Tumor Targeting Strategies Research Articles

Enhanced Tumor Accumulation of Multimodal Magneto-Plasmonic Nanoparticles via an Implanted Micromagnet-Assisted Delivery Strategy.

One of the major shortcomings of nano carriers-assisted cancer therapeutic strategies continues to be the inadequate tumor penetration and retention of systemically administered nanoformulations and its off-target toxicity. Stromal parameters-related heterogeneity in enhanced permeability and retention effect and physicochemical properties of the nanoformulations immensely contributes to their poor tumor extravasation. Herein, a novel tumor targeting strategy, where an intratumorally implanted micromagnet can significantly enhance accumulation of magneto-plasmonic nanoparticles (NPs) at the micromagnet-implanted tumor in bilateral colorectal tumor models while limiting their off-target accumulation, is demonstrated. To this end, novel multimodal gold/iron oxide NPs comprised of an array of multifunctional moieties with high therapeutic, sensing, and imaging potential are developed. It is also discovered that cancer cell targeted NPs in combination with static magnetic field can selectively induce cancer cell death. A multimodal caspase-3 nanosensor is also developed for real-time visualization of selective induction of apoptosis in cancer cells. In addition, the photothermal killing capability of these NPs in vitro is evaluated, and their potential for enhanced photothermal ablation in tissue samples is demonstrated. Building on current uses of implantable devices for therapeutic purposes, this study envisions the proposed micromagnet-assisted NPs delivery approach may be used to accelerate the clinical translation of various nanoformulations.

Targeting to Tumor-Harbored Bacteria for Precision Tumor Therapy.

The differential tumor environment guides various antitumor drug delivery strategies for efficient cancer treatment. Here, based on the special bacteria-enriched tumor environment, we report a different drug delivery strategy by targeting bacteria inhabiting tumor sites. With a tissue microarray analysis, it was found that bacteria amounts displayed significant differences between tumor and normal tissues. Bacteria-targeted mesoporous silica nanoparticles decorated with bacterial lipoteichoic acid (LTA) antibody (LTA-MSNs) could precisely target bacteria in tumors and deliver antitumor drugs. By the intravenous administration of bacteria-targeted nanoparticles, we showed in mice with colon cancer, lung cancer, and breast cancer that LTA-MSNs exhibited a high tumor-targeting ability. As a proof-of-concept study, tumor microbes as some of the characteristics of a tumor environment could be utilized as potential targets for tumor targeting. This bacteria-guided tumor-targeting strategy might have great potential in differential drug delivery and cancer treatment.

Strategies for persistent retention of macromolecules and nanoparticles in the blood circulation.

The enhanced permeability and retention (EPR) effect has been the gold standard in developing drug delivery systems for passive tumor targeting. Although the importance of this concept remains unchanged, some controversies have arisen. In this review, various strategies for tumor targeting using macromolecules and nanoparticles based on the EPR effect are discussed from the viewpoint of pharmacokinetics. Overall, such strategies seek to retain therapeutic material in the blood circulation, which is a key factor for successful targeting. Strategies using macromolecules, including antibody-drug conjugates, serum albumin-based delivery systems, PEGylated recombinant proteins, and stealth liposomes as well as nanoparticle-based strategies such as those based on lipid nanoparticles, and polymeric micelles, have been discussed. The feasibility of small extracellular vesicles, a new class of nanosized delivery carriers, is also discussed.

Design Strategies of Tumor-Targeted Delivery Systems Based on 2D Nanomaterials.

Conventional chemotherapy and radiotherapy are nonselective and nonspecific for cell killing, causing serious side effects and threatening the lives of patients. It is of great significance to develop more accurate tumor-targeting therapeutic strategies. Nanotechnology is in a leading position to provide new treatment options for cancer, and it has great potential for selective targeted therapy and controlled drug release. 2D nanomaterials (2D NMs) have broad application prospects in the field of tumor-targeted delivery systems due to their special structure-based functions and excellent optical, electrical, and thermal properties. This review emphasizes the design strategies of tumor-targeted delivery systems based on 2D NMs from three aspects: passive targeting, active targeting, and tumor-microenvironment targeting, in order to promote the rational application of 2D NMs in clinical practice.

