment of Nanoparticle-Mediated Tumor Oxygen Modulation by Photoacoustic Imaging.

Photoacoustic imaging (PAI) is an invaluable tool in biomedical imaging, as it provides anatomical and functional information in real time. Its ability to image at clinically relevant depths with high spatial resolution using endogenous tissues as contrast agents constitutes its major advantage. One of the most important applications of PAI is to quantify tissue oxygen saturation by measuring the differential absorption characteristics of oxy and deoxy Hb. Consequently, PAI can be utilized to monitor tumor-related hypoxia, which is a crucial factor in tumor microenvironments that has a strong influence on tumor invasiveness. Reactive oxygen species (ROS)-based therapies, such as photodynamic therapy, radiotherapy, and sonodynamic therapy, are oxygen-consuming, and tumor hypoxia is detrimental to their efficacy. Therefore, a persistent demand exists for agents that can supply oxygen to tumors for better ROS-based therapeutic outcomes. Among the various strategies, NP-mediated supplemental tumor oxygenation is especially encouraging due to its physio-chemical, tumor targeting, and theranostic properties. Here, we focus on NP-based tumor oxygenation, which includes NP as oxygen carriers and oxygen-generating strategies to alleviate hypoxia monitored by PAI. The information obtained from quantitative tumor oxygenation by PAI not only supports optimal therapeutic design but also serves as a highly effective tool to predict therapeutic outcomes.

Precision control of the large-scale green synthesis of biodegradable gold nanodandelions as potential radiotheranostics.

Herein, we report a new type of biodegradable, high surface-area gold nanodandelions (GNDs). This report possesses important features and some are the first of its kind: (1) the large scale green synthesis of GNDs with high monodispersity and a circa 100% yield with consistent chemistry, manufacturing and controls (CMC); (2) cellular/physiological degradability of GNDs leading to its disassembly into debris, which is indicative of the potential for possible body clearance; (3) precision control of the chemicophysical properties of the GNDs including shape, petal number and size, all can be judiciously fine-tuned by the synthetic parameters; (4) highly efficient radiotheranostics of GNDs encompassing better enhanced computed tomography (CT) contrast and pronounced X-ray induced reactive oxygen species (ROS) generation than conventional spherical gold nanoparticles (AuNP). It is noteworthy that the GNDs demonstrate a unique combinational effect of radiosensitization (production of superoxide anions and hydroxyl radicals) and type II photodynamic interaction (generation of singlet oxygen). Given the above, our reported GNDs are promising in clinical translation as radiotheranostics.

Seeing Better and Going Deeper in Cancer Nanotheranostics.

Biomedical imaging modalities in clinical practice have revolutionized oncology for several decades. State-of-the-art biomedical techniques allow visualizing both normal physiological and pathological architectures of the human body. The use of nanoparticles (NP) as contrast agents enabled visualization of refined contrast images with superior resolution, which assists clinicians in more accurate diagnoses and in planning appropriate therapy. These desirable features are due to the ability of NPs to carry high payloads (contrast agents or drugs), increased in vivo half-life, and disease-specific accumulation. We review the various NP-based interventions for treatments of deep-seated tumors, involving "seeing better" to precisely visualize early diagnosis and "going deeper" to activate selective therapeutics in situ.

Evolution of Nanoparticle-Mediated Photodynamic Therapy: From Superficial to Deep-Seated Cancers.

Enthusiasm for photodynamic therapy (PDT) as a potential therapeutic intervention for cancer has increased exponentially in recent decades. Photodynamic therapy constitutes a clinically approved, minimally invasive treatment modality that uses a photosensitizer (light absorbing molecule) and light to kill cancer cells. The principle of PDT is, when irradiated with a light of a suitable wavelength, a photosensitizer absorbs the light energy and generates cytotoxic free radicals through various mechanisms. The overall efficiency of PDT depends on characteristics of activation light and in-situ dosimetry, including the choice of photosensitizer molecule, wavelength of the light, and tumor location and microenvironment, for instance, the use of two-photon laser or an X-ray irradiator as the light source increases tissue-penetration depth, enabling it to achieve deep PDT. In this mini-review, we discuss the various designs and strategies for single, two-photon, and X-ray-mediated PDT for improved clinical outcomes.

Nanoparticle-facilitated functional and molecular imaging for the early detection of cancer.

Cancer detection in its early stages is imperative for effective cancer treatment and patient survival. In recent years, biomedical imaging techniques, such as magnetic resonance imaging, computed tomography and ultrasound have been greatly developed and have served pivotal roles in clinical cancer management. Molecular imaging (MI) is a non-invasive imaging technique that monitors biological processes at the cellular and sub-cellular levels. To achieve these goals, MI uses targeted imaging agents that can bind targets of interest with high specificity and report on associated abnormalities, a task that cannot be performed by conventional imaging techniques. In this respect, MI holds great promise as a potential therapeutic tool for the early diagnosis of cancer. Nevertheless, the clinical applications of targeted imaging agents are limited due to their inability to overcome biological barriers inside the body. The use of nanoparticles has made it possible to overcome these limitations. Hence, nanoparticles have been the subject of a great deal of recent studies. Therefore, developing nanoparticle-based imaging agents that can target tumors via active or passive targeting mechanisms is desirable. This review focuses on the applications of various functionalized nanoparticle-based imaging agents used in MI for the early detection of cancer.

