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A multifunctional ICG-FA-PPD nanostructure is constructed by a facile self-assembly method through the negatively charged indocyanine green (ICG)- and positively charged folic acid-modified PEI-PEG-gadoteric acid (FA-PPD). The resulting ICG-FA-PPD is not only able to be used for targeting tumors, magnetic resonance imaging (MRI), and near-infrared imaging, but, more importantly, it enables photodynamic therapy for tumor.

The rapid development of fluorescence imaging technologies requires concurrent improvements in the performance of fluorescent probes. Quantum dots have been extensively used as an imaging probe in various research areas because of their inherent advantages based on unique optical and electronic properties. However, their clinical translation has been limited by the potential toxicity especially from cadmium. Here, a versatile bioimaging probe is developed by using highly luminescent cadmium-free CuInSe2/ZnS core/shell quantum dots conjugated with CGKRK (Cys–Gly–Lys–Arg–Lys) tumor-targeting peptides. This probe exhibits excellent photostability, reasonably long circulation time, minimal toxicity, and strong tumor-specific homing property. The most important feature of this probe is that it shows distinctive versatility in tumor-targeted multimodal imaging including near-infrared, time-gated, and two-photon imaging in different tumor models. In a glioblastoma mouse model, the targeted probe clearly denotes tumor boundaries and positively labels a population of diffusely infiltrating tumor cells, suggesting its utility in precise tumor detection during surgery. This work lays a foundation for potential clinical translation of the probe.

Molecular imaging enables noninvasive visualization of cancer-related biological processes for tumor diagnostics; engineering molecular probes for accurate and efficient tumor imaging remains challenge. Herein, by using a biosynthetic strategy, we prepared a tumor-targeted fluorescence/magnetic resonance protein-based probe for dual-modal imaging. The probe was biosynthesized by the fusion of targeting peptide (RGD) with fluorescence protein (RFP) and a small peptide (LBT) that had strong affinity with Gd3+. The probe showed excellent RGD-mediated tumor targeting and stable infrared emission, enabling sensitive tumor-specific imaging. Moreover, efficient T1-weighted magnetic resonance imaging was observed both in vitro and at tumor sites, facilitating high spatial resolution tumor imaging. The simultaneous dual-modal imaging provided more complementary information than each imaging modality. Our work demonstrates the capability of biosynthetic strategy to engineer molecular imaging probes for tumor-targeted multimodal bioimaging, and the probes can be customized to precisely localize and monitor other types of diseases.

Enhanced drug delivery can improve the therapeutic efficacy of drugs and help overcome side effects. However, many reported drug-delivery systems are too complex and irreproducible for practical use. In this work, the design of a hypoxia-responsive molecular container based on calixarene, called CAC4A, which presents a significant advance in practical, hypoxia-targeted drug-delivery, is reported. CAC4A enables a wide variety of clinical drugs to be quantitatively loaded to improve their solubility and stability, as well as enable the administration of reduced doses. Furthermore, as a result of its azo functional groups, which are sensitive to reduction within a hypoxic environment, it is possible to achieve tumor-targeted drug-release with reduced side effects. CAC4A fulfils all essential requirements for a drug-delivery system in addition to multiple advantages, including facile preparation, well-defined molecular weight, and structure, and universal applicability. Such features collectively enable supramolecular prodrugs to be formulated simply and reproducibly, with potential for bench-to-bedside translation. Moreover, CAC4A is amenable to other therapy modalities and can be facilely decorated with functional groups and hybridized with nanomaterials, providing ample possibilities for its role in future drug-delivery systems.