"Motile-targeting" drug delivery platforms based on micro/nanorobots for tumor therapy.

Traditional drug delivery systems opened the gate for tumor-targeted therapy, but they generally took advantage of enhanced permeability and retention or ligand-receptor mediated interaction, and thus suffered from limited recognition range (<0.5 nm) and low targeting efficiency (0.7%, median). Alternatively, micro/nanorobots (MNRs) may act as emerging “motile-targeting” drug delivery platforms to deliver therapeutic payloads, thereby making a giant step toward effective and safe cancer treatment due to their autonomous movement and navigation in biological media. This review focuses on the most recent developments of MNRs in “motile-targeting” drug delivery. After a brief introduction to traditional tumor-targeted drug delivery strategies and various MNRs, the representative applications of MNRs in “motile-targeting” drug delivery are systematically streamlined in terms of the propelling mechanisms. Following a discussion of the current challenges of each type of MNR in biomedical applications, as well as future prospects, several promising designs for MNRs that could benefit in “motile-targeting” drug delivery are proposed. This work is expected to attract and motivate researchers from different communities to advance the creation and practical application of the “motile-targeting” drug delivery platforms.

Hepatocyte-targeting and tumor microenvironment-responsive liposomes for enhanced anti-hepatocarcinoma efficacy

To increase the antitumor drug concentration in the liver tumor site and improve the therapeutic effects, a functionalized liposome (PPP-LIP) with tumor targetability and enhanced internalization after matrix metalloproteinase-2 (MMP2)-triggered cell-penetrating peptide (TATp) exposure was modified with myrcludex B (a synthetic HBV preS-derived lipopeptide endowed with compelling liver tropism) for liver tumor-specific delivery. After intravenous administration, PPP-LIP was mediated by myrcludex B to reach the hepatocyte surface. The MMP2-overexpressing tumor microenvironment deprotected PEG, exposing it to TATp, facilitating tumor penetration and subsequent efficient destruction of tumor cells. In live imaging of small animals and cellular uptake, PPP-LIP was taken up much more than typical unmodified liposomes in the ICR mouse liver and liver tumor cells. Hydroxycamptothecin (HCPT)-loaded PPP-LIP showed a better antitumor effect than commercially available HCPT injections among MTT, three-dimensional (3 D) tumor ball, and tumor-bearing nude mouse experiments. Our findings indicated that PPP-LIP nanocarriers could be a promising tumor-targeted medication delivery strategy for treating liver cancers with elevated MMP2 expression.

Near-infrared fluorescence guided surgery: State of the evidence from a health technology assessment perspective.

Different applications of near-infrared fluorescence-guided surgery are very promising, and techniques that help surgeons in intraoperative guidance have been developed, thereby bridging the gap between preoperative imaging and intraoperative visualization and palpation. Thus, these techniques are advantageous in terms of being faster, safer, less invasive, and cheaper. There are a few fluorescent dyes available, but the most commonly used dye is indocyanine green. It can be used in its natural form, but different nanocapsulated and targeted modifications are possible, making this dye more stable and specific. A new active tumor-targeting strategy is the conjugation of indocyanine green nanoparticles with antibodies, making this dye targeted and highly selective to various tumor proteins. In this mini-review, we discuss the application of near-infrared fluorescence-guided techniques in thoracic surgery. During lung surgery, it can help find small, non-palpable, or additional tumor nodules, it is also useful for finding the sentinel lymph node and identifying the proper intersegmental plane for segmentectomies. Furthermore, it can help visualize the thoracic duct, smaller bullae of the lung, phrenic nerve, or pleural nodules. We summarize current applications and provide a framework for future applications and development.

PERK reprograms hematopoietic progenitor cells to direct tumor-promoting myelopoiesis in the spleen.

