Specific Recognition Of Cancer Cells Research Articles

Multifunctional DNA Nanoflower Applied for High Specific Photodynamic Cancer Therapy In Vivo.

Photodynamic therapy (PDT) is a newly emerged strategy for disease treatment. One challenge of the application of PDT drugs is the side-effect caused by the non-specificity of the photosensitive molecules. Most of the photosensitizers may invade not only the pathogenic cells but also the normal cells. In recent, people tried to use special cargoes to deliver the drugs into target cells. DNA nanoflowers (NFs) are a kind of newly-emerged nanomaterial which constructed through DNA rolling cycle amplification (RCA) reaction. It is reported that the DNA NFs were suitable materials which have been widely applied as nanocargos for drug delivery in cancer chemotherapeutic treatment. In this paper, we have introduced a new multifunctional DNA NF which could be prepared through an one-pot RCA reaction. This proposed DNA NF contained a versatile AS1411 G-quadruplex moiety, which plays key roles not only for specific recognition of cancer cells but also for near-infrared ray based photodynamic therapy when conjugating with a special porphyrin molecule. We demonstrated that the DNA NF showed good selectivity toward cancer cells, leading to highly efficient photo-induced cytotoxicity. Moreover, the in vivo experiment results suggested this DNA NF is a promising nanomaterial for clinical PDT.

Multifunctional aptamer grafted targeted nano‐drugs execute molecular cross‐talks with cancer cells

AbstractThe biggest obstacles in treating cancer with traditional chemotherapy are unpleasant side effects and drug resistance. A growing amount of interest has been exhibited in using aptamers as target ligands for targeted cancer therapy and specific cancer cell identification due to their distinct benefits. Aptamer‐conjugated nano‐materials have recently provided new prospects in cancer treatment with their improved therapeutic efficacy and capability of reducing toxicity. Consequently, they are not perceived as alien substances our body, which allows their comfortable acceptance. Several tumor markers such as nucleolin, mucin, and the epidermal growth factor receptor can be effectively recognized by aptamers. In addition, glycoproteins on the surface of tumor cells can be recognized using aptamers. So surface modification of drug by aptamer are accomplished for enhanced tumor‐specific recognition by which drug‐specific accretion, internalization, and drug retention in tumors increased through specific ligand‐mediated interactions and thus therapeutic index is increased. Here, we highlight some promising classes of aptamer‐conjugated nanoparticles for the specific recognition of cancer cells and targeted drug delivery and the molecular mechanism and immunomodulatory regulation of these aptamer have been focused.

Screening a DNA Aptamer Specifically Targeting Integrin β3 and Partially Inhibiting Tumor Cell Migration.

Due to its key roles in malignant tumor progression and reprograming of the tumor microenvironment, integrin β3 has attracted great attention as a new target for tumor therapy. However, the structure-function relationship of integrins β3 remains incompletely understood, leading to the shortage of specific and effective targeting probes. This work uses a purified extracellular domain of integrin β3 and integrin β3-positive cells to screen aptamers, specifically targeting integrin β3 in the native conformation on live cells through the SELEX approach. Following meticulous truncation and characterization of the initial aptamer candidates, the optimized aptamer S10yh2 was produced, exhibiting a low equilibrium dissociation constant (Kd) in the nanomolar range. S10yh2 displays specific recognition of cancer cells with varying levels of integrin β3 expression and demonstrates favorable stability in serum. Subsequent analysis of docking sites revealed that S10yh2 binds to the seven amino acid residues located in the core region of integrin β3. The S10yh2 aptamer can downregulate the level of integrin heterodimer αvβ3 on integrin β3 overexpressed cancer cells and partially inhibit cell migration behavior. In summary, S10yh2 is a promising probe with a small size, simple synthesis, good stability, high binding affinity, and selectivity. It therefore holds great potential for investigating the structure-function relationship of integrins.

Remodeling Tumor Immunogenicity with Dual-Activatable Binary CRISPR Nanomedicine for Cancer Immunotherapy.

