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Here, a novel targeted nanostructure complex was designed as an alternative to the traditional treatment approaches for breast cancer. A delivery system utilizing CuS nanoparticles (CuS NPs) was developed for the purpose of targeted administration of doxorubicin (Dox), an anticancer agent. To regulate Dox release, chitosan (CS), a biodegradable and hydrophilic polymer with biocompatible properties, was applied to coat the Dox-loaded CuS NPs. Furthermore, AS1411 aptamer, served as a targeting agent for breast cancer cells (MCF-7 and 4T1 cells), was conjugated with CS-Dox-CuS NPs effectively. To assess the effectiveness of APT-CS-CuS NPs, various methods such as flow cytometry analysis, MTT assay, fluorescence imaging, and in vivo antitumor efficacy were employed. The hollow core and porous surface of CuS NPs improved the Dox loading capacity and entrapment efficiency (almost 100%). The rate of drug release at the tumor site (citrate buffer with pH 5.6) exhibited a marked increase in comparison to that observed within the physiological environment (phosphate buffer with pH 7.4). The targeted formulation (APT-CS-Dox-CuS NPs) significantly increased cytotoxicity of the Dox payload in target cells, including 4T1 (p ≤ 0.0001 (****)) and MCF7 (p ≤ 0.01 (**)) cells compared to CHO cells. Moreover, the ability of tumor growth inhibition of the targeted system was significantly (p ≤ 0.05 (*)) more than free Dox in tumor-bearing mice. The findings indicate that the targeted formulation augmented effectiveness and specificity while minimizing harm to non-targeted cells, signifying its potential as a sophisticated cancer drug delivery system. [Display omitted] • A delivery system utilizing CuS nanoparticles (CuS NPs) was developed for the targeted administration of Dox. • To regulate Dox release, chitosan (CS) was applied to coat the Dox-loaded CuS NPs. • CS-Dox-CuS NPs was modified with AS1411 aptamer as a targeting agent for breast cancer cells. • The targeted formulation (APT-CS-Dox-CuS NPs) significantly increased cytotoxicity of the Dox payload in target cancer cells. • The ability of tumor growth inhibition of the targeted system was significantly more than free Dox in tumor-bearing mice. [ABSTRACT FROM AUTHOR]

Development of AS1411aptamer-conjugated liposomes for targeted delivery of arsenic trioxide is the primary goal of this study. AS1411aptamer was used as ligand to target nucleolin, which is highly expressed on the surface of melanoma cancer cells. The targeted liposomes were constructed by the thin film method, and arsenic trioxide was loaded as cobalt (II) hydrogen arsenite (CHA) to increase the loading efficiency and stability of the liposomes. The liposomal structure was characterized by Fourier Transform Infrared Spectroscopy (FT-IR) and field emission scanning electron microscopy (FESEM). In addition, particle sizes and zeta potential of the CHA-loaded liposomes (CHAL) and aptamer-functionalized CHA-loaded liposomes (AP-CHAL) were determined. In vitro cytotoxicity of CHAL and AP-CHAL were evaluated using MTT assay in murine melanoma (B16) and mouse embryonic fibroblast (MEF) cell lines. The encapsulation efficiency of CHAL and AP-CHAL was reported as 60.2 ± 6.5% and 58.7 ± 4.2%, respectively. In vivo antitumor activity of CHAL and AP-CHAL in the B16 tumor-xenograft mouse model was dramatically observed. All mice of both groups survived until the end of treatment and showed body weight gain. The tumor protrusion completely disappeared in 50% of the mice in these groups. Furthermore, histopathology studies demonstrated that CHAL and AP-CHAL did not induce significant toxicity in healthy mice tissues. However, unlike the CHAL group, which showed an initial increase in tumor volume, a specific antitumor effect was observed in the AP-CHAL group from the beginning of treatment. The results showed that AP-CHAL can be used as an effective drug delivery system with high potential in the treatment of solid tumors. [ABSTRACT FROM AUTHOR]

Abstract Due to its complicated pathophysiology, propensity for metastasis, and poor prognosis, colon cancer is challenging to treat and must be managed with a combination of therapy. Using rolling circle transcription (RCT), this work created a nanosponge therapeutic medication system (AS1411@antimiR-21@Dox). Using the AS1411 aptamer, this approach accomplished targeted delivery to cancer cells. Furthermore, analysis of cell viability, cell apoptosis, cell cycle arrest, reactive oxygen species (ROS) content, and mitochondrial membrane potential (MMP) levels revealed that functional nucleic acid nanosponge drug (FND) can kill cancer cells. Moreover, transcriptomics uncovered a putative mechanism for the FND anti-tumor effect. These pathways, which included mitotic metaphase and anaphase as well as the SMAC-mediated dissociation of the IAP: caspase complexes, were principally linked to the cell cycle and cell death. In conclusion, by triggering cell cycle arrest and apoptosis, the nano-synergistic therapeutic system allowed for the intelligent and effective targeted administration of RNA and chemotherapeutic medicines for colon cancer treatment. The system allowed for payload efficiency while being customizable, targeted, reliable, stable, and affordable.

Abstract Targeted chemo-phototherapy has received widespread attention in cancer treatment for its advantages in reducing the side effects of chemotherapeutics and improving therapeutic effects. However, safe and efficient targeted-delivery of therapeutic agents remains a major obstacle. Herein, we successfully constructed an AS1411-functionalized triangle DNA origami (TOA) to codeliver chemotherapeutic drug (doxorubicin, DOX) and a photosensitizer (indocyanine green, ICG), denoted as TOADI (DOX/ICG-loaded TOA), for targeted synergistic chemo-phototherapy. In vitro studies show that AS1411 as an aptamer of nucleolin efficiently enhances the nanocarrier’s endocytosis more than 3 times by tumor cells highly expressing nucleolin. Subsequently, TOADI controllably releases the DOX into the nucleus through the photothermal effect of ICG triggered by near-infrared (NIR) laser irradiation, and the acidic environment of lysosomes/endosomes facilitates the release. The downregulated Bcl-2 and upregulated Bax, Cyt c, and cleaved caspase-3 indicate that the synergistic chemo-phototherapeutic effect of TOADI induces the apoptosis of 4T1 cells, causing ~ 80% cell death. In 4T1 tumor-bearing mice, TOADI exhibits 2.5-fold targeted accumulation in tumor region than TODI without AS1411, and 4-fold higher than free ICG, demonstrating its excellent tumor targeting ability in vivo. With the synergetic treatment of DOX and ICG, TOADI shows a significant therapeutic effect of ~ 90% inhibition of tumor growth with negligible systemic toxicity. In addition, TOADI presents outstanding superiority in fluorescence and photothermal imaging. Taken together, this multifunctional DNA origami-based nanosystem with the advantages of specific tumor targeting and controllable drug release provides a new strategy for enhanced cancer therapy.