The spleen is an important site of hematopoietic stem/progenitor cell (HSPC) preconditioning and tumor-promoting myeloid cell generation in cancer, but the regulatory mechanism remains unclear. Here, we found that PKR-like endoplasmic reticulum kinase (PERK) mediated HSPC reprogramming into committed MDSC precursors in the spleen via PERK-ATF4-C/EBPβ signaling. Pharmacological and genetic inhibition of this pathway in murine and human HSPCs prevented their myeloid descendant cells from becoming MDSCs even with subsequent exposure to tumor microenvironment (TME) factors. In mice, the selective delivery of PERK antagonists to the spleen was not only sufficient but more effective than the tumor-targeted strategy in preventing MDSC activation in the tumor, leading to profound TME reshaping and tumor regression. Clinically, HSPCs in the spleen of cancer patients exhibit increased PERK signaling correlated with enhanced myelopoiesis. Our findings indicate that PERK-mediated HSPC preconditioning plays a crucial role in MDSC generation, suggesting novel spleen-targeting therapeutic opportunities for restraining the tumor-promoting myeloid response at its source.

Mesoporous Silica Nanoparticle-Based Drug Delivery Systems for the Treatment of Pancreatic Cancer: A Systematic Literature Overview.

Pancreatic cancer is a devastating disease with the worst outcome of any human cancer. Despite significant improvements in cancer treatment in general, little progress has been made in pancreatic cancer (PDAC), resulting in an overall 5-year survival rate of less than 10%. This dismal prognosis can be attributed to the limited clinical efficacy of systemic chemotherapy due to its high toxicity and consequent dose reductions. Targeted delivery of chemotherapeutic drugs to PDAC cells without affecting healthy non-tumor cells will largely reduce collateral toxicity leading to reduced morbidity and an increased number of PDAC patients eligible for chemotherapy treatment. To achieve targeted delivery in PDAC, several strategies have been explored over the last years, and especially the use of mesoporous silica nanoparticles (MSNs) seem an attractive approach. MSNs show high biocompatibility, are relatively easy to surface modify, and the porous structure of MSNs enables high drug-loading capacity. In the current systematic review, we explore the suitability of MSN-based targeted therapies in the setting of PDAC. We provide an extensive overview of MSN-formulations employed in preclinical PDAC models and conclude that MSN-based tumor-targeting strategies may indeed hold therapeutic potential for PDAC, although true clinical translation has lagged behind.

Tumor-targeted delivery of honokiol via polysialic acid modified zein nanoparticles prevents breast cancer progression and metastasis

In this work, we developed polysialic acid (PSA) modified zein nanoparticles for targeted delivery of honokiol (HNK) to enhance drug delivery efficiency and specific biodistribution at tumor sites. The antisolvent precipitation and electrostatic interaction methods were employed to fabricate the PSA-Zein-HNK nanoparticles, which exhibited mean size of 107.2 ± 10.1 nm and HNK encapsulation efficiency of 79.2 ± 2.3%. The PSA-Zein-HNK maintained a uniform dispersion in serum for 48 h, implying the improved colloid stability of zein nanoparticles via PSA coating. The cellular uptake of PSA-Zein-Cou6 nanoparticles in 4 T1 cells was 2.58-fold higher than non-targeting Zein-Cou6. In addition, the IC50 value at 48 h for PSA-Zein-HNK (4.37 μg/mL) was significantly higher than the Zein-HNK (7.74 μg/mL). Enhanced tumor accumulation of the PSA-Zein-HNK was confirmed in 4 T1 breast cancer-bearing mice by near-infrared fluorescence imaging, resulting in desirable antitumor efficacy and favorable biosafety. Besides, compared with non-targeting zein nanoparticles, the PSA-Zein-HNK achieved a higher tumor growth inhibition rate of 52.3%. In particular, the metastasis of breast cancer to the lung or liver was remarkably suppressed by PSA-Zein-HNK. Together, our results demonstrated that the PSA-Zein-HNK could be a potential tumor-targeted drug delivery strategy for efficient treatment of breast cancer.

A 3D Platform to Investigate Dynamic Cell-to-Cell Interactions Between Tumor Cells and Mesenchymal Progenitors.