The specific recognition of cancer cells by the body's immune system is an essential step in initiating antitumor immunity. However, the decreased expression of major histocompatibility complex class I (MHC-1) and overexpression of programmed death ligand 1 (PD-L1) causes insufficient tumor-associated antigens presentation and inactivation of T cells, which accounts for poor immunogenicity. To remodel tumor immunogenicity, herein, a dual-activatable binary CRISPR nanomedicine (DBCN) that can efficiently deliver a CRISPR system into tumor tissues and specifically control its activation is reported. This DBCN is made of a thioketal-cross-linked polyplex core and an acid-detachable polymer shell, which can maintain stability during blood circulation, while detaching a polymer shell to facilitate the cellular internalization of the CRISPR system after entering tumor tissues and ultimately activating gene editing under exogenous laser irradiation, thereby maximizing the therapeutic benefits and reducing potential safety concerns. With the collaborative application of multiple CRISPR systems, DBCN efficiently corrects both dysregulation of MHC-1 and PD-L1 expression in tumors, thus initiating robust T cell-dependent antitumor immune responses to inhibit malignant tumor growth, metastasis, and recurrence. Given the increasing abundance of CRISPR toolkits, this research provides an appealing therapeutic strategy and a universal delivery platform to develop more advanced CRISPR-based cancer treatments.

Combination Cancer Treatment: Using Engineered DNAzyme Molecular Machines for Dynamic Inter‐ and Intracellular Regulation

AbstractDespite the promise of combination cancer therapy, it remains challenging to develop targeted strategies that are nontoxic to normal cells. Here we report a combination therapeutic strategy based on engineered DNAzyme molecular machines that can promote cancer apoptosis via dynamic inter‐ and intracellular regulation. To achieve external regulation of T‐cell/cancer cell interactions, we designed a DNAzyme‐based molecular machine with an aptamer and an i‐motif, as the MUC‐1‐selective aptamer allows the specific recognition of cancer cells. The i‐motif is folded under the tumor acidic microenvironment, shortening the intercellular distance. As a result, T‐cells are released by metal ion activated DNAzyme cleavage. To achieve internal regulation of mitochondria, we delivered another DNAzyme‐based molecular machine with mitochondria‐targeted peptides into cancer cells to induce mitochondria aggregation. Our strategy achieved an enhanced killing effect in zinc deficient cancer cells.

Combination Cancer Treatment: Using Engineered DNAzyme Molecular Machines for Dynamic Inter- and Intracellular Regulation.

Despite the promise of combination cancer therapy, it remains challenging to develop targeted strategies that are nontoxic to normal cells. Here we report a combination therapeutic strategy based on engineered DNAzyme molecular machines that can promote cancer apoptosis via dynamic inter- and intracellular regulation. To achieve external regulation of T-cell/cancer cell interactions, we designed a DNAzyme-based molecular machine with an aptamer and an i-motif, as the MUC-1-selective aptamer allows the specific recognition of cancer cells. The i-motif is folded under the tumor acidic microenvironment, shortening the intercellular distance. As a result, T-cells are released by metal ion activated DNAzyme cleavage. To achieve internal regulation of mitochondria, we delivered another DNAzyme-based molecular machine with mitochondria-targeted peptides into cancer cells to induce mitochondria aggregation. Our strategy achieved an enhanced killing effect in zinc deficient cancer cells.

Poly(N-Isopropylacrylamide)-Functional Silicon Nanocrystals for Thermosensitive Fluorescence Cellar Imaging.

Silicon nanocrystals (Si NCs) have received surging interest as a type of quantum dot (QD) due to the availability of silicon in nature, tunable fluorescence emission properties and excellent biocompatibility. More importantly, compared with many group II–VI and III–V based QDs, they have low toxicity. Here, thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm)-functional Si NCs were firstly prepared for thermoresponsive detection of cancer cells. Si NCs were prepared under normal pressure with excellent water solubility. Then folic acid was bonded to the silicon nanocrystals through the reaction of amino and carboxyl groups for specific recognition of cancer cells. The folic-acid-modified silicon crystals (Si NCs-FA) could be modified by a one-pot copolymerization process into PNIPAAm nanospheres during the monomer polymerization process (i.e., Si NCs-FA-PNIPAAm) just by controlling the temperature below the lower critical solution temperature (LCST) and above the LCST. The results showed that the Si-FA-PNIAAm nanospheres exhibited not only reversible temperature-responsive on-off fluorescence properties, but also can be used as temperature indicators in cancer cells.