3596 Background: Immuno-checkpoint (IC) inhibitors targeting PD1-PD-L1 pathway have proven highly effective at extending survival of cancer patients. However, the clinical benefits of IC inhibitors are limited to only about 20% patients who have moderate to high levels of tumor PD1 and/or PD-L1 expression. To develop therapeutics that would provide clinical benefits to a larger proportion of cancer patients, we engineered oncolytic adenovirus for targeted infection of human tumor cells via CD46 and integrins of α3β1 or α6β4 classes, overexpressed on many epithelial human cancers. Methods: Here, we analyzed the infectivity and cytotoxicity of this novel oncolytic virus in a panel of human non-small cell lung cancers (NCSLC) cell lines, primary patient derived NSCLC xenografts, and tumor surgical explants from patients with renal cell carcinoma (RCC). Results: The in vitro analysis of NSCLC cells lines (N = 17) demonstrated that over 60% of them were highly sensitive to virus infection. The genome-wide transcriptional profiling showed that only 3 out of 12 cell lines that were sensitive to oncolytic virus infection, expressed PD-L1 ( > 4.5 Log2 RPMK). Furthermore, although the pre-treatment of these cell lines with IFN-I activated PD-L1 expression, IFN-I treatment did not reduce the efficacy of tumor cell infection by the oncolytic virus. The analysis of virus infectivity on primary human tumor cells from patients with NSCLC (N = 4) and RCC (N-24) demonstrated that primary tumors were highly sensitive to oncolytic virus infection. Specifically, tumor-targeted oncolytic virus demonstrated strong cytotoxicity in 22 out of 24 analyzed primary isolated RCC cell samples. Next, we subcutaneously grafted PD-L1-negative NSCLC A549 cells to NSG mice, treated them with oncolytic virus intravenously, and the kinetics of tumor growth and animal survival was monitored. This analysis showed that after intravenous administration, oncolytic virus was able to infect tumor cells and suppress tumor growth. Whereas the median survival in mock-treated group was 26 days, all mice survived up to 100 days post oncolytic virus therapy (endpoint). Conclusions: Our study showed that tumor-targeted oncolytic adenovirus infects human tumor cell lines independently of their PD-L1 expression status and is not sensitive to IFN-I inhibition. This novel tumor-targeted oncolytic virus has the potential to provide clinical benefits to cancer patients, who do not respond or became resistant to ICI drugs.

3110 Background: Solid tumors are replete with myeloid cells which, when activated, drive potent anti-tumor responses. Clinical development of systemically administered myeloid cell agonists, however, has been hindered by acute toxicities due to peripheral activation of the targeted cell types. Intratumoral administration, the route of delivery typically used for innate immune/myeloid cell agonists, is limited by tumor accessibility and a dependence on abscopal responses. A systemically delivered myeloid cell agonist with tumor-localized activity has the potential to overcome challenges encountered with other innate immune/myeloid cell agonists in clinical development. Methods: SBT6050 is a novel therapeutic comprised of a potent toll-like receptor (TLR) 8 agonist payload conjugated to a HER2-directed monoclonal antibody. Delivery of the payload into the endosome of human myeloid cells, where TLR8 resides, requires the co-engagement of HER2 on tumor cells and Fc gamma receptor on human myeloid cells. Thus, SBT6050 is designed for systemic delivery and tumor-targeted activation of human myeloid cells. Results: Studies with human immune cells show that SBT6050 potently induces, in a HER2-dependent manner, multiple anti-tumor immune activities due to its direct activation of myeloid cells and the subsequent induction of T and NK cell cytolytic activity. SBT6050 is designed to activate human myeloid cells only in the presence of HER2-positive tumor cells with moderate (2+ by IHC) or high (3+ by IHC) expression levels. Tumor-localized activity has been demonstrated in mouse models using a SBT6050 mouse surrogate. Systemic delivery results in robust single agent efficacy in multiple mouse tumor models, even those engineered to lack T cells, without accompanying peripheral cytokine production. Trastuzumab and SBT6050 bind to distinct epitopes on HER2 and enhanced activity is observed when the two agents are combined. Conclusions: SBT6050 is a systemically administered, tumor-targeted myeloid cell agonist that demonstrates single agent efficacy in multiple mouse tumor models without peripheral cytokine production. A first-in-human study with SBT6050 is expected to begin this year for patients with HER2-expressing solid tumors.

Correction for ‘Paclitaxel prodrug based mixed micelles for tumor-targeted chemotherapy’ by Dongyang Tang et al., RSC Adv., 2018, 8, 380–389.

In past decades, rapid progress in nanoparticle (NP) synthesis and engineering has provided a broad range of nanoscale agents affording both therapeutic and diagnostic functions. More recently, the emergence of biomimetic NPs as an efficient and promising technology has further expanded this field. The employment of biomemetic NPs offers many distinct advantages, including enhanced stability, the solubilization of hydrophobic payloads, extended blood residence times and the ability to better target a region of interest. In this review, we focus on two main categories of biomimetic NPs, protein/peptide-templated biomimetic NPs and cell membrane-derived biomimetic NPs. The properties, applications and challenges of these biomimetic NPs in tumor diagnosis and treatment are discussed. The pros and cons, and future development, of biomimetic NPs are also considered.