A nanoassembly of PEI-passivated Gd@CDs, a type of aptamer, is presented which was designed and characterized in order to target specific cancer cells based on their recognition of the receptor nucleolin (NCL), which is overexpressed on the cell membrane of breast cancer cells for fluorescence and magnetic resonance imaging and treatment. Using hydrothermal methods, Gd-doped nanostructures were synthesized, then modified by a two-step chemical procedure for subsequent applications: the passivating of Gd@CDs with branched polyethyleneimine (PEI) (to form Gd@CDs-PEI1 and Gd@CDs-PEI2), and using AS1411 aptamer (AS) as a DNA-targeted molecule (to generate AS/Gd@CDs-PEI1 and AS/Gd@CDs-PEI2). Consequently, these nanoassemblies were constructed as a result of electrostatic interactions between cationic Gd@CDs-passivated PEI and AS aptamers, offering efficient multimodal targeting nanoassemblies for cancer cell detection. It has been demonstrated through in vitro studies that both types of AS-conjugated nanoassemblies are highly biocompatible, have high cellular uptake efficiency (equivalent concentration of AS: 0.25 μΜ), and enable targeted fluorescence imaging in nucleolin-positive MCF7 and MDA-MB-231 cancer cells compared to MCF10-A normal cells. Importantly, the as-prepared Gd@CDs, Gd@CDs-PEI1, and Gd@CDs-PEI2 exhibit higher longitudinal relaxivity values (r1) compared with the commercial Gd-DTPA, equal to 5.212, 7.488, and 5.667 mM−1s−1, respectively. Accordingly, it is concluded that the prepared nanoassemblies have the potential to become excellent candidates for cancer targeting and fluorescence/MR imaging agents, which can be applied to cancer imaging and personalized nanomedicine. [ABSTRACT FROM AUTHOR]

AS1411 aptamer is able to recognise the nucleolin overexpressed on cancer cell membranes and has shown promise as a carrier of doxorubicin (Dox) to the cells. This study aimed to study the interaction between nucleolin and aptamers, in either the absence or presence of Dox, using molecular dynamics simulation. AS22nt aptamer was constructed by joining AS1411 aptamer with an additional 22 nucleotide (nt) sequence. NPT simulations were performed from initial docked configuration predicted by HDOCK. The binding of Dox to AS22nt aptamer occurred at the minor groove and the intercalation site in the duplex region. Nucleolin exhibited less flexibility upon binding to AS22nt. The dominant interaction between nucleolin and AS22nt was the electrostatic interaction. The presence of Dox in AS22nt affected the AS22nt-nucleolin interaction contributed by hydrogen bond, hydrophobic contact and ionic interaction. However, the presence of Dox in AS22nt had no impact on the interaction between nucleolin and AS22nt because the magnitudes of binding energy of nucleolin and aptamer with Dox or without Dox were comparable and they were within their calculated deviation. This understanding of nucleolin, AS1411 aptamer, and Dox interactions could provide us a way to prepare an effective targeted anticancer agent for cancer-suffering patients. [ABSTRACT FROM AUTHOR]

Targeted chemo-phototherapy has received widespread attention in cancer treatment for its advantages in reducing the side effects of chemotherapeutics and improving therapeutic effects. However, safe and efficient targeted-delivery of therapeutic agents remains a major obstacle. Herein, we successfully constructed an AS1411-functionalized triangle DNA origami (TOA) to codeliver chemotherapeutic drug (doxorubicin, DOX) and a photosensitizer (indocyanine green, ICG), denoted as TOADI (DOX/ICG-loaded TOA), for targeted synergistic chemo-phototherapy. In vitro studies show that AS1411 as an aptamer of nucleolin efficiently enhances the nanocarrier's endocytosis more than 3 times by tumor cells highly expressing nucleolin. Subsequently, TOADI controllably releases the DOX into the nucleus through the photothermal effect of ICG triggered by near-infrared (NIR) laser irradiation, and the acidic environment of lysosomes/endosomes facilitates the release. The downregulated Bcl-2 and upregulated Bax, Cyt c, and cleaved caspase-3 indicate that the synergistic chemo-phototherapeutic effect of TOADI induces the apoptosis of 4T1 cells, causing ~ 80% cell death. In 4T1 tumor-bearing mice, TOADI exhibits 2.5-fold targeted accumulation in tumor region than TODI without AS1411, and 4-fold higher than free ICG, demonstrating its excellent tumor targeting ability in vivo. With the synergetic treatment of DOX and ICG, TOADI shows a significant therapeutic effect of ~ 90% inhibition of tumor growth with negligible systemic toxicity. In addition, TOADI presents outstanding superiority in fluorescence and photothermal imaging. Taken together, this multifunctional DNA origami-based nanosystem with the advantages of specific tumor targeting and controllable drug release provides a new strategy for enhanced cancer therapy. [ABSTRACT FROM AUTHOR]

Due to its complicated pathophysiology, propensity for metastasis, and poor prognosis, colon cancer is challenging to treat and must be managed with a combination of therapy. Using rolling circle transcription (RCT), this work created a nanosponge therapeutic medication system (AS1411@antimiR-21@Dox). Using the AS1411 aptamer, this approach accomplished targeted delivery to cancer cells. Furthermore, analysis of cell viability, cell apoptosis, cell cycle arrest, reactive oxygen species (ROS) content, and mitochondrial membrane potential (MMP) levels revealed that functional nucleic acid nanosponge drug (FND) can kill cancer cells. Moreover, transcriptomics uncovered a putative mechanism for the FND anti-tumor effect. These pathways, which included mitotic metaphase and anaphase as well as the SMAC-mediated dissociation of the IAP: caspase complexes, were principally linked to the cell cycle and cell death. In conclusion, by triggering cell cycle arrest and apoptosis, the nano-synergistic therapeutic system allowed for the intelligent and effective targeted administration of RNA and chemotherapeutic medicines for colon cancer treatment. The system allowed for payload efficiency while being customizable, targeted, reliable, stable, and affordable. [ABSTRACT FROM AUTHOR]

Nucleolin protein expression is higher on the ovarian cancer cell surface. AS1411, a DNA aptamer, can bind with nucleolin protein specifically. In this study, we developed HA and ST DNA tiles to assemble six AS1411 aptamers to deliver doxorubicin. In addition, to superior serum stability and drug loading, HA-6AS and ST-6AS outperformed TDN-AS in cellular uptake. HA-6AS and ST-6AS exhibited satisfactory targeted cytotoxicity and achieved resounding lysosomal escape. Moreover, when injected into nude mice subcutaneous xenograft models, HA-6AS reached the peak in tumor more quickly than ST-6AS, and better expressed the active targeting ability of AS1411. Our study suggests that designing appropriate DNA tiles to assemble different aptamers to deliver different chemotherapeutic drugs is a promising treatment for ovarian cancer. [ABSTRACT FROM AUTHOR]

The detection of Circulating Tumor Cells (CTCs) is of profound importance for cancer diagnosis and monitoring in diseased patients. In the presented work, an aptasensor for CTC detection was developed using AS1411 aptamer specific for nucleolin on cancer cells’ surface as receptor on Gold NanoParticles (GNPs) decorated U-bent optical fiber. The aptamer binds to target upon folding into a parallel G-quadruplex structure, and therefore, components of folding and running buffer were optimized to 50 mM tris buffer and 100 mM KCl with and without 5 mM Mg+2 based on Circular Dichroism spectroscopy (CD) and bright field microscopy respectively. Further, the binding of aptamer and MCF-7 cells to GNP coated U-bent fiber were validated by fluorescence microscopy. The aptasensor showed significantly higher absorbance for 104 cancer cells (retinoblastoma, meningioma, breast, cervical, and colon cancer cells) as compared to non-cancer cells (MCF-10A and WBCs) with a t-test p-value of 0.0012. On an optical bench, aptasensor was able to detect as low as 500 cells/mL. To develop a portable and small CTC detection system, aptasensor was integrated with a hand-held opto-electronic device μSens (custom developed in our lab) and was able to detect 50 cells/mL. This is the first time a portable sensing system based on U-bent optical fiber was tested for sensing cancer cells. The ability to detect diverse types of cancer cells by AS1411 aptamer is promising and paves the way for the detection of circulating tumor cells in blood samples, with relative ease and low cost.