Carboxymethyl dextran-cyclodextrin conjugate as the carrier of doxorubicin.

The carboxymethyl dextran-y-cyclodextrin (CMD-yCD) conjugate was prepared as the carrier for the delivery of the poorly water-soluble anticancer drug, doxorubicin (DOX). The conjugate could form self-assembled nanoparticles (315 nm in diameter) in an aqueous solution, which might be due to the hydrogen bonding among yCD molecules in the conjugate. DOX was effectively encapsulated into CMD-yCD nanoparticles (CMD-NPs) by the emulsion method. In particular, regardless of the feed amount of DOX, its loading efficiencies were always greater than 70%. CMD-NPs released DOX in a sustained manner, owing to the inclusion complex formation between DOX and yCD. When Cy5.5-labeled CMD-NPs were treated with SCC7 cancer cells, strong fluorescence signals were observed at the cytosol, indicating effective intracellular uptake. In addition, DOX-loaded CMD-NPs exhibited dose-dependent cytotoxicity to SCC7 cancer cells. However, the empty nanoparticles did not show toxicity to the cells, implying their high biocompatibility. Overall, these results suggest that the CMD-gammaCD conjugate could be a useful carrier for the delivery of DOX.

Cyclodextrin-based nanocomplexes for sustained delivery of human growth hormone.

The use of human growth hormone (hGH) as a therapeutic protein has been limited by its instability in biological fluids and short biological half-life in vivo. In this study, glycol chitosan (GC) bearing beta-cyclodextrin (GC-betaCD) as the carrier of hGH was synthesized by the covalent attachment of a carboxymethyl derivative of betaCD to the GC backbone via amide bond formation. The GC-betaCD conjugate could form self-assembled nanoparticles (340 nm in mean diameter) in an aqueous solution, resulting from hydrogen bonding among betaCDs at the backbone of the conjugate. hGH was effectively encapsulated into the nanoparticles because of hydrophobic interactions between the hydrophobic cavity of betaCD and alkyl or aromatic groups of amino acids in hGH. From the in vitro release experiments, it was found that the nanoparticles released hGH in a sustained manner for 9 days. Overall, the GC-betaCD conjugate might be a promising carrier for sustained delivery of hGH.

Mineralized cyclodextrin nanoparticles for sustained protein delivery.

The extensive therapeutic potential of protein drugs has been severely limited by their instability and short biological half-lives in vivo. To prolong their therapeutic effects, a sustained delivery system is required. In this study, cyclodextrin-based polymeric nanoparticles (CD-NPs), mineralized by calcium phosphate as the diffusion barrier, were developed as a carrier for sustained protein delivery. Spherical CD-NPs were readily prepared by a conjugate, composed of ß-CD as the protein-binding moiety and carboxymethyl dextran as the substrate for mineralization in a physiological solution. Owing to the presence of carboxylic acids in CD-NPs, they were effectively mineralized by sequential addition of calcium nitrate and ammonium phosphate. The physicochemical characteristics of mineralized CD-NPs were characterized using FT-IR, thermogravimetric analysis, transmission electron microscopy and energy dispersive X-ray photoelectron spectroscopy. Mineralization reduced CD-NP particle size from 310 nm to 121 nm in PBS (pH 7.4) indicating the formation of compact nanoparticles. Carbonic anhydrase B (CAB), chosen as the model protein, was loaded into the mineralized CD-NPs with a high loading efficiency (80%) by a simple dialysis method. In vitro release tests showed that CAB was completely released from bare CD-NPs in 3 days. Interestingly, the mineralized CD-NPs released CAB in a sustained manner for 21 days, which was due to the stable calcium phosphate barrier inhibiting CAB release. The enzymatic activity of CAB, which was released from the nanoparticles, did not significantly deteriorate compared to native CAB. Overall, mineralized CD-NPs could be a promising carrier for sustained protein delivery.

Thiolated glycol chitosan bearing α-cyclodextrin for sustained delivery of PEGylated human growth hormone.

The extensive use of human growth hormone (hGH), emerging as protein therapeutics, has been limited by its instability in biological fluids and short biological half-life. In this study, thiolated glycol chitosan bearing α-cyclodextrin (TGC-CD), in situ cross-linked by poly(ethylene glycol)-diacrylate (PEG-DA), was synthesized to develop a sustained release system for PEGylated hGH (PEG-hGH). TGC-CD could form a stable inclusion complex with PEG-hGH by the physical interaction between the inner cavity of CD and PEG. Such a complex was readily cross-linked in the presence of PEG-DA via a Michael-type addition reaction. From the in vitro release experiments of PEG-hGH, it was confirmed that PEG-hGH was completely released from the complex for 12 h in PBS (pH 7.4), whereas the release rate of PEG-hGH was significantly reduced by the chemical cross-linking of the complex. PEG-hGH, released from the cross-linked complexes, maintained its structural integrity, which was demonstrated using circular dichroism spectroscopy. Overall, TGC-CD might be useful for sustained delivery of PEG-hGH.