Inspired by the bionics of marine mussels, polydopamine (PDA), a new polymer with unique physicochemical properties was discovered. Due to its simple preparation, good biocompatibility, unique drug-loading methods, PDA has attracted tremendous attentions in field of drug delivery and imaging, and the combination of chemotherapy and other therapies or diagnostic methods, such as photothermotherapy (PTT), photoacoustic imaging (PAI), magnetic resonance imaging (MRI), etc. As an excellent drug carrier in tumor targeted drug delivery system, the drug release behavior of drug-loaded PDA-based nanoparticles is also an important factor to be considered in the establishment of drug delivery systems. Therefore, the purpose of this review is to provide a comprehensive overview of the various applications of PDA in tumor targeted drug delivery systems and to gain insight into the release behavior of the drug-loaded PDA-based nanocarriers. A sufficient understanding and discussion of these aspects is expected to provide a better way to design more rational and effective PDA-based tumor nano-targeted delivery systems. Apart from this, the prospects for the future application of PDA in this field and some unique insights are listed at the end of the article.

The paper considers the optimization issue of eight dipole antennas array surrounding the tested object. The goal was to maximize the specific absorption rate (SAR) in the target volume, while minimizing the same parameter in the outer ob- ject. The SAR optimization was prepared by means of the powers (amplitudes) and the phases used to excite the individual antenna elements of the array. Presented consideration may have a great importance in tumor targeted thermal therapy.

Self-assembled nanovehicles of chemotherapy drug with photothermal agent are regarded as intriguing chemo-photothermal therapy nanoplatform. However, most of the drugs and photothermal agents have poor water solubility and poor interactions to drive the formation of self-assembled nanovehicles, which is a bottleneck of co-assembled drug/photothermal agent for cancer therapy. Here, we proposed a versatile strategy to create self-assembled chemo-photothermal therapy nanoplatform based on the chemical modification of photothermal agent and drug. The IR-780 and camptothecin (CPT) were chosen as the studied models since they are important photothermal agent and anticancer drug, both of which have such poor water solubility with strong itself molecular interactions that they cannot co-assemble together. IR-780 was modified with an active targeting ligand lactobionic acid (LA) to result in amphiphilic IR780-LA while CPT was modified into redox-sensitive prodrug CPT-ss-CPT through a disulfide linkage to realize its assembly. Well-defined nanoparticles (NPs) could be created through the co-assembling of IR780-LA and CPT-ss-CPT. The IR780-LA/CPT-ss-CPT nanoparticles were demonstrated to be an excellent fluorescence imaging-guided, redox-responsive and enhanced synergistic chemo-photothermal therapy nanoplatform against tumors. Specifically, our chemical modification strategy offers a universal way to create self-assembled chemo-photothermal therapy nanoplatform, which solves the bottleneck of co-assembled drug/photothermal agent for cancer therapy. STATEMENT OF SIGNIFICANCE: Self-assembled nanoparticles of chemotherapeutics with photothermic drugs are regarded as intriguing chemo-photothermal therapy nanoplatform. However, most drugs have too poor solubility and interactions to form into self-assembled nanoparticles. We proposed a versatile strategy to create co-assembled chemo-photothermal therapy nanoparticles based on the chemical modification of common drugs. The IR-780 was modified with an active targeting ligand LA to result in amphiphilic IR780-LA molecules, while CPT was modified into redox-sensitive prodrug CPT-ss-CPT through disulfide linkage. Well-defined IR780-LA/CPT-ss-CPT nanoparticles were created through the co-assembling of IR780-LA and CPT-ss-CPT. The nanoparticles were demonstrated to be an excellent fluorescence imaging-guided, redox-responsive, active targeting chemo-photothermal therapy nanoplatform against tumors. Our strategy offers a versatile way to construct smart chemo-photothermal therapy nanoplatform from common drugs.

Photophysical properties of new tumor targeted photosensitizers based on cationic porphyrins and human transferrin were investigated. It was demonstrated that incorporation of the porphyrins into the protein causes slight changes of the photophysical properties of the photosensitizers. The kinetics of singlet oxygen luminescence photosensitized by porphyrin-transferrin complexes were studied.

With ever increasing scientific knowledge and awareness, research is underway around the globe to design new types of stimuli (external/internal) responsive nano-carriers for biotechnological applications at large and biomedical/pharmaceutical in particular. Based on literature evidence, stimuli-responsive carriers have been classified into four major categories, i.e. (1) physical, (2) chemical, (3) biological, and (4) dual (combination of any of the first three classes). Among various types, redox-responsive nano-carriers are of supreme interests and discussed here in this review. The difference in redox potential in tumor and normal tissue is considered as a potential target for tumor targeting leading to the development of redox-responsive drug delivery systems (DDS). In this regard, a high concentration of glutathione in tumor/intracellular environment has extensively been exploited. Disulfide bonds were found as a promising tool for designing redox-responsive which tend to cleave in a reductive environment forming sulfhydryl groups. Many nano-carriers have been explored widely to control tumor growth. These systems were used against the tumor xenograft animal model and showed improved tumor targeting with tumor growth inhibition. Herein, an effort has been made to summarize various aspects from design to development of numerous types of redox-responsive DDS including liposomes, micelles, nanoparticles, nanogel and prodrug based nanomedicines. An emphasis is also given on various types of nano-carriers with special reference to the tumor-targeted drug delivery applications. Also, dual responsive nano-carriers (in addition to redox-responsive) have also been briefly discussed. Towards the end of the chapter, the information is also given on their future perspectives.