The combination of photothermal therapy with chemotherapy has gradually developed into promising cancer therapy. Here, a synergistic photothermal-chemotherapy nanoplatform based on polydopamine (PDA)-coated gold nanoparticles (AuNPs) were facilely achieved via the in situ polymerization of dopamine (DA) on the surface of AuNPs. This nanoplatform exhibited augmented photothermal conversion efficiency and enhanced colloidal stability in comparison with uncoated PDA shell AuNPs. The i-motif DNA nanostructure was assembled on PDA-coated AuNPs, which could be transformed into a C-quadruplex structure under an acidic environment, showing a characteristic pH response. The PDA shell served as a linker between the AuNPs and the i-motif DNA nanostructure. To enhance the specific cellular uptake, the AS1411 aptamer was introduced to the DNA nanostructure employed as a targeting ligand. In addition, Dox-loaded NPs (DAu@PDA-AS141) showed the pH/photothermal-responsive release of Dox. The photothermal effect of DAu@PDAAS141 elicited excellent photothermal performance and efficient cancer cell inhibition under 808 nm near-infrared (NIR) irradiation. Overall, these results demonstrate that the DAu@PDA-AS141 nanoplatform shows great potential in synergistic photothermalchemotherapy. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) as emerging phototherapy has attracted extensive attention in cancer therapy. However, the overexpressed glutathione (GSH) and hypoxic conditions of the tumor microenvironment (TME) sevely limit the therapeutic efficiency of PDT. Herein, we design a multifunctional nanoplatform (CBDM) for cancer therapy consisting of photosensitizer (Ce6), bovine serum albumin (BSA), and polydopamine-manganese dioxide (MnO2) nanocomplex, which is simultaneously modified by nucleolin-targeting AS1411 aptamer. This MnO2-based nanoplatform ameliorates tumor hypoxia and promotes oxygen production via the reaction between MnO2 and endogenous H2O2 and acid H+ in the TME. Besides, this biocompatibility nanoplatform exhibits an augmented PDT effect and high photothermal conversion efficiency under 808 nm laser irradiation. Importantly, the MnO2-based nanoplatform achieves a significant in vivo synergistic therapeutic effect and fights against liver metastasis of breast cancer. As a result, the excellent biocompatibility, especially the superior anticancer efficacy, and suppression of tumor metastasis make the MnO2-based nanoplatform a promising candidate for cancer therapy.

Herein, we presented a novel DOX-loaded multi-storey DNA nanostructure, including AS1411 aptamer as a targeting agent for treatment of target cells (MCF-7 and 4T1). Gel retardation test and fluorometric analysis were used to examine the construction of DNA nanostructure and loading of DOX in the complex. At pH 5.5 and 7.4, the release patterns of DOX from the prepared formulation were studied. Cell viability test was conducted to analyse the cell cytotoxicity ability of the DOX loaded multi-storey DNA nanostructure compared to free DOX in 4T1, MCF-7 (target) and CHO cells (non-target). Flow cytometry analysis was used to examine the DOX-loaded DNA nanostructure internalisation. Finally, the developed DOX-loaded multi-storey DNA nanostructure was tested in vivo to see if it could prevent tumour growth. The drug was released from the nanocomplex in a pH-related process (higher release in acidic pH compared to neutral pH). According to MTT assay, DOX-loaded DNA nanostructure damaged nucleolin positive cells while not significantly affecting nucleolin negative cells. The formulation was efficaciously internalised into target cells (4T1 and MCF-7), but not into non-target ones. Moreover, DOX-loaded DNA nanostructure can restrict tumour growth, increase survival rate, and accumulate significantly more in the tumour site than free DOX. [ABSTRACT FROM AUTHOR]

The present study expanded the magnetic pH‐dependent, and nucleolin receptor‐targeted nano‐drug delivery system consists of synthesized superparamagnetic iron oxide nanoparticles (SPIONs) and poly N‐isopropyl acrylamide (PNIPAM) with aptamer AS1411 to deliver the erlotinib (ERL) to prostate cancer (PC) cells. Their properties were characterized using different techniques. The encapsulation efficiency (EE) and drug loading (DL) were found to be about 34% and 85%, respectively. The characterization studies disclosed that formulated SPION‐PNIPAM/ERL@AS1411 nanoparticles (NPs) were spherical with an average particle size of 97.8 nm, polydispersity index (PDI) of 0.03, and the zeta potential of −2 mV. The flow cytometry and cell viability assay results disclosed that SPION‐PNIPAM/ERL@AS1411 NPs operated cancer cell death via the pH‐sensitive release of ERL. The conjugation of the AS1411 modified the cellular uptake of ERL as proved by cellular sensing fluorescence. Therefore, the present study revealed that the SPION‐PNIPAM/ERL@AS1411 NPs improved the treatment effect of ERL in PC via the nucleolin‐targeted drug release. [ABSTRACT FROM AUTHOR]

Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy. Among vascular coagulation agents, the extracellular domain of coagulation-inducing protein tissue factor, truncated tissue factor (tTF), is the most widely used. Since the truncated protein exhibits no coagulation activity and is rapidly cleared in the circulation, free tTF cannot be used for cancer treatment on its own but must be combined with other moieties. We here developed a novel, tumor-specific tTF delivery system through coupling tTF with the DNA aptamer, AS1411, which selectively binds to nucleolin receptors overexpressing on the surface of tumor vascular endothelial cells and is specifically cytotoxic to target cells. Systemic administration of the tTF-AS1411 conjugates into tumor-bearing animals induced intravascular thrombosis solely in tumors, thus reducing tumor blood supply and inducing tumor necrosis without apparent side effects. This conjugate represents a uniquely attractive candidate for the clinical translation of vessel occlusion agent for cancer therapy.

[Display omitted] Breast cancer treatment can be challenging, but a targeted drug delivery system (DDS) has the potential to make it more effective and reduce side effects. This study presents a novel nanotherapeutic targeted DDS developed through the self-assembly of an amphiphilic di-block copolymer to deliver the chemotherapy drug SN38 specifically to breast cancer cells. The vehicle was constructed from the PHPMA-b-PEAMA diblock copolymer synthesized via RAFT polymerization. A single emulsion method was then used to encapsulate SN38 within nanoparticles (NPs) formed from the PHPMA-b-PEAMA copolymer. The AS1411 DNA aptamer was covalently bonded to the surface of the micellar NPs, producing a targeted DDS. Molecular dynamics (MD) simulation studies were also performed on the di block polymeric system, demonstrating that SN38 interacted well with the di block. The in vitro results demonstrated that AS1411- decorated SN38-loaded HPMA NPs were highly toxic to breast cancer cells while having a minimal effect on non-cancerous cells. Remarkably, in vivo studies elucidated the ability of the targeted DDS to enhance the antitumor effect of SN38, suppressing tumor growth and improving survival rates compared to free SN38. [ABSTRACT FROM AUTHOR]

Objective(s): Mitoxantrone (MTX) is one of the most commonly used chemotherapeutic agents for treatment of different cancers. However, prolonged treatment with MTX results in unwanted side effects and drug resistant cancer cells. Combination therapies and exploiting of targeted nanoparticles have the potential of improving the efficiency of drug treatment as well as reducing the side effects. Curcumin (CUR) is a biological molecules with anticancer property. In this study, we investigated whether targeted PLGA (Poly Lactic-co-Glycolic Acid)–CUR nanoparticles (NPs) can reinforce the effect of MTX on breast cancer cells.Materials and Methods: PLGA NPs containing CUR targeted with AS1411 aptamer were prepared by single emulsion evaporation method. Physicochemical properties of NPs were investigated. The cytotoxicity of non-targeted and targeted NPs along with MTX was evaluated on MCF7, 4T1 and L929 cell lines. Results: The results showed that PLGA-CUR NPs were synthetized with an average encapsulation efficiency of 66% with a mean size of 186±3.2 nm. The drug release of curcumin from these NPs within 72h was about 59% in neutral medium and 90% in acidic medium. Interestingly, the combined treatment with PLGA-CUR-Apt and MTX inhibited the cancer cell's proliferation significantly more than the non-targeted nanoparticles, CUR and MTX-treated group alone. Conclusion: These results suggest that targeted PLGA-CUR nanoparticles may consider as a potential therapeutic contender in improving the efficacy of MTX in Breast cancer therapy.