Tumor microenvironment (TME)-activatable circular aptamer-PEG as an effective hierarchical-targeting molecular medicine for photodynamic therapy

Photodynamic therapy (PDT) is an effective and noninvasive therapeutic strategy employing light-triggered singlet oxygen (SO) and reactive oxygen species (ROS) to kill lesional cells. However, for effective in vivo delivery of PDT agent into the cancer cells, various biological obstacles including blood circulation and condense extracellular matrix (ECM) in the tumor microenvironment (TME) need to be overcome. Furthermore, the enormous challenge in design of smart drug delivery systems is meeting the difference, even contradictory required functions, in different steps of the complicated delivery process. To this end, we present that TME-activatable circular pyrochlorophyll A (PA)-aptamer-PEG (PA-Apt–CHO–PEG) nanostructures, which combine the advantages of PEG and aptamer, would be able to realize efficient in vivo imaging and PDT. Upon intravenous (i.v.) injection, PA-Apt–CHO–PEG shows “stealth-like” long circulation in blood compartments without specific recognition capacity, but once inside solid tumor, PA-Apt–CHO–PEG nanostructures are cleaved and then form PA-Apt Aptamer-drug conjugations (ApDCs) in situ, allowing deep penetration into the solid tumor and specific recognition of cancer cells, both merits, considering anticipated future clinical translation of ApDCs.

A basic insight into aptamer-drug conjugates (ApDCs)

Aptamers are often compared with antibodies since both types of molecules function as targeting ligands for specific cancer cell recognition. However, aptamers offer several advantages, including small size, facile chemical modification, high chemical stability, low immunogenicity, rapid tissue penetration, and engineering simplicity. Despite these advantages, several crucial factors have delayed their clinical translation, such as concerns over inherent physicochemical stability and safety. Meanwhile, steps have been taken to make aptamer-drug conjugates, or ApDCs, a clinically practical tool. In this review, we highlight the development of ApDCs and discuss how researchers are solving some problems associated with their clinical application for targeted therapy.

Folate-Conjugated and Dual Stimuli-Responsive Mixed Micelles Loading Indocyanine Green for Photothermal and Photodynamic Therapy.

A folic acid targeted mixed micelle system based on co-assembly of poly(ε-caprolactone)-b-poly(methoxytri(ethylene glycol) methacrylate-co-N-(2-methacrylamido)ethyl folatic amide) and poly(ε-caprolactone)-b-poly(diethylene glycol monomethyl ether methacrylate) is developed to encapsulate indocyanine green (ICG) for photothermal therapy and photodynamic therapy. In this study, the use of folic acid is not only for specific cancer cell recognition, but also in virtue of the carboxylic acid on folic acid to regulate the pH-dependent thermal phase transition of polymeric micelles for controlled drug release. The prepared ICG-loaded mixed micelles possess several superior properties such as a preferable thermoresponsive behavior, excellent storage stability, and good local hyperthermia and reactive oxygen species generation under near-infrared (NIR) irradiation. The photototoxicity induced by the ICG-loaded micelles has efficiently suppressed the growth of HeLa cells (folate receptor positive cells) under NIR irradiation compared to that of HT-29, which has low folate receptor expression. Hence, this new type of mixed micelles with excellent features could be a promising delivery system for controlled drug release, effective cancer cell targeting, and photoactivated therapy.