Background:Ultrasound has been widely used in clinical diagnosis because it is noninvasive, inexpensive, simple, and reproducible. With the development of molecular imaging, material science, and ultrasound contrast agents, ultrasound-targeted delivery technology has emerged. The interaction of ultrasound and molecular probes can be exploited to change the structures of cells and tissues in order to promote the targeted release of therapeutic substances to local tumors. The targeted delivery of drugs, genes, and gases would not only improve the efficacy of tumor treatment but also avoid the systemic toxicity and side effects caused by antitumor treatments. This technology was recently applied in clinical trials and showed enormous potential for clinical application.Objective:This article briefly introduces the characteristics of the tumor microenvironment and the principle of ultrasound-targeted delivery technology. To present recent progress in this field, this review focuses on the application of ultrasound-targeted delivery technology in tumor-targeted therapy, including drug delivery, gene transfection, and gas treatment.Results:The results of this study show that ultrasound-targeted delivery technology is a promising therapeutic strategy for tumor treatment.Conclusion:Ultrasound-targeted delivery technology shows promise with regard to cancer treatment.

Unique physicochemical characteristics of graphitic carbon nitride (g-CN) nanosheets suit them to be a useful tool for two-photon fluorescence bioimaging. Current g-CN nanosheets based imaging probes typically use the "always-on" design strategies, which may suffer from increased fluorescence background and limited contrast. To advance corresponding applications, g-CN nanosheets based activatable two-photon fluorescence probes remain to be explored. For the first time, we developed an activatable two-photon fluorescence probe, constructed from a nanoassembly of g-CN nanosheets and hyaluronic acid (HA)-gold nanoparticles (HA-AuNPs), for detection and imaging of hyaluronidase (HAase) in cancer cells. The deliberately introduced HA in our design not only functions as the buffering layer for stabilizing AuNPs and inducing corresponding self-assembly on g-CN nanosheets but also as a pilot for targeting HA receptors overexpressed on cancer cell surfaces. Our results show that the developed nanoassembly enables specific detection and activatable imaging of HAase in cancer cells and deep tissues, with superb signal-to-background ratio and high sensitivity. This nanoassembly can afford a promising platform for highly specific and sensitive imaging of HAase and for related cancer diagnosis.

International audience; Despite approval for the treatment of various malignancies, clinical application of cytokines such as type I interferon (IFN) is severely impeded by their systemic toxicity. AcTakines (Activity-on-Target cytokines) are optimized immunocytokines that, when injected in mice, only reveal their activity upon cell-specific impact. We here show that type I IFN-derived AcTaferon targeted to the tumor displays strong antitumor activity without any associated toxicity, in contrast with wild type IFN. Treatment with CD20-targeted AcTaferon of CD20+ lymphoma tumors or melanoma tumors engineered to be CD20+, drastically reduced tumor growth. This antitumor effect was completely lost in IFNAR- or Batf3-deficient mice, and depended on IFN signaling in conventional dendritic cells. Also the presence of, but not the IFN signaling in, CD8+ T lymphocytes was critical for proficient antitumor effects. When combined with immunogenic chemotherapy, low-dose TNF, or immune checkpoint blockade strategies such as anti-PDL1, anti-CTLA4 or anti-LAG3, complete tumor regressions and subsequent immunity (memory) were observed, still without any concomitant morbidity, again in sharp contrast with wild type IFN. Interestingly, the combination therapy of tumor-targeted AcTaferon with checkpoint inhibiting antibodies indicated its ability to convert nonresponding tumors into responders. Collectively, our findings demonstrate that AcTaferon targeted to tumor-specific surface markers may provide a safe and generic addition to cancer (immuno)therapies.

With the increase in cancer incidences, developments of precise diagnostic and therapeutic methods have gained further significance. Iron oxide nanoparticles have been used as targeted cancer therapy agents and contrast enhancement agents for targeted cancer diagnosis. In this chapter, we discuss the applications of iron oxide nanoparticles for targeted tumor therapy and as multimodal imaging contrast agents.