Cancer treatment commonly relies on chemotherapy. This treatment faces many challenges, including treatment specificity and undesired side effects. To address these, a Dox‐loaded Chol–aptamer molecular hybrid (Dox‐CAH) was developed. This multivalent interaction system combines the key function of each integrated species: doxorubicin, cholesterol, and two aptamers binding to nucleolin and platelet‐derived growth factor BB (PDGF‐BB). The study has four stages: preparation of CAH via oligonucleotide hybridization, intercalation of doxorubicin into CAH, verification of CAH binding on SW480 by fluorescence microscopy and flow cytometry, and investigation of effect of Dox‐CAH on SW480 proliferation. CAH was successfully prepared, as confirmed by electrophoresis. Flow cytometry and fluorescence microscopy demonstrated CAH binding to SW480, due to the presence of the AS1411 aptamer. This molecular hybrid exhibited specific binding because it did not bind to CCD 841 CoN. CAH binding to PDGF‐BB compromises its function, as shown by enzyme‐linked immunosorbent assay (ELISA) and cell assay. The DNA duplex in this molecular hybrid reduces the cytotoxicity of the Dox‐CAH. Binding and the reduction of Dox‐CAH toxicity may improve treatment specificity and minimize side effects. Dox‐CAH is a model for more effective anticancer therapy, allowing incorporation of chemotherapeutic drugs and recognition elements. [ABSTRACT FROM AUTHOR]

Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy. Among vascular coagulation agents, the extracellular domain of coagulation-inducing protein tissue factor, truncated tissue factor (tTF), is the most widely used. Since the truncated protein exhibits no coagulation activity and is rapidly cleared in the circulation, free tTF cannot be used for cancer treatment on its own but must be combined with other moieties. We here developed a novel, tumor-specific tTF delivery system through coupling tTF with the DNA aptamer, AS1411, which selectively binds to nucleolin receptors overexpressing on the surface of tumor vascular endothelial cells and is specifically cytotoxic to target cells. Systemic administration of the tTF-AS1411 conjugates into tumor-bearing animals induced intravascular thrombosis solely in tumors, thus reducing tumor blood supply and inducing tumor necrosis without apparent side effects. This conjugate represents a uniquely attractive candidate for the clinical translation of vessel occlusion agent for cancer therapy. This study reported a novel, tumor-specific tTF delivery system through coupling tTF with the DNA aptamer, AS1411, which selectively binds to nucleolin receptors overexpressing on the surface of tumor vascular endothelial cells and is specifically cytotoxic to target cells. [Display omitted] [ABSTRACT FROM AUTHOR]

Herein, we constructed innovative reduction-sensitive and targeted gelatin-based micelles for doxorubicin (DOX) delivery in tumor therapy. AS1411 aptamer-modified gelatin-ss-tocopherol succinate (AGSST) and the control GSST without AS1411 modification were synthesized and characterized. Antitumor drug DOX-containing AGSST (AGSST-D) and GSST-D nanoparticles were prepared, and their shapes were almost spherical. Reduction-responsive characteristics of DOX release in vitro were revealed in AGSST-D and GSST-D. Compared with non-targeted GSST-D, AGSST-D demonstrated better intracellular uptake and stronger cytotoxicity against nucleolin-overexpressed A549 cells. Importantly, AGSST-D micelles showed more effective killing activity in A549-bearing mice than GSST-D and DOX⋅HCl. It was revealed that AGSST-D micelles had no obvious systemic toxicity. Overall, AGSST micelles would have the potential to be an effective drug carrier for targeted tumor therapy. [Display omitted] • Reduction-sensitive and targeted gelatin-based micelle for doxorubicin (D) delivery. • AS1411 aptamer-modified gelatin-ss-tocopherol succinate (AGSST). • AGSST-D enhances uptake and cytotoxicity against nucleolin-overexpressed A549 cells. • AGSST-D effectively inhibits tumor growth in A549 mouse models. [ABSTRACT FROM AUTHOR]

The aim of this study is to construct a SYL3C aptamer-anchored microemulsion based on β-elemene and PTX (SYL3C/EP-MEs) for enhancement on colorectal cancer therapy. Such microemulsion is consist of encapsulated drugs (β-elemene and PTX), tumor targeting ligand (3’-end thiolated SYL3C aptamer), thiol conjugated site (maleimide-modified PEGylated 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, mal-DOPE-PEG), pH-sensitive component (DOPE) and other necessary excipients. SYL3C/EP-MEs showed a spherical particle with an average particle size around 30 nm and a high encapsulation efficiency (>80%) for both drugs. β-elemene and PTX could be released controllably from SYL3C/EP-MEs as pH values changed. SYL3C/EP-MEs displayed a selective affinity to HT-29 cells, leading to an obvious increase in cellular uptake, cell apoptosis and cytotoxicity. In the HT-29 tumor xenograft-bearing nude mice model studies, SYL3C/EP-MEs showed an overwhelming tumor growth inhibition, the longest survival time and the lowest systemic toxicity among all the treatments. The potential mechanism of enhanced anti-cancer ability was probably associated with the induction of M1 macrophage polarization, the downregulation of mutant p53 protein and the reduction of bcl-2 protein expression. Collectively, the microemulsion codelivery of β-elemene and PTX using functionalization with SYL3C aptamer provides a novel approach for combinational colorectal cancer-targeted treatment.

A novel suicide gene therapy approach was tested in U87 MG glioblastoma multiforme cells. A 26nt G-rich double-stranded DNA aptamer (AS1411) was integrated into a vector at the 5′ of a mammalian codon-optimized saporin gene, under CMV promoter. With this plasmid termed “APTSAP”, the gene encoding ribosome-inactivating protein saporin is driven intracellularly by the glioma-specific aptamer that binds to cell surface-exposed nucleolin and efficiently kills target cells, more effectively as a polyethyleneimine (PEI)-polyplex. Cells that do not expose nucleolin at the cell surface such as 3T3 cells, used as a control, remain unaffected. Suicide gene-induced cell killing was not observed when the inactive saporin mutant SAPKQ DNA was used in the (PEI)-polyplex, indicating that saporin catalytic activity mediates the cytotoxic effect. Rather than apoptosis, cell death has features resembling autophagic or methuosis-like mechanisms. These main findings support the proof-of-concept of using PEI-polyplexed APTSAP for local delivery in rat glioblastoma models.