The benefits of folic acid-modified gold nanoparticles in CT-based molecular imaging: radiation dose reduction and image contrast enhancement

X-ray computed tomography (CT) requires an optimal compromise between image quality and patient dose. While high image quality is an important requirement in CT, the radiation dose must be kept minimal to protect the patients from ionizing radiation-associated risks. The use of probes based on gold nanoparticles (AuNPs) along with active targeting ligands for specific recognition of cancer cells may be one of the balanced solutions. Herein, we report the effect of folic acid (FA)-modified AuNP as a targeted nanoprobe on the contrast enhancement of CT images as well as its potential for patient dose reduction. For this purpose, nasopharyngeal KB cancer cells overexpressing FA receptors were incubated with AuNPs with and without FA modification and imaged in a CT scanner with the following X-ray tube parameters: peak tube voltage of 130 KVp, and tube current–time products of 60, 90, 120, 160 and 250 mAs. Moreover, in order to estimate the radiation dose to which the patient was exposed during a head CT protocol, the CT dose index (CTDI) value was measured by an X-ray electrometer by changing the tube current–time product. Raising the tube current–time product from 60 to 250 mAs significantly increased the absorbed dose from 18 mGy to 75 mGy. This increase was not associated with a significant enhancement of the image quality of the KB cells. However, an obvious increase in image brightness and CT signal intensity (quantified by Hounsfield units [HU]) were observed in cells exposed to nanoparticles without any increase in the mAs product or radiation dose. Under the same Au concentration, KB cells exposed to FA-modified AuNPs had significantly higher HU and brighter CT images than those of the cells exposed to AuNPs without FA modification. In conclusion, FA-modified AuNP can be considered as a targeted CT nanoprobe with the potential for dose reduction by keeping the required mAs product as low as possible while enhancing image contrast.

Synthesis of a hemoglobin-conjugated triblock copolymer for oxygen carrying and specific recognition of cancer cells

Considering that hypoxia causes resistance to anti-cancer therapeutics, we synthesized a hemoglobin-based nanocarrier for oxygen carrying and recognition of cancer cells.

Interaction of cadmium sulfide quantum dots with jacalin for specific recognition of cancer cells

Surface functionalizations of quantum dots (QDs) are expected to improve their optoelectronic properties and advance their targeting nature, which is highly warranted for application in molecular imaging and biomedical diagnostics. Therefore, an understanding the interaction between surface functionalization agents and QDs is a prerequisite for their application. Herein, we investigated the interaction between cadmium sulfide (CdS) QDs and dietary T-antigen binding lectin (jacalin) isolated from Indian jack fruit seeds. Fluorescence spectroscopy study showed that CdS QDs effectively quenched the intrinsic fluorescence of jacalin. Analysis of fluorescence quenching at a different temperature indicated that the mechanism of interaction is static and a non-radiation energy transfer occurred within the molecules. The obtained binding constant, Ka value in the order of 104M−1 at the tested temperature range suggested that the binding affinity between jacalin and CdS QDs is in the same range as those obtained for the interaction of lectin with carbohydrate. Thermodynamic analysis of the binding data, ΔH0=−44.24±1.21kJmol−1, ΔS0=−60.92±4.10Jmol−1K−1 and ΔG0=−26.21±0.1kJmol−1 suggested that the binding reaction is enthalpy-driven spontaneous process. Hemagglutination activity of jacalin is well preserved even after binding to CdS QDs, indicating that the jacalin-CdS QDs complex can recognize T-antigens of the malignant tissues. To support the claim, we demonstrated selective fluorescence labeling of chronic myeloid leukemia cells, K562 with jacalin-CdS QDs complex.

Self-assembled multifunctional DNA nanoflowers for the circumvention of multidrug resistance in targeted anticancer drug delivery

Cancer chemotherapy has been impeded by side effects and multidrug resistance (MDR) partially caused by drug efflux from cancer cells, which call for targeted drug delivery systems additionally able to circumvent MDR. Here we report multifunctional DNA nanoflowers (NFs) for targeted drug delivery to both chemosensitive and MDR cancer cells and circumvent MDR in both leukemia and breast cancer cell models. NFs are self-assembled via liquid crystallization of DNA generated by Rolling Circle Replication, during which NFs are incorporated with aptamers for specific cancer cell recognition, fluorophores for bioimaging, and Doxorubicin (Dox)-binding DNA for drug delivery. NF sizes are tunable (down to ~200 nm in diameter), and the densely packed drug-binding motifs and porous intrastructures endow NFs with high drug loading capacity (71.4%, wt/wt). The Dox-loaded NFs (NF-Dox) are stable at physiological pH, yet drug release is facilitated in acidic or basic conditions. NFs deliver Dox into target chemosensitive and MDR cancer cells, preventing drug efflux and enhancing drug retention in MDR cells. Consequently, NF-Dox induces potent cytotoxicity in both target chemosensitive cells and MDR cells, but not nontarget cells, thus concurrently circumventing MDR and reducing side effects. Overall, these NFs are promising to circumvent MDR in targeted cancer therapy.