We here investigated the dynamic cell-to-cell interactions between tumor and mesenchymal stromal/stem cells (MSCs) by the novel VITVOⓇ 3D bioreactor that was customized to develop in vivo-like metastatic nodules of Ewing’s sarcoma (ES). MSCs are known to contribute to tumor microenvironment as cancer associated fibroblast (CAF) precursors and, for this reason, they have also been used as anti-cancer tools. Using dynamic conditions, the process of tissue colonization and formation of metastatic niches was recreated through tumor cell migration aiming to mimic ES development in patients. ES is an aggressive tumor representing the second most common malignant bone cancer in children and young adults. An urgent and unmet need exists for the development of novel treatment strategies to improve the outcomes of metastatic ES. The tumor-tropic ability of MSCs offers an alternative approach, in which these cells can be used as vehicles for the delivery of antitumor molecules, such as the proapoptotic TNF-related apoptosis inducing ligand (TRAIL). However, the therapeutic targeting of metastases remains challenging and the interaction occurring between tumor cells and MSCs has not yet been deeply investigated. Setting up in vitro and in vivo models to study this interaction is a prerequisite for novel approaches where MSCs affinity for tumor is optimized to ultimately increase their therapeutic efficacy. Here, VITVOⓇ integrating a customized scaffold with an increased inter-fiber distance (VITVO50) was used to develop a dynamic model where MSCs and tumor nodules were evaluated under flow conditions. Colonization and interaction between cell populations were explored by droplet digital PCR (ddPCR). VITVO50 findings were then applied in vivo. An ES metastatic model was established in NSG mice and biodistribution of TRAIL-expressing MSCs in mice organs affected by metastases was investigated using a 4-plex ddPCR assay. VITVOⓇ proved to be an easy handling and versatile bioreactor to develop in vivo-like tumor nodules and investigate dynamic cell-to-cell interactions with MSCs. The proposed fluidic system promises to facilitate the understanding of tumor-stroma interaction for the development of novel tumor targeting strategies, simplifying the analysis of in vivo data, and ultimately accelerating the progress towards the early clinical phase.

Identification of Significant Genes and Pathways Associated with Tenascin-C in Cancer Progression by Bioinformatics Analysis.

Background:Tenascin-C (TNC) is a large glycoprotein of the extracellular matrix which associated with poor clinical outcomes in several malignancies. TNC over-expression is repeatedly observed in several cancer tissues and promotes several processes in tumor progression. Until quite recently, more needs to be known about the potential mechanisms of TNC as a key player in cancer progression and metastasis.Materials and Methods:In the present study, we performed a bioinformatics analysis of breast and colorectal cancer expression microarray data to survey TNC role and function with holistic view. Gene expression profiles were analyzed to identify differentially expressed genes (DEGs) between normal samples and cancer biopsy samples. The protein-protein interaction (PPI) networks of the DEGs with CluePedia plugin of Cytoscape software were constructed. Furthermore, after PPI network construction, gene-regulatory networks analysis was performed to predict long noncoding RNAs and microRNAs associated with TNC and cluster analysis was performed. Using the Clue gene ontology (GO) plugin of Cytoscape software, the GO and pathway enrichment analysis were performed.Results:PPI and DEGs-miRNA-lncRNA regulatory networks showed TNC is a significant node in a huge network, and one of the main gene with high centrality parameters. Furthermore, from the regulatory level perspective, TNC could be significantly impressed by miR-335-5p. GO analysis results showed that TNC was significantly enriched in cancer-related biological processes.Conclusions:It is important to identify the TNC underlying molecular mechanisms in cancer progression, which may be clinically useful for tumor-targeting strategies. Bioinformatics analysis provides an insight into the significant roles that TNC plays in cancer progression scenarios.

Gold Nanoclusters: Imaging, Therapy, and Theranostic Roles in Biomedical Applications.