Objective(s): Mitoxantrone (MTX) is one of the most commonly used chemotherapeutic agents for treatment of different cancers. However, prolonged treatment with MTX results in unwanted side effects and drug resistant cancer cells. Combination therapies and exploiting of targeted nanoparticles have the potential of improving the efficiency of drug treatment as well as reducing the side effects. Curcumin (CUR) is a biological molecules with anticancer property. In this study, we investigated whether targeted PLGA (Poly Lactic-co-Glycolic Acid)-CUR nanoparticles (NPs) can reinforce the effect of MTX on breast cancer cells. Materials and Methods: PLGA NPs containing CUR targeted with AS1411 aptamer were prepared by single emulsion evaporation method. Physicochemical properties of NPs were investigated. The cytotoxicity of non-targeted and targeted NPs along with MTX was evaluated on MCF7, 4T1 and L929 cell lines. Results: The results showed that PLGA-CUR NPs were synthetized with an average encapsulation efficiency of 66% with a mean size of 186±3.2 nm. The drug release of curcumin from these NPs within 72h was about 59% in neutral medium and 90% in acidic medium. Interestingly, the combined treatment with PLGA-CURApt and MTX inhibited the cancer cell's proliferation significantly more than the non-targeted nanoparticles, CUR and MTX-treated group alone. Conclusion: These results suggest that targeted PLGA-CUR nanoparticles may consider as a potential therapeutic contender in improving the efficacy of MTX in Breast cancer therapy. [ABSTRACT FROM AUTHOR]

Conventional chemotherapy and poor targeted delivery in brain cancer resulting to poor treatment and develop resistance to anticancer drugs. Meanwhile, it is quite challenging to diagnose/detection of brain tumor at early stage of cancer which resulting in severity of the disease. Despite extensive research, effective treatment with real-time imaging still remains completely unavailable, yet. In this study, two brain cancer cell specific moieties i.e., AS1411 aptamer and RGD are decorated on the surface of chitosan-PLGA nanoparticles to improve targeted co-delivery of docetaxel (DTX) and upconversion nanoparticles (UCNP) for effective brain tumor therapy and real-time imaging. The nanoparticles were developed by a slightly modified emulsion/solvent evaporation method. This investigation also translates the successful synthesis of TPGS-chitosan, TPGS-RGD and TPGS-AS1411 aptamer conjugates for making PLGA nanoparticle as a potential tool of the targeted co-delivery of DTX and UCNP to the brain cancer cells. The developed nanoparticles have shown an average particle size <200 nm, spherical in shape, high encapsulation of DTX and UCNP in the core of nanoparticles, and sustained release of DTX up to 72 h in phosphate buffer saline (pH 7.4). AS1411 aptamer and RGD functionalized theranostic chitosan-PLGA nanoparticles containing DTX and UCNP (DUCPN-RGD-AS1411) have achieved greater cellular uptake, 89-fold improved cytotoxicity, enhanced cancer cell arrest even at lower drug conc., improved bioavailability with higher mean residence time of DTX in systemic circulation and brain tissues. Moreover, DUCPN-RGD-AS1411 have greatly facilitated cellular internalization and higher accumulation of UCNP in brain tissues. Additionally, DUCPN-RGD-AS1411 demonstrated a significant suppression in tumor growth in brain-tumor bearing xenograft BALB/c nude mice with no impressive sign of toxicities. DUCPN-RGD-AS1411 has great potential to be utilized as an effective and safe theranostic tool for brain cancer and other life-threatening cancer therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Improving the selective delivery and uptake efficiency of chemotherapeutic drugs remains a challenge for cancer-targeted therapy. In this work, a DNA tetrahedron is constructed as a targeted drug delivery system for efficient delivery of doxorubicin (Dox) into cancer cells. The DNA tetrahedron is composed of a tetrahedral DNA nanostructure (TDN) with two strands of AS1411 aptamer as recognition elements which can target the nucleolin protein on the cell membrane of cancer cells. The prepared DNA tetrahedron has a high drug-loading capacity and demonstrates pH-responsive Dox release properties. This enables efficient delivery of Dox into targeted cancer cells while reducing side effects on nontarget cells. The proposed drug delivery system exhibits significant therapeutic efficacy in vitro compared to free Dox. Accordingly, this work provides a good paradigm for developing a targeted drug delivery system for cancer therapy based on DNA tetrahedrons., (© 2023 Wiley‐VCH GmbH.)

Yang Li,1,2,* Yanhong Duo,1,3,* Jiangang Bi,1 Xiaowei Zeng,4 Lin Mei,4 Shiyun Bao,1 Lisheng He,5 Aijun Shan,2 Yue Zhang,1 Xiaofang Yu1 1Department of Hepatobiliary and Pancreas Surgery, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, China; 2Department of Emergency, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, China; 3Key Laboratory of Plant Cell Activities and Stress Adaptation, Ministry of Education, School of Life Sciences, Lanzhou University, Lanzhou 730000, China; 4Division of Life and Health Sciences, Graduate School at Shenzhen, Tsinghua University, Shenzhen 518020, China; 5Department of Pathology, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen 518020, China *These authors contributed equally to this work Introduction: MicroRNA-155 (miR-155) is an oncogenic microRNA, which is upregulated in many human cancers including colorectal cancer (CRC). Overexpression of miR-155 has been found to regulate several cancer-related pathways, and therefore, targeting miR-155 may be an effective strategy for cancer therapy. However, effective and safe delivery of anti-miR-155 to tumors remains challenging for the clinical applications of anti-miR-155-based therapeutics.Methods: In this study, we explored the expression of miR-155 and the transcription factor nuclear factor kappa B (NF-κB) in CRC tissues and cell lines, and the possible relationship between miR-155 and NF-κB. We further report on anti-miR-155-loaded mesoporous silica nanoparticles (MSNs) modified with polymerized dopamine (PDA) and AS1411 aptamer (MSNs-anti-miR-155@PDA-Apt) for the targeted treatment of CRC.Results: Results showed that miR-155 is overexpressed in CRC tissues and cell lines, and there is a positive feedback loop between NF-κB and miR-155. Compared to the control groups, MSNs-anti-miR-155@PDA-Apt could efficiently downregulate miR-155 expression in SW480 cells and achieve significantly high targeting efficiency and enhanced therapeutic effects in both in vivo and in vitro experiments. Furthermore, inhibition of miR-155 by MSNs-anti-miR-155@PDA-Apt can enhance the sensitivity of SW480 to 5-fluorouracil chemotherapy.Conclusion: Thus, our results suggested that MSNs-anti-miR-155@PDA-Apt is a promising nanoformulation for CRC treatment. Keywords: miR-155, mesoporous silica nanoparticles, AS1411 aptamer, NF-κB, 5-fluorouracil