Adaptive Immune Resistance: How Cancer Protects from Immune Attack.

Adaptive immune resistance is a process in which the cancer changes its phenotype in response to a cytotoxic or proinflammatory immune response, thereby evading it. This adaptive process is triggered by the specific recognition of cancer cells by T cells, which leads to the production of immune-activating cytokines. Cancers then hijack mechanisms developed to limit inflammatory and immune responses and protect themselves from the T-cell attack. Inhibiting adaptive immune resistance is the mechanistic basis of responses to PD-1 or PD-L1-blocking antibodies, and may be of relevance for the development of other cancer immunotherapy strategies. Several new immunotherapy strategies to treat cancer are based on inhibiting processes through which cancer adapts and evades from an immune response. Recognizing the specific adaptive resistance mechanisms in each case is likely to allow the personalized development of immunotherapies tailored to block how a particular cancer protects itself from the immune system.

Nuclease-resistant synthetic drug-DNA adducts: programmable drug-DNA conjugation for targeted anticancer drug delivery

Targeted drug delivery is poised to improve cancer therapy, for which synthetic DNA can serve as targeting ligands (for example, aptamers) or drug nanocarriers. Inspired by natural DNA adducts, we report synthetic drug-DNA adducts (DDAs) for targeted anticancer drug delivery. Multiple copies of anthracycline drugs were site specifically (on deoxyguanosine) conjugated on each DNA, enabling programmable design of DNA and drugs for DDA preparation. DDAs were nuclease-resistant and stable for storage, yet gradually released drugs at physiological temperature. DDAs maintained DNA functionalities, including hybridization-mediated DNA nanoadduct formation and aptamer-mediated target recognition and targeted drug delivery into cancer cells. In a tumor xenograft mouse model, doxorubicin-aptamer adducts significantly inhibited target tumor growth while reducing the side effects. Using histopathological analysis and in situ immunohistochemical analysis of caspase-3 cleavage in mouse tumor and heart, DDAs were confirmed to have a potent antitumor efficacy while reducing tissue deformation and apoptosis in the heart, thus providing a new therapeutic avenue to prevent cardiomyopathy, the most dangerous side effect of doxorubicin leading to heart failure. Overall, DDAs are promising for scale-up production and clinical application in targeted anticancer drug delivery. Drug–DNA adducts have been developed for targeted drug delivery to inhibit tumor growth in mice while reducing side effects. Inspired by natural DNA adducts, researchers in China and USA have developed a simple but programmable way of producing synthetic drug-DNA adducts for targeted cancer therapy. They conjugated multiple copies of anthracycline drugs on each DNA base, using a one-step reaction in physiological buffer. The resultant DNA–drug adducts maintained the capability of DNA backbone to form specific aptamer conformations or to form DNA nanostructures by hybridization. Experiments on mice involving a commonly used chemotherapy drug revealed that the use of the adducts reduces toxicity in the heart, lowering the probability of cardiomyopathy, a frequently lethal side effect of chemotherapy. Drug–DNA adducts are promising for scale-up production and clinical applications of targeted drug delivery. We report nature-inspired drug-DNA adducts (DDAs) as a simple yet programmable platform for site-specific drug-DNA conjugation and application in targeted anticancer drug delivery. With multiple copies of drugs conjugated on one DNA, the DDAs were nuclease-resistant and stable for storage, yet gradually released drugs at physiological temperature. Designer DDAs were able to form nanoadducts by hybridization and fold into drug-aptamer adducts (DAAs) for specific recognition of cancer cells and targeted anticancer drug delivery. In a tumor xenograft mouse model, DAAs significantly inhibited tumor growth and reduced side effects, as verified by tissue analysis of tumors and hearts.