For the past two decades, atomic gold nanoclusters (AuNCs, ultrasmall clusters of several to 100 gold atoms, having a total diameter of <2 nm) have emerged as promising agents in the diagnosis and treatment of cancer. Owing to their small size, significant quantization occurs to their conduction band, which leads to emergent photonic properties and the disappearance of the plasmonic responses observed in larger gold nanoparticles. For example, AuNCs exhibit native luminescent properties, which have been well-explored in the literature. Using proteins, peptides, or other biomolecules as structural scaffolds or capping ligands, required for the stabilization of AuNCs, improves their biocompatibility, while retaining their distinct optical properties. This paved the way for the use of AuNCs in fluorescent bioimaging, which later developed into multimodal imaging combined with computer tomography and magnetic resonance imaging as examples. The development of AuNC-based systems for diagnostic applications in cancer treatment was then made possible by employing active or passive tumor targeting strategies. Finally, the potential therapeutic applications of AuNCs are extensive, having been used as light-activated and radiotherapy agents, as well as nanocarriers for chemotherapeutic drugs, which can be bound to the capping ligand or directly to the AuNCs via different mechanisms. In this review, we present an overview of the diverse biomedical applications of AuNCs in terms of cancer imaging, therapy, and combinations thereof, as well as highlighting some additional applications relevant to biomedical research.

A Tumor-Targeting Metal-Organic Nanoparticle Constructed by Dynamic Combinatorial Chemistry toward Accurately Redressing Carcinogenic Wnt Cascade.

Targeted and immunological therapy have revolutionized the malignancy treatment, but is suffering from the dose-limiting side effects and inadequate responsiveness. The emerging nanoscale infinite coordination polymers provide a feasible strategy for tumor targeting and immune sensitization. Herein, a "one-pot" self-assembled strategy based on dynamic combinatorial chemistry (DCC) principle is designed to construct a tumor-targeting metal-organic nanoparticle (MOICP) through a spontaneous co-assembling among three metal-organic coordination polymers tuned by a Wnt-inhibitor carnosic acid (CA). Responding to the tumor microenvironment, MOICP presents an optimized tumor-preferential accumulation and the satisfactory biosafety. MOICP is more active in vitro and in vivo than CA in suppressing of Wnt signaling pathway, and potently inhibits tumor growth in a patient-derived xenograft model of Wnt-activated pancreatic carcinoma. Moreover, MOICP reverses the lack of intratumoral infiltration of T lymphocytes, and hence augments the action of Anti-PD1 (programmed cell death protein 1) immunotherapy in B16F10 melanoma allograft mice model. This clinically viable MOICP can not only be applied to Wnt inhibition for cancer targeted therapy and immunotherapeutic sensitization, but also provides a de novo pattern for nanomedicine architecture with cargo-initiated co-self-assembly guided by DCC, thereby bringing new inspiration in general for disease intervention.

Arming of iPSC-Derived NK Cells Expressing a Novel CD64 Fusion Receptor with Therapeutic Antibodies Represents a Novel Off-the-Shelf, Antigen-Targeting Strategy for Cancer