At the end of the nineteenth century in 1894, Dr. Pierre-Paul Emile Roux from the Pasteur Institute in Paris demonstrated the clinical efficacy of serotherapy to treat diphtheria. A century later in 1994, Prof. Ronald Levy from Stanford University, CA, USA, demonstrated that antibodies could also be used to treat cancers. Since then, major improvements have been made in the design and production of antibodies, and they are now part of the conventional therapies of many cancers. More recently, it has been shown that antibodies could also be used to generate adaptive antitumor immunity in patients with cancer, by targeting co-inhibitory receptors expressed at the surface of T cells. The promising results obtained with such immunomodulatory antibodies open many perspectives for synergistic combinatorial strategies between tumor-targeted and immune-targeted antibodies.

Dual-modal imaging techniques have gained intense attention for their potential role in the dawning era of tumor early accurate diagnosis. Chelate-free robust dual-modal imaging nanoprobes with high efficiency and low toxicity are of essential importance for tumor targeted dual-modal in vivo imaging. It is still a crucial issue to endow Cd-free dual-modal nanoprobes with bright fluorescence as well as high relaxivity. Herein, a facile synthetic strategy was developed to prepare Gd-doped CuInS/ZnS bimodal quantum dots (GCIS/ZnS, BQDs) with optimized properties. The fluorescent properties of the GCIS/ZnS BQDs can be thoroughly optimized by varying reaction temperature, aging time, and ZnS coating. The amount of Gd precursor can be well-controlled to realize the optimized balance between the MR relaxivity and optical properties. The obtained hydrophobic GCIS/ZnS BQDs were surface engineered into aqueous phase with PEGylated dextran-stearyl acid polymeric lipid vesicles (PEG-DS PLVs). Upon the phase transfer, the hydrophilic GCIS/ZnS@PLVs exhibited pronounced near-infrared fluorescence as well as high longitudinal relaxivity (r1 = 9.45 mM(-1) S(-1)) in water with good colloidal stability. In vivo tumor-bearing animal experiments further verified GCIS/ZnS@PLVs could achieve tumor-targeted MR/fluorescence dual-modal imaging. No toxicity was observed in the in vivo and ex vivo experiments. The GCIS/ZnS@PLVs present great potential as bimodal imaging contrast agents for tumor diagnosis.

Advances in the application of nanotechnology in medicine have given rise to multifunctional smart nanocarriers that can be engineered with tunable physicochemical characteristics to deliver one or more therapeutic agent(s) safely and selectively to cancer cells, including intracellular organelle-specific targeting. Dendrimers having properties resembling biomolecules, with well-defined 3D nanopolymeric architectures, are emerging as a highly attractive class of drug and gene delivery vector. The presence of numerous peripheral functional groups on hyperbranched dendrimers affords efficient conjugation of targeting ligands and biomarkers that can recognize and bind to receptors overexpressed on cancer cells for tumor-cell-specific delivery. The present review compiles the recent advances in dendrimer-mediated drug and gene delivery to tumors by passive and active targeting principles with illustrative examples.

The key issues, associated with nanocarriers for small interfering RNAs (siRNAs), are their poor stability and lack of tumor targetability in vivo. To address these issues, we developed gold-installed polyethyleneimine/siRNA complexes with a corona of PEGylated hyaluronic acid.

Acid/redox dual-activated liposomes consisting of a synthetic functional lipid were developed to overcome the multiple barriers to the intravenous delivery of an anticancer drug from the injection site to the target site. The liposome exhibited tumor pH-promoted cellular uptake, endocytic pH-responsive endo-lysosomal escape and redox-triggered intracellular drug release, thereby yielding enhanced antitumor activity.

Nanomedicines based on biodegradable polymers for tumor imaging and therapy receive more and more attention due to their improved water solibility, bioavailability, and extended blood circulation times. Advanced polymer chemistry combined with a thorough understanding of the tumor microenvironment, allows the design and evaluation of improved multifunctional polymer-based nanomedicines for more effective cancer imaging and therapy. This thesis focuses on the design and evaluation of novel reduction-sensitive polymer-based nanomedicines for improved tumor-targeted imaging and therapy. The use of ligands (mono or dual) for targeting the nanosystems to the tumors and uptake by cells in the tumor have been described as well as the release of drugs from a nanosystem designed to release the drug in the tumor area by an external trigger. The in vivo performance of the nanomedicines described in this thesis including the stability, tumor targeting efficiency and antitumor efficacy have been evaluated using various tumor models.