Droplet electrochemical study of the pH dependent redox behavior of novel ferrocenyl-carborane derivatives and its application in specific cancer cell recognition

Novel ferrocenyl based carboranes (FcCBs) and their distinguish behavior for cancer cell recognition have been explored in this contribution. The voltammetric study in a droplet of 10μL placed on the surface of a glassy carbon electrode demonstrates the excellent electrochemical behavior of FcCBs, which could be further exploited for establishing the promising and sensitive biosensors. The FcCBs’ redox behavior is examined in a wide pH range, and square wave voltammetry revealed the reversible and irreversible nature of first and second anodic peaks. The obvious shifts in peak potentials corresponding with the change of pH values demonstrate the abstraction of electrons to be accompanied with the transfer of protons. By using the droplet electrochemical technique, FcCBs can be employed to distinguish normal and cancer cells with a linear range from 1.0×103 to 3.0×104cellsmL−1 and the limit of detection at 800cellsmL−1. The novel carborane derivatives could be utilized as important potential molecular probes for specific recognition of cancer cells like leukemia cells from normal cells.

Aptamer-conjugated nanomaterials for specific cancer cell recognition and targeted cancer therapy.

Based on their unique advantages, increasing interest has been shown in the use of aptamers as target ligands for specific cancer cell recognition and targeted cancer therapy. Recently, the development of aptamer-conjugated nanomaterials has offered new therapeutic opportunities for cancer treatment with better efficacy and lower toxicity. We highlight some of the promising classes of aptamer-conjugated nanomaterials for the specific recognition of cancer cells and targeted cancer therapy. Recent developments in the use of novel strategies that enable sensitive and selective cancer cell recognition are introduced. In addition to targeted drug delivery for chemotherapy, we also review how aptamer-conjugated nanomaterials are being incorporated into emerging technologies with significant improvement in efficiency and selectivity in cancer treatment.

Photolabile plasmonic vesicles assembled from amphiphilic gold nanoparticles for remote-controlled traceable drug delivery

We have developed a new type of photo-responsive plasmonic vesicles that allow for active delivery of anticancer payloads to specific cancer cells and personalized drug release regulated by external photo-irradiation. Our results show that amphiphilic gold nanoparticles carrying hydrophilic poly(ethylene glycol) (PEG) and photo-responsive hydrophobic poly(2-nitrobenzyl acrylate) (PNBA) can assemble into plasmonic vesicles with gold nanoparticles embedded in the hydrophobic shell of PNBA, which can be converted into hydrophilic poly(acrylic acid) upon photo exposure. Benefiting from the interparticle plasmonic coupling of gold nanoparticles in close proximity, the plasmonic vesicles assembled from amphiphilic gold nanoparticles exhibit distinctively different optical properties from single nanoparticle units, which offer the opportunity to track the photo-triggered disassembly of the vesicles and the associated cargo release by plasmonic imaging. We have shown the dense layer of PEG grafts on the vesicles not only endow plasmonic vesicles with excellent colloidal stability, but also serve as flexible spacers for bioconjugation of targeting ligands to facilitate the specific recognition of cancer cells. The targeted delivery of model anticancer drug doxorubicin, investigated by dual-modality plasmonic and fluorescence imaging and toxicity studies, clearly demonstrated the potential of photolabile plasmonic vesicles as multi-functional drug carriers.

Orientation‐Controlled Conjugation of Haloalkane Dehalogenase Fused Homing Peptides to Multifunctional Nanoparticles for the Specific Recognition of Cancer Cells

In control: The ligand positioning and orientation on multifunctional nanoparticles (MNP) are controlled by using a versatile bimodular approach that exploits an 11 amino acid (U11) homing peptide genetically fused with a haloalkane dehalogenase (HALO) enzyme. The resultant nanoparticles have good targeting efficiency and selectivity toward broadly occurring urokinase plasminogen activator receptor positive human cancer cells.