Natural killer (NK) cells are innate lymphocytes that target malignant cells via non-clonotypic receptors to induce natural cytotoxicity and that recognize tumor-bound antibodies to induce antibody-dependent cell-mediated cytotoxicity (ADCC). Human NK cells exclusively mediate ADCC through the IgG Fc receptor, CD16A, and studies have demonstrated that increasing the binding affinity between CD16A and therapeutic monoclonal antibodies (mAbs), mediated by the high-affinity 158V polymorphism, can augment clinical efficacy. Given the exquisite specificity and diverse antigen detection of anti-tumor mAbs, we sought to arm iPSC-derived NK (iNK) cells expressing a high-affinity recombinant FcγR with various mAbs as unique tumor-targeting strategy for various malignancies.As a member of the FcγR family, CD64 (FcγRI) possesses the highest affinity and can uniquely facilitate antibody preabsorption but it is normally expressed by myeloid cells. To leverage CD64 in NK cells, we developed a novel FcγR recombinant fusion comprising the extracellular region of CD64 with the transmembrane and intracellular regions of other NK cell activating receptors, including CD16A (CD64/16A) (figure 1A). The recombinant CD64/16A engineered into a clonal master induced pluripotent stem cell (iPSC) line for mass production of off-the-shelf iPSC-derived CD64/16A NK (iNK-CD64/16A) cells, can be armed with mAbs, including various combinations thereof to enable multi-antigen targeting and to address tumor heterogeneity (figures 1B and 2).To determine optimal binding and FcR saturation of iNK-CD64/16 cells, rituximab (anti-CD20 therapeutic mAb) was added in a two-hour preabsorbtion assay (figure 3A). Using an in vitro Delfia® ADCC assay, we show that iNK-CD64/16A cells mediated ADCC against Raji cells, a Burkitt Lymphoma cell line, when the iNKs were preabsorbed and armed with rituximab (figure 3B). Considering the high-affinity state of CD64, we examined the effects of free IgG on ADCC by iNK-CD64/16A cells. Using an IncuCyte® Live Cell Analysis, ADCC was evaluated in the presence of purified human IgG. Despite the high levels of excess IgG, iNK-CD64/16A cells mediated efficient ADCC when rituximab was either added to the assay (figure 4A) or preabsorbed to the cells (figure 4B), demonstrating that saturating levels of free IgG did not prevent ADCC in either setting. To determine the ability of preabsorbed and armed iNK-CD64/16 cells to retain rituximab and perform serial killing, we performed a sequential killing assay using an IncuCyte® Live Cell Analysis where preabsorbed iNK-CD64/16A cells were thawed and co-cultured with or without Raji cells for 48 hours, followed by a second round of co-culture. As shown in figure 5, iNK-CD64/16A cells armed with rituximab retain ADCC capacity and perform serial killing for an extended time.To establish that iNK-CD64/16A cells can be armed with assorted therapeutic mAbs to target other tumor-associated antigens, we next determined the ability of iNK-CD64/16A cells preabsorbed and armed with anti-HER2 mAb, trastuzumab, to target the adenocarcinoma ovarian cancer cell line SKOV-3. Indeed iNK-CD64/16A cells armed with preabsorbed trastuzumab were able to effectively kill SKOV-3 cells via in vitro ADCC by IncuCyte® Live Cell Analysis (figure 6). We next investigated in vivo ADCC using NSG mice implanted with 3x10 5 SKOV-3 cells expressing firefly luciferase intraperitoneally (IP). 10 million iNK-CD64/16A with or without preabsorbed trastuzumab were injected IP (figure 7A), and a significant reduction in tumor volume in animals treated with iNK-CD64/16A cells armed with trastuzumab compared to unarmed iNK-CD64/16A cells (figure 7B).Collectively, our data show that iNK-CD64/16A cells can be armed with various therapeutic mAbs through a unique preabsorption strategy to mediate a potent and durable ADCC activity. The versatility of mAb-armed iNK-CD64/16A cells is being further investigated in various preclinical models to further elucidate the potential of this approach to overcome antigen escape and address tumor heterogeneity. [Display omitted] DisclosuresLee: Fate Therapeutics, Inc: Current Employment. Chu: Fate Therapeutics: Current Employment. Rogers: Fate Therapeutics: Current Employment. Bjordahl: Fate Therapeutics: Current Employment. Hosking: Fate Therapeutics: Current Employment. Shirinbak: Fate Therapeutics, Inc.: Current Employment. Miller: Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Vycellix: Consultancy; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Wugen: Membership on an entity's Board of Directors or advisory committees. Valamehr: Fate Therapeutics, Inc.: Current Employment. Walcheck: Fate Therapeutics: Research Funding.