Tetrahedral DNA nanostructures (TDNs) are considered promising drug delivery carriers because they are able to permeate cellular membrane and are biocompatible and biodegradable. Furthermore, they can be modified by functional groups. To improve the drug-delivering ability of TDNs, we chose anticancer aptamer AS1411 to modify TDNs for tumor-targeted drug delivery. AS1411 can specifically bind to nucleolin, which is overexpressed on the cell membrane of tumor cells. Furthermore, AS1411 can inhibit NF-κB signaling and reduce the expression of bcl-2. In this study, we compared the intracellular localization of AS1411-modified TDNs (Apt-TDNs) with that of TDNs in different cells under hypoxic condition. Furthermore, we compared the effects of Apt-TDNs and TDNs on cell growth and cell cycle under hypoxic condition. A substantial amount of Apt-TDNs entered and accumulated in the nucleus of MCF-7 cells; however, the amount of Apt-TDNs that entered L929 cells was comparatively less. TDNs entered in much lower quantity in MCF-7 cells than Apt-TDNs. Moreover, there was little difference in the amount of TDNs that entered L929 cells and MCF-7 cells. Apt-TDNs can inhibit MCF-7 cell growth and promote L929 cell growth, while TDNs can promote both MCF-7 and L929 cell growth. Thus, the results indicate that Apt-TDNs are more effective tumor-targeted drug delivery vehicles than TDNs, with the ability to specifically inhibit tumor cell growth.

Thermosensitive liposomes (TSLs) have been an important research area in the field of tumor targeted chemotherapy. Since the first TSLs appeared that using 1,2-dipalmitoyl-sn-glyce-ro-3-phosphocholine (DPPC) as the primary liposomal lipid, many studies have been done using this type of liposome from basic and practical aspects. While TSLs composed of DPPC enhance the cargo release near the phase transition temperature, it has been shown that many factors affect their temperature sensitivity. Thus numerous attempts have been undertaken to develop new TSLs for improving their thermal response performance. The main objective of this review is to introduce the development and recent update of innovative TSLs formulations, including combination of radiofrequency ablation (RFA), high-intensity focused ultrasound (HIFU), magnetic resonance imaging (MRI) and alternating magnetic field (AMF). In addition, various factors affecting the design of TSLs, such as lipid composition, surfactant, size and serum components are also discussed., Graphical abstract Image, graphical abstract

Incorporation of T1 and T2 contrast material in one nanosystem performing their respective MR contrast role and simultaneously serving as an efficient drug delivery system (DDS) has a significant potential application for clinical diagnosis and chemotherapy of cancer. However, inappropriate incorporation always encountered many issues, such as low contact area of T1 contrast material with water-proton, inappropriate distance between T2 contrast material and water molecule, and undesirable disturbance of T2 contrast material for T1 imaging. Those issues seriously limited the T1 or T2 contrast effect. In this work, we developed a yolk-like Fe3O4@Gd2O3 nanoplatform functionalized by polyethylene glycol and folic acid (FA), which could efficiently exert their tumor targeted T1–T2 dual-mode MR imaging and drug delivery role. First, this nanoplatform possessed a high longitudinal relaxation rate (r1) (7.91 mM–1 s–1) and a stronger transverse relaxation rate (r2) (386.5 mM–1 s–1) than that of original Fe3O4 (268...

To develop an effective therapeutic treatment, the potential of poly (lactic-co-glycolic acid)-polyethylene glycol-retinoic acid (PLGA-PEG-RA) polymeric micelles for targeted delivery of irinotecan to hepatocellular carcinoma (HepG2) and colorectal cancer cell lines (HT-29) was evaluated. PLGA-PEG-RA was synthesized by amide reaction of PLGA with NH2-PEG-NH

A new acidly sensitive PEGylated polyethylenimine linked by Schiff base (PEG-s-PEI) was designed to render pH-sensitive PEGylation nanoassemblies through multiple interactions with indomethacin and docetaxel (DTX). DTX nanoassemblies driven by PEG-s-PEI thus formulated exhibited an excellent pH-sensitivity PEGylation cleavage performance at extracellular pH of tumor microenvironment, compared to normal tissues, thereby long circulated in blood but were highly phagocytosed by tumor cells. Consequently, this smart pH-sensitive PEGylation cleavage provided an efficient strategy to target tumor microenvironment, in turn afforded superior therapeutic outcome in anti-tumor activity.

Biocompatibility, targeting, and clearance are key challenges in the design of new MRI contrast agents. Herein, we report on a tumor-targeting, gadolinium biomineralized human transferrin (Tf) protein-based nanoparticle (Gd@Tf NP) for MRI use. As compared to the conventionally used gadolinium chelates, the resultant Gd@Tf NPs possess outstanding chemical stability and exhibited superior longitudinal relaxation. More importantly, our MR images show that Gd@Tf indeed retained the natural tumor targeting ability and the subsequent tumor retrieval biofunctions of Tf. Thus, such Tf protein-based MR NPs integrate T1 signal amplification, precise tumor targeting, and systematic clearance capabilities. They offer a new approach to design biocompatible multifunctional MRI contrast agents for a wide range of clinical imaging and treatment applications.