• Camptothecin was loaded into the rod-shaped MSN NPs and then PEGylated. • The prepared system was condensed with iSur-DNA to form PEG@MSNR-CPT/Sur. • Results indicated synergistic effect of iSur-DNA and CPT in apoptosis induction. • Tagging the codelivery system with AS1411 aptamer increased cytotoxicity. • The targeted codelivery system considerably suppressed the tumor growth in C26 tumor model. Simultaneous drug and gene delivery to cancer cells has been introduced to provide advantages of the synergistic effects of gene to sensitize the cancer cells to chemotherapeutic agent. In the current study, nucleolin-targeted co-delivery system, based on PEGylated rod-shaped mesoporous silica NPs was developed as a biocompatible nanocarrier for simultaneous delivery of camptothecin and survivin shRNA-expressing plasmid (iSur-DNA) to colon adenocarcinoma. The structural characterization including hydrodynamic radius and morphological characteristics of the prepared system demonstrated the mesoporous rod-shaped structure of the prepared system with 100–150 nm diameter. Camptothecin was loaded into the rod-shaped MSN NPs with encapsulation efficiency of 32%. At the next stage, the prepared camptothecin-loaded system was PEGylated and then iSur-DNA was condensed with C/P ratio of 6 to form PEG@MSNR-CPT/Sur. Then, the prepared camptothecin-iSur-DNA loaded PEGylated rod-shaped mesoporous silica NPs were tagged with AS1411 DNA aptamer (Apt-PEG@MSNR-CPT/Sur) in order to provide selective therapy against colorectal adenocarcinoma. The obtained results showed that the prepared platform controlled the release of anticancer drug, camptothecin. The experimental results indicated potent synergistic effect of iSur-pDNA and CPT in in vitro cytotoxicity, apoptosis induction and in vivo antitumor effect. In addition, tagging the system with AS1411 DNA aptamer facilitated drug uptake into nucleolin positive colorectal cancer cells leading to higher cellular toxicity and apoptosis induction in C26 cells compared to nucleolin-negative CHO cell line. Apt-PEG@MSNR-CPT/Sur system significantly supressed tumor growth rate in C26 tumor bearing mice while improving survival rate and pharmacokinetics of the platform in comparison with PEG@MSNR-CPT and PEG@MSNR-CPT/Sur. It could be concluded that the developed nucelolin targeted nanomedicine for co-delivery of camptothecin and iSur-DNA could serve as a versatile nanotherapeutic system against colorectal cancer. [ABSTRACT FROM AUTHOR]

Nucleolin or C23, is one of the most abundant non-ribosomal phosphoproteins of nucleolus. However, in several cancers, nucleolin is highly expressed both intracellularly and on the cell surface. So, it is considered as a potential target for the diagnosis and cancer therapy. Targeting nucleolin by compounds such as AS1411 aptamer can reduce tumor cell growth. In this regard, interest has increased in nucleolin as a molecular target for overcoming cancer therapy challenges. This review paper addressed recent progresses in nucleolin targeting by the G-rich AS1411 aptamer in the field of cancer therapy mainly over the past three years. • Nucleolin is highly expressed both intracellularly and on the cell surface. • It is considered as a potential target for the cancer diagnosis and therapy. • AS1411 a 26-mer DNA aptamer that binds nucleolin. • This review paper addressed recent progresses in nucleolin targeting by the AS1411. [ABSTRACT FROM AUTHOR]

[Display omitted] • Amphiphilic copolymer of PLA 121 - b -PAPMA 103 was obtained using ROP and RAFT. • The synthesized copolymer was self-assembled into spherical micelle. • The prepared micelle was used for the delivery of shRNA plasmid against survivin. • AS1411 aptamer was electrostatically decorated on the surface of the polyplex. • The prepared polymplex indicated potential therapeutic index in preclinical stage. In this study, synthesis of Polylactic acid (PLA) polymer was carried out through ring-opening polymerization (ROP) method. Then, 4-cyano-4-(phenylcarbonothioylthio)pentanoic acid as the CTA molecule was attached to the PLA, and subsequently, amphiphilic copolymer, with estimated structure of Poly(lactic acid) 121 - b -Poly(N -(3-aminopropyl)methacrylamide) 103 (PLA 121 - b -PAPMA 103) was obtained through the Reversible Addition Fragmentation chain Transfer (RAFT) reaction. The synthesized copolymer was self-assembled into spherical nanoparticles with size, Poly Dispersity Index (PDI) and zeta potential of 181.5 ± 21.3, 0.643 and of 44.9 ± 2.5 mV, respectively. The optimal copolymer/plasmid ratio was 4 with size, PDI and zeta potential of 161.7 ± 10.2, 0.277 and 36.5 ± 0.7, respectively for the delivery of short hairpin RNA (shRNA) plasmid against survivin. Additionally, the AS1411 aptamer was electrostatically decorated on the surface of the polyplex. In vitro studies on C26 cells revealed that the aptamer rendered nanoparticle transfer into the cell, dependent solely on the aptamer-receptor interactions. Lastly, in vivo studies involving tumor size and body weight change, survival and histological analysis indicated potential therapeutic index of the targeted nanoparticles with good safety profile. [ABSTRACT FROM AUTHOR]

The aim of this study is to construct a SYL3C aptamer-anchored microemulsion based on β-elemene and PTX (SYL3C/EP-MEs) for enhancement on colorectal cancer therapy. Such microemulsion is consist of encapsulated drugs (β-elemene and PTX), tumor targeting ligand (3'-end thiolated SYL3C aptamer), thiol conjugated site (maleimide-modified PEGylated 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, mal-DOPE-PEG), pH-sensitive component (DOPE) and other necessary excipients. SYL3C/EP-MEs showed a spherical particle with an average particle size around 30 nm and a high encapsulation efficiency (>80%) for both drugs. β-elemene and PTX could be released controllably from SYL3C/EP-MEs as pH values changed. SYL3C/EP-MEs displayed a selective affinity to HT-29 cells, leading to an obvious increase in cellular uptake, cell apoptosis and cytotoxicity. In the HT-29 tumor xenograft-bearing nude mice model studies, SYL3C/EP-MEs showed an overwhelming tumor growth inhibition, the longest survival time and the lowest systemic toxicity among all the treatments. The potential mechanism of enhanced anti-cancer ability was probably associated with the induction of M1 macrophage polarization, the downregulation of mutant p53 protein and the reduction of bcl-2 protein expression. Collectively, the microemulsion codelivery of β-elemene and PTX using functionalization with SYL3C aptamer provides a novel approach for combinational colorectal cancer-targeted treatment. [ABSTRACT FROM AUTHOR]

Abstract AS1411 is a 26-mer G-rich DNA aptamer which has been broadly employed in the field of targeted drug delivery, due to its capability to bind to nucleolin protein on the surface of cancer cells. In this work, it has been shown for the first time that in addition to nucleolin, AS1411 aptamer could bind to copper ions (Cu2+) with high affinity and selectivity, affecting AS1411 usage in drug delivery systems as a targeting agent. In this study, besides the evaluations of the affinity of AS1411 to different ions and the impact of Cu2+ on targeted drug delivery employed AS1411 aptamer as a targeting agent, a simple and ultra-sensitive fluorescent aptasensor was fabricated for Cu2+ detection through applying AS1411, its complementary strand and magnetic beads coated with streptavidin. Gel Red (GR) was also used as a fluorescent dye. The fabricated aptasensor offered the possibility of condensing samples with different volumes. The detection limit of the sensor was 0.01 μM towards Cu2+ in serum samples. The efficacy of this sensor was further confirmed by comparing Cu2+ levels in serums of healthy people with patients suffering from Wilson's disease, Alzheimer's disease and Diabetes Mellitus using the proposed sensing platform. Highlights • AS1411 is a DNA aptamer which has been broadly employed in the field of targeted drug delivery. • In addition to nucleolin, AS1411 aptamer could bind to copper ions (Cu2+) with high affinity and selectivity. • The results showed that the interaction of AS1411 aptamers with nucleolin was significantly restricted by Cu2+. • A fluorescent aptasensor was developed for rapid and high sensitive detection of Cu2+ in both water and serum. • This sensing platform was utilized to determine Alzheimer and Wilson diseases. [ABSTRACT FROM AUTHOR]