An SMVT-targeting and peroxynitrite-activating fluorescent probe for head and neck cancer imaging and peroxynitrite detection

Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide. For better diagnosis and precise resection of HNSCC, Fluorescent probe has been developed as an ideal tool to visualize tumor sites and to detect biological molecules. However, the targeting strategies of small molecular probes are limited. We designed probe RB-PN (Rhodamine biotin-peroxynitrite) with both sodium-dependent multivitamin transporter (SMVT)-targetable and peroxynitrite (ONOO−)-activatable tumor-targeting strategies. It can detect ONOO− with high specificity and selectivity, and rapid response. Besides, it exhibits prominent imaging abilities with enhanced accumulation by SMVT-transportation. The remarkable sensitivity, selectivity, turn-on signal change and rapid responsive time have been identified. We evidenced the dual-targeting strategy, and applied it in tumor visualization and ONOO− detection both in HNSCC cells and in vivo. We also identified the potential application of it in cytokine therapy using 3D micro-spheroid models. We expect RB-PN with a dual-targeting strategy could be conducive to the diagnosis of tumor pre-operatively or even intra-operatively.

Requirements for Designing an Effective Metallic Nanoparticle (NP)-Boosted Radiation Therapy (RT).

Simple SummaryRecent advances in nanotechnology gave rise to trials with various types of metallic nanoparticles (NPs) to enhance the radiosensitization of cancer cells while reducing or maintaining the normal tissue complication probability during radiation therapy. This work reviews the physical and chemical mechanisms leading to the enhancement of ionizing radiation’s detrimental effects on cells and tissues, as well as the plethora of experimental procedures to study these effects of the so-called “NPs’ radiosensitization”. The paper presents the need to a better understanding of all the phases of actions before applying metallic-based NPs in clinical practice to improve the effect of IR therapy. More physical and biological experiments especially in vivo must be performed and simulation Monte Carlo or mathematical codes based on more accurate models for all phases must be developed.Many different tumor-targeted strategies are under development worldwide to limit the side effects and improve the effectiveness of cancer therapies. One promising method is to enhance the radiosensitization of the cancer cells while reducing or maintaining the normal tissue complication probability during radiation therapy using metallic nanoparticles (NPs). Radiotherapy with MV photons is more commonly available and applied in cancer clinics than high LET particle radiotherapy, so the addition of high-Z NPs has the potential to further increase the efficacy of photon radiotherapy in terms of NP radiosensitization. Generally, when using X-rays, mainly the inner electron shells are ionized, which creates cascades of both low and high energy Auger electrons. When using high LET particles, mainly the outer shells are ionized, which give electrons with lower energies than when using X-rays. The amount of the produced low energy electrons is higher when exposing NPs to heavy charged particles than when exposing them to X-rays. Since ions traverse the material along tracks, and therefore give rise to a much more inhomogeneous dose distributions than X-rays, there might be a need to introduce a higher number of NPs when using ions compared to when using X-rays to create enough primary and secondary electrons to get the desired dose escalations. This raises the questions of toxicity. This paper provides a review of the fundamental processes controlling the outcome of metallic NP-boosted photon beam and ion beam radiation therapy and presents some experimental procedures to study the biological effects of NPs’ radiosensitization. The overview shows the need for more systematic studies of the behavior of NPs when exposed to different kinds of ionizing radiation before applying metallic-based NPs in clinical practice to improve the effect of IR therapy.

Self-targeting nanotherapy based on functionalized graphene oxide for synergistic thermochemotherapy

Nanotherapy based on thermochemotherapy has boomed as a promising alternative for oncotherapy due to the enhanced permeability and retention (EPR) effect. However, a lack of self-targeting capacity prevents nanotherapy from efficiently accumulating in tumor tissue and internalizing into tumor cells, resulting in a suboptimal therapeutic effect. To overcome these bottlenecks, a kind of methotrexate (MTX)-soybean phospholipid (SPC) inclusion complex (MTX-SPC)-modified graphene oxide (CGO) nanotherapy (CGO-MTX-SPC) is constructed by CGO nanosheets as a supporter for MTX-SPC, thereby realizing active-targeting and synergistic thermochemotherapy. As an FDA-approved chemotherapeutic drug, MTX can be regarded as a tumor-targeting enhancer against the folate receptor on account of its similar structure to folic acid (FA). The fabricated CGO-MTX-SPC has a sheet shape with a size of ca. 109 nm and tumor microenvironment-responsive on-demand drug release. It is worth noting that the physiological stability of CGO-MTX-SPC is better than that of CGO while displaying an improved photothermal effect. In addition, CGO-MTX-SPC can specifically recognize tumor cells and then achieve on-demand drug burst release by dual stimuli of internal lysosomal acidity and an external laser. Moreover, in vivo experimental results further demonstrate that CGO-MTX-SPC displays significant enrichment at the tumor location by active targeting mechanisms due to the introduction of MTX-SPC, endowing the synergistic thermochemotherapy effect upon 808 nm laser irradiation and almost thorough tumor elimination while significantly erasing undesirable side effects. Taken together, the design idea of our nanotherapy not only provides a potential tumor-targeting therapeutic strategy but also broadens the drug payload method of two-dimensional nanomaterials.