A novel reduction and pH dual-sensitive nonviral vector for long-circulating and tumor-targeted siRNA delivery is described. The nanomedicine is negatively charged at neutral pH of bloodstream whereas it is positively charged at lower pH of tumor tissue (ca. 6.8). Interlayer crosslinking with disulfide bonds stabilizes the nanomedicine during blood circulation and allows quick intracellular siRNA release after endocytosis.

Structure activity relationship (SAR) of fibroblast activation protein alpha (FAP) inhibitors will be useful to evaluate bioactivities of candidates. To discuss SAR of FAP inhibitors, two alignment styles were carried out to build QSAR models of FAP inhibitors. HQSAR was used to construct 2D-QSAR after the selection of training set and test set by principal component analysis method. Meanwhile, 3D-QSAR models were constructed by comparative molecular field analysis and comparative molecular similarity indices analysis method and optimized by FOCUS method. All the QSAR models were validated by cross-validation and test set, and the targeted QSAR model was selected by comprehensive evaluation containing cross-validation coefficient, correlation coefficient and consistency with docking studies. The result suggests that 2D-QSAR model may be insufficient to evaluate SAR of FAP inhibitors, while 3D-QSAR model with S+H+D_F functional fields could be applied to characterize the SAR based on docking conformation alignment.

101 Background: Targeted gene delivery in vivo has long been considered the “Holy Grail” of gene therapy. Methods: We reviewed long-term data of patients with advanced chemotherapy-resistant malignancies, previously-treated patients with two tumor-targeted retrovectors: (1) encoding cytotoxic dominant negative cyclin G1, DeltaRex-G (formerly Rexin-G), and (2) encoding cytokine GMCSF plus suicide gene HStk, DeltaVax (formerly Reximmune-C). Results: Ninety-nine patients received > 5,000 intravenous infusions of DeltaRex-G; another 16 patients received 288 intravenous infusions of DeltaRex-G + 96 infusions of DeltaVax followed by valacyclovir p.o. No therapy-related bone marrow suppression, organ dysfunction or delayed treatment related adverse events were observed. Survival analysis showed 5.0% 10-year overall survival rate for patients who received DeltaRex-G alone, and 18.8% for DeltaRex-G + DeltaVax. Conclusions: Data analysis indicates that tumor-targeted gene delivery in vivo, represented by cytocidal DeltaRex-G, with or without immuno-stimulatory DeltaVax, has induced prolonged ( > 10 years) sustained remissions in cancer patients presenting with advanced chemotherapy-resistant solid and hematologic malignancies—plausibly due to safety, selectivity, and immune modulation. While the curative potential of precision targeted genetic medicine necessarily remains an academic question; it is clear that these initial long-term, cancer-free ( > 10 year) survivors represent a major milestone in both cancer therapy and immunotherapy. Phase 2-3 clinical trials are planned for these hard-to treat malignancies.

Hyperthemia (>50 °C) induced heating damage of nearby normal organs and inflammatory diseases are the main challenges for photothermal therapy (PTT) of cancers. To overcome this limitation, a redox-responsive biomodal tumor-targeted nanoplatform is synthesized, which can achieve multispectral optoacoustic tomography/X-ray computed tomography imaging-guided low-temperature photothermal-radio combined therapy (PTT RT). In this study, Bi2 Se3 hollow nanocubes (HNCs) are first fabricated based on a mild cation exchange way and Kirkendall effect and then modified with hyaluronic acid (HA) through redox-cleavable linkage (-s-s-), thus enabling the HNC to target cancer cells overexpressing CD-44 and control the cargo release profile. Finally, gambogic acid (GA), a type of heat-shock protein (HSP) inhibitor, which is vital to cells resisting heating-caused damage is loaded, into Bi2 Se3 HNC. Such HNC-s-s-HA/GA under a mild NIR laser irradiation can induce efficient cancer cell apoptosis, achieving PTT under relatively low temperature (≈43 °C) with remarkable cancer cell damage efficiency. Furthermore, enhanced radiotherapy (RT) can also be experienced without depth limitation based on RT sensitizer Bi2 Se3 HNC. This research designs a facile way to synthesize Bi2 Se3 HNC-s-s-HA/GA possessing theranostic functionality and cancer cells-specific GSH, but also shows a low-temperature PTT RT method to cure tumors in a minimally invasive and highly efficient way.