Recently DNA aptamers have attracted remarkable attention as possible targeting ligands since selective targeting of cancer cells is a critical step in cancer diagnosis and therapy. Here, the development of AS1411 aptamer-functionalized albumin nanoparticles loaded on iron oxide and gold nanoparticles is reported for target delivery of the well-known anticancer drug of doxorubicin (Dox). Iron oxide nanoparticles (IONPs) and gold nanoparticles (GNPs) were prepared by ultrasound-assisted and controlled seeded growth synthetic methods, respectively. The nanocarrier was synthesized by a desolvation cross-linking method and characterized by dynamic light scattering, zeta potential measurement, thermogravimetric analysis, transmission electron microscopy, as well as vibrating sample magnetometer. The synthesized nanoparticles were found to be spherical with an average diameter of 120 nm and zeta potential of about −50.3 mV. The in-vitro anti-tumor effect of the designed delivery vehicle on MCF7 and SKBR3 human cancer cells was evaluated by MTT assay. The experimental results revealed that it could significantly inhibit the proliferation of cancerous cells. Moreover, GNPs and IONPs with the coating of albumin did not show any toxicity. AS1411 aptamer-functionalized nanoparticles improved cellular uptake and efficiency to MCF7 breast cancer cells as compared to non-targeting nanoparticles because of the high affinity of mentioned aptamer toward the overexpressed nucleolin on MCF7 cell surface. [ABSTRACT FROM AUTHOR]

A novel bispecific α‐Gal liposome was constructed by self‐assembling AS1411 aptamers into the α‐Gal containing liposomes. The α‐Gal liposomes were prepared using cell membranes of red blood cells from rabbit, which are composed of cholesterol, phospholipids, and α‐Gal glycolipids. AS1411 is a DNA aptamer with high specificity and affinity for nucleolin and could integrate into liposomes by the modification of cholesterol. The bispecific α‐Gal liposomes surface‐functionalized by α‐Gal and AS1411 aptamer could recognize anti‐Gal antibodies and nucleolin overexpressed by tumor cells simultaneously, followed by activating the immune system to attack the tumor cells, resulting in the lysis of the tumor cells by antibody dependent cell‐mediated cytotoxicity. Under simulated tumor environment, the lysis rate of MCF‐7 cells treated by the AS1411 modified α‐Gal liposomes drastically increased compared to the liposomes without AS1411 aptamer. This study suggests that the AS1411 modified α‐Gal liposomes can recognize nucleolin‐overexpressing tumor cells selectively, subsequently improve the effect of the immunotherapy with high specificity. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1176–1183, 2019. [ABSTRACT FROM AUTHOR]

Brain tumors represent an aggressive form of cancer, posing significant challenges in achieving complete remission. Development of advanced therapies is crucial for improving clinical outcomes in cancer patients. This study aimed to create a novel treatment approach using dual-targeted transferrin (TF) and AS1411 conjugated micelles, designed to enhance therapeutic effectiveness of docetaxel (DTX) and facilitate gadolinium (Gd) based imaging in brain cancer. Micelles were prepared using a slightly modified solvent-casting method, and the dual-targeting ligands were attached to the micelle's surface through a physical adsorption process. Average particle size of micelles ranged from 117.49 ± 3.90–170.38 ± 3.39 nm, with a low polydispersity index. Zeta potential ranged from − 1.5 ± 0.02 to − 18.7 ± 0.04 mV. Encapsulation efficiency of DTX in micelles varied from 92.64 ± 4.22–79.77 ± 4.13 %. Simultaneously, encapsulation of Gd in micelles was found to be 48.27 ± 3.18–58.52 ± 3.17, respectively. In-vitro drug release studies showed a biphasic sustained release profile, with DTX and Gd release continuing up to 72 h with their t 50 % at 4.95, 11.29, and 24.14 h for GDTP, GDTP-TF and GDTP-TF-AS1411 micelles, respectively. Cytotoxicity effect of GDTP-TF-AS1411 micelles has shown significant improvement (P < 0.001) and reduced IC 50 value up to 0.19 ± 0.14 μg/ml compared to Taxotere® (2.73 ± 0.73 μg/ml). Theranostic study revealed higher accumulation of GDTP-TF and GDTP-TF-AS1411 micelles free GD treated animal brains. The AUC of GDTP-TF-AS1411 micelles exhibited 23.79 ± 17.82 μg.h/ml higher than Taxotere® (14.14 ± 10.59 μg.h/ml). These findings direct enhanced effectiveness in brain cancer therapy leading to improved therapeutics in brain cancer patients. The combined targeted ligands and therapeutic agents strategy can direct advancement in brain cancer therapy and offer improved therapy for patients. [Display omitted] • It translates the easy method to develop transferrin-AS1411 conjugated micelles. • Developed micelles have shown better physicochemical suitability for theranostic delivery. • GDTP-TF-AS1411 exhibits 72-hour sustained in-vitro release of theranostic agents. • GDTP-TF-AS1411 micelles showed better drug pharmacokinetics compared to Taxotere®. • Micelle preparations demonstrated greater biocompatibility as compared Taxotere®. [ABSTRACT FROM AUTHOR]

Guojun Xu,1–3,* Xinghua Yu,2,* Jinxie Zhang,1,2,* Yingchao Sheng,4 Gan Liu,2 Wei Tao,1,2 Lin Mei1,2 1School of Life Sciences, Tsinghua University, Beijing, 2Graduate School at Shenzhen, Tsinghua University, Shenzhen, 3School of Materials Science and Engineering, Tsinghua University, Beijing, 4Department of Orthopedic Surgery, Changshu Hospital of TCM, Changshu, People’s Republic of China *These authors contributed equally to this work Abstract: One limitation of current biodegradable polymeric nanoparticles (NPs) is the contradiction between functional modification and maintaining formerly excellent bioproperties with simple procedures. Here, we reported a robust aptamer–polydopamine-functionalized mannitol-functionalized poly(lactide-co-glycolide) (M-PLGA)–D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) nanoformulation (Apt-pD-NPs) for the delivery of docetaxel (DTX) with enhanced cervical cancer therapy effects. The novel DTX-loaded Apt-pD-NPs possess satisfactory advantages: 1) increased drug loading content and encapsulation efficiency induced by star-shaped copolymer M-PLGA–TPGS; 2) significant active targeting effect caused by conjugated AS1411 aptamers; and 3) excellent long-term compatibility by incorporation of TPGS. Therefore, with simple preparation procedures and excellent bioproperties, the new functionalized Apt-pD-NPs could maximally increase the local effective drug concentration on tumor sites, achieving enhanced treatment effectiveness and minimizing side effects. In a word, the robust DTX-loaded Apt-pD-NPs could be used as potential nanotherapeutics for cervical cancer treatment, and the aptamer–polydopamine modification strategy could be a promising method for active targeting of cancer therapy with simple procedures. Keywords: dopamine, AS1411 aptamer, active targeting, polymeric NPs, enhanced cervical chemotherapy

Objective: Herein, a dual-targeting delivery system using mesoporous silica nanoparticles with hollow structures (HMSNs) was developed for the specific delivery of epirubicin (EPI) to cancer cells and introducing a H + -triggered bubble generating nanosystem (BGNS). HMSNs containing EPI are covered by hyaluronic acid (HA) shell and AS1411 aptamer to create the BGNS-EPI-HA-Apt complex, which is highly selective against CD44 marker and nucleolin overexpressed on the surface of tumor cells., Methods: MTT assay compared the cytotoxicity of different treatments in CHO (Chinese hamster ovary) cells as well as 4T1 (murine mammary carcinoma) and MCF-7 (human breast adenocarcinoma) cells. The internalization of Epi was assessed by flow cytometry along with fluorescence imaging. In vivo studies were conducted on BALB/c mice bearing a tumor from 4T1 cell line where monitoring included measuring tumor volume, mouse weight changes over time alongside mortality rate; accumulation levels for Epi within organs were also measured during this process., Results: The collected data illustrated that BGNS-EPI-HA-Apt complex controlled the release of EPI in a sustained method. Afterward, receptor-mediated internalization via nucleolin and CD44 was verified in 4T1 and MCF-7 cells using fluorescence microscopy assay and flow cytometry analysis. The results of tumor inhibitory effect study exhibited that BGNS-EPI-HA-Apt complex decreased off-target effect and improved on-target effects because of its targeting ability., Conclusion: The data acquired substantiates that HA-surface modified HMSNs functionalized with aptamers possess significant potential as a focused platform for efficient transportation of anticancer agents to neoplastic tissues.