Designing and Formulation Optimization of Hyaluronic Acid Conjugated PLGA Nanoparticles of Tamoxifen for Tumor Targeting.

Tamoxifen is widely used for the treatment of estrogen receptor-positive breast cancer. However, it is associated with severe side effects of cancerous proliferation on the uterus endometrium. The tumor-targeting formulation strategies can effectively overcome drug side effects of tamoxifen and provide safer drug treatment. This study aimed to design tumor-targeted PLGA nanoparticles of tamoxifen by attaching hyaluronic acid (HA) as a ligand to actively target the CD44 receptors present at breast cancer cells surface. PLGA-PEG-HA conjugate was synthesized in the laboratory, and its tamoxifen-loaded nanoparticles were fabricated and characterized by FTIR, NMR, DSC, and XRD analysis. Formulation optimization was done by Box-Behnken design using Design-Expert software. The formulations were evaluated for in vitro drug release and cytotoxic effect on MCF-7 cell lines. The particle size, PDI, and drug encapsulation efficiency of optimized nanoparticles were 294.8, 0.626, and 65.16%, respectively. Optimized formulation showed 9.56% burst release and sustained drug release for 8h. The drug release was affected by non-Fickian diffusion process and supplemented further by the erosion of polymeric matrix which followed the Korsmeyer-Peppas model. MTT cell line assay showed 47.48% cell mortality when treated with tamoxifen-loaded PLGA- PEG-HA nanoparticles. Hyaluronic acid conjugated PLGA-PEG nanoparticles of tamoxifen were designed for active targeting to cancerous breast cells. The results of the MTT assay showed that tamoxifen nanoparticles formulation was more cytotoxic than tamoxifen drug alone, which is attributed to their preferential uptake by cell lines by the affinity of CD44 receptors of cell lines to HA ligand present in nanoparticles.

The Cellular and Chemical Biology of Endocytic Trafficking and Intracellular Delivery-The GL-Lect Hypothesis.

Lipid membranes are common to all forms of life. While being stable barriers that delimitate the cell as the fundamental organismal unit, biological membranes are highly dynamic by allowing for lateral diffusion, transbilayer passage via selective channels, and in eukaryotic cells for endocytic uptake through the formation of membrane bound vesicular or tubular carriers. Two of the most abundant fundamental fabrics of membranes—lipids and complex sugars—are produced through elaborate chains of biosynthetic enzymes, which makes it difficult to study them by conventional reverse genetics. This review illustrates how organic synthesis provides access to uncharted areas of membrane glycobiology research and its application to biomedicine. For this Special Issue on Chemical Biology Research in France, focus will be placed on synthetic approaches (i) to study endocytic functions of glycosylated proteins and lipids according to the GlycoLipid–Lectin (GL–Lect) hypothesis, notably that of Shiga toxin; (ii) to mechanistically dissect its endocytosis and intracellular trafficking with small molecule; and (iii) to devise intracellular delivery strategies for immunotherapy and tumor targeting. It will be pointed out how the chemical biologist’s view on lipids, sugars, and proteins synergizes with biophysics and modeling to “look” into the membrane for atomistic scale insights on molecular rearrangements that drive the biogenesis of endocytic carriers in processes of clathrin-independent endocytosis.