A radioactive metallofullerene 177LuxLu(3−x)N@C80 was firstly synthesized by means of neutron irradiation on Lu3N@C80. After modification by methoxypolyethylene glycol amine, in vivo investigation on tumor-bearing mice was performed. The results reveal favorable affinity toward tumors, suggesting that the obtained 177LuxLu(3−x)N@C80–PCBPEG could be promising for tumor diagnosis and therapy.

Long circulating liposomal drug carriers are widely used in experimental cancer therapy because they avoid excretion and benefit from the enhanced permeability and retention-effect to accumulate at the tumor site while simultaneously limiting systemic exposure to the cytotoxic drug due to their high stability. A drawback of the stability of the formulation is that the unloading of the drug at the target site is very poor. This opens up a new challenge to trigger drug release at the target site, while still retaining most of the drug inside the carrier while it resides in the bloodstream.A short introduction is given about lipid polymorphism and phase behavior. To illustrate how this can be used to design triggered release systems, the development of delivery systems that are activated by tumor environment, UV or visible light and mild heat are discussed. The most recent triggered release systems have evolved even further, creating a need for more sophisticated triggers, which are as non-invasive and patient friendly as possible.Currently the most promising triggered release systems that have advanced furthest are thermosensitive liposomal delivery systems. As mild hyperthermia also increases tissue permeability it appears a suitable trigger for drug release while it also assists in drug accumulation. Combined with an advanced imaging system in the MR-high intensity focused ultrasound, this could be the combination of delivery system and trigger that can achieve clinical success.

Photothermal therapy (PTT) is attracting increasing interest and becoming more widely used for skin cancer therapy in the clinic, as a result of its noninvasiveness and low systemic adverse effects. However, there is an urgent need to develop biocompatible PTT agents, which enable accurate imaging, monitoring, and diagnosis. Herein, a biocompatible Gd-integrated CuS nanotheranostic agent (Gd:CuS@BSA) was synthesized via a facile and environmentally friendly biomimetic strategy, using bovine serum albumin (BSA) as a biotemplate at physiological temperature. The as-prepared Gd:CuS@BSA nanoparticles (NPs) with ultrasmall sizes (ca. 9 nm) exhibited high photothermal conversion efficiency and good photostability under near-infrared (NIR) laser irradiation. With doped Gd species and strong tunable NIR absorbance, Gd:CuS@BSA NPs demonstrate prominent tumor-contrasted imaging performance both on the photoacoustic and magnetic resonance imaging modalities. The subsequent Gd:CuS@BSA-mediated PTT result shows high therapy efficacy as a result of their potent NIR absorption and high photothermal conversion efficiency. The immune response triggered by Gd:CuS@BSA-mediated PTT is preliminarily explored. In addition, toxicity studies in vitro and in vivo verify that Gd:CuS@BSA NPs qualify as biocompatible agents. A biodistribution study demonstrated that the NPs can undergo hepatic clearance from the body. This study highlights the practicality and versatility of albumin-mediated biomimetic mineralization of a nanotheranostic agent and also suggests that bioinspired Gd:CuS@BSA NPs possess promising imaging guidance and effective tumor ablation properties, with high spatial resolution and deep tissue penetration.

Increasing incidents of patients diagnosed with cancer have brought massive improvement in the delivery technologies to help patients receiving chemotherapy. However, tumor specific targeting of the chemotherapeutics still remains as a challenge mainly due to the difficulties in the conjugation and manipulation of bio-specific molecules on the surface. Herein, we genetically engineered bacterial protoplast to develop nanovesicles having no toxic outer membrane components that can specifically target and deliver chemotherapeutics to tumor tissues. The bacterial protoplast nanovesicles expressing tumor-targeting moieties on the surface were prepared by serial extrusions through nano-sized membrane filters. The nano-sized vesicular structure of protoplast nanovesicles offers passive targeting to solid tumor site and expression of tumor-targeting moiety enhance tumor-specific uptake via receptor-mediated targeting. Chemotherapeutics-loaded in the nanovesicles induce dose-dependent cytotoxicity in tumor cells in vitro. Moreover, specific trafficking of drug-loaded nanovesicles to the tumor tissue and efficient prevention of tumor growth in tumor xenografted mice are shown. Importantly, this tumor growth suppression of protoplast nanovesicles has shown to reduce the chemotherapeutics-induced adverse effects after systemic administration to mice. This study offers great potential of protoplast nanovesicles as effective and safe delivery system to optimize and contribute to the development of advanced chemotherapy.