Abstract Chemo-immunotherapy represents an appealing approach to improving cancer treatment. Simultaneously administrating chemotherapeutics with immunoadjuvants can elicit potent tumor death and immune responses. Herein, high density lipoprotein (HDL) inspired immune lipoprotein was proposed for relay drug delivery and amplifying antitumor therapy. Lipophilic AS1411 aptamer-immunoadjuvant CpG fused sequences (Apt-CpG-DSPE) were conjugated to facilitate decoration onto HDLs; and doxorubicin (Dox) was successively intercalated into the consecutive base pairs of Apt-CpG to complete immune HDL nanodrug imHDL/Apt-CpG-Dox. For relay drug delivery, imHDL/Apt-CpG-Dox underwent site-specific structure collapse in tumor intercellular substances inspired from HDL biofunctions (sequential module I); subsequently, dissociated Apt-CpG-Dox was endocytosed into tumor cells mediated by the recognition of AS1411 and nucleolin (sequential module II), translocating Dox to nucleus and enabling tumor ablation and antigens release. The liberated CpG motif further evoked antigen recognition, induced vast secretion of pro-inflammatory cytokines and potentiated host antitumor immunity. Our studies demonstrated that HDL biomimetic platform based relay drug delivery strategy outperformed the monotherapy counterparts in malignant tumor models, eventually generating an augmented antitumor efficacy. [ABSTRACT FROM AUTHOR]

Aim: The overexpression of miRNA-21 correlates with the cisplatin (CIS) resistance in the ovarian cancers. Methods: AS1411 antinucleolin aptamer-decorated PEGylated poly(lactic-co-glycolic acid) nanoparticles containing CIS (Ap–CIS–NPs) and anti-miR-21 (Ap-anti-miR-21-NPs) were prepared, physicochemically investigated and their cancer-targeting ability was confirmed. CIS-resistant A2780 cells (A2780 R) were infected with anti-miR-21 using Ap-anti-miR-21-NPs to decrease the drug resistance and sensitize the cells to CIS. Afterward, miR-21-inhibited cells were exposed to the Ap–CIS–NPs. Results: Ap-anti-miR-21-NPs could infect the A2780 R cells mainly through nucleolin-mediated endocytosis and inhibit the endogenous miR-21. Targeted delivery of CIS using Ap–CIS–NPs into the miR-21-inhibited cells caused an enhanced mortality. Conclusion: The targeted delivery of chemotherapeutics to the oncomiR-inhibited cells may find a robust application in cancer chemo/gene therapy. [ABSTRACT FROM AUTHOR]

Aim: Herein, the AS1411 aptamer-targeted ultrasmall gold nanoclusters (GNCs) were assessed at different aspects as a radiosensitizer. Materials & methods: AS1411 aptamer-conjugated gold nanoclusters (Apt–GNCs) efficacy was evaluated at cancer cells targeting, radiosensitizing effect, tumor targeting, and biocompatibility in breast tumor-bearing mice. Results: Flow cytometry and fluorescence microscopy exhibited more cellular uptake for Apt–GNCs in comparison with GNCs. In addition, inductively coupled plasma optical emission spectrometry results demonstrated its effective tumor targeting as the tumors' gold content for GNCs and Apt–GNCs were 8.53 and 15.33 μg/g, respectively. Apt–GNCs significantly enhanced radiotherapy efficacy as mean tumors' volume decreased about 39% and 9 days increase in the mice survival was observed. Both GNCs and Apt–GNCs were biocompatible. Conclusion: The Apt–GNCs is a novel and efficient radiosensitizer. [ABSTRACT FROM AUTHOR]

The combination of phototherapy and chemotherapy has become attractive and effective cancer treatment. However, the accurate delivery of both chemo-phototherapy drugs to the target site as well as the development of high-efficient phototherapy and chemotherapy drugs remain major challenges. In this study, indocyanine green (ICG) and paclitaxel (PTX)-loaded aptamer ferritin (HAS1411-PTX-ICG) was developed as a biocompatible nanoplatform for combined chemo/photothermal/photodynamic (PTT/PDT) therapy that was safe and highly effective against tumors. HAS1411 was prepared by coupling aptamer AS1411 to the surface of human H chain ferritin (HFtn) by the carbon diimide method to further enhance the targeting of HFtn. Both ICG and PTX were effectively encapsulated in the HAS1411 by incubation at 60 ℃. Moreover, under near-infrared (NIR) light irradiation, HAS1411 enhanced the photothermal effect and cell internalization of ICG, as well as the production of reactive oxygen species in cancer cells. HAS1411-PTX-ICG displayed effective cytotoxicity and a significant tumor spheroids inhibitory effect owning to the improved internalization of PTX and ICG mediated by TfR1 and nucleolin dual receptors. Co-loaded PTX combined with ICG can produce chemo/PTT/PDT under near-infrared (NIR) light irradiation, enhancing the anti-tumor effect. The dual-targeting HAS1411 nanocarrier developed in this study can be a promising delivery system for cancer therapy and the fabricated HAS1411-PTX-ICG possesses potential application in chemo-phototherapy. [Display omitted] • Covalently coupled AS1411 aptamers significantly improved the cellular uptake of HFtn. • Hydrophobic PTX and hydrophilic ICG were co-loaded into HAS1411 NPs. • Combination of chemo/PTT/PDT significantly improved the antitumor efficacy. [ABSTRACT FROM AUTHOR]

Leukemia is a cancer of blood cells and bone marrow, leading to death in many patients mainly in children. Over the last several years, aptamers generated by SELEX (Systematic evolution of ligands by exponential enrichment) method, have quickly become a new class of targeting ligands for drug delivery applications and recently have been widely exploited in different biomedical applications, due to several potent properties such as high binding affinity and selectivity, low or no immunogenicity and toxicity, low cost and thermal stability. In this review, we presented in details about aptamers involved in targeting, and treatment of leukemia. Moreover, some analytical approaches such as electrochemical and optical aptasensors were introduced for detection and diagnosis of leukemia. Finally, we discussed about the directions and challenges of aptamer application in this field. [ABSTRACT FROM AUTHOR]

Recently, targeted drug delivery systems (TDDS) have offered a great potential and benefits towards the anti-tumor drug delivery. In this work, we designed the TDDS using a biocompatible poly(ethylene glycol)-poly( β-amino esters) amphiphilic block copolymer (PEG-PAEs) synthesized by Michael addition polymerization for combinatorial therapy. Further, the chemotherapeutic agents' doxorubicin (DOX) and AS1411 DNA aptamer (Apt) are encapsulated in the PEG-PAEs NPs (PDANs) for co-delivery therapeutics. PDANs have shown the monodisperse spherical shape, smooth surface with a net positive charge (average diameter-183.1 ± 27.2 nm, zeta potential-31.2 ± 6.3 mV), and good colloidal stability (critical micelle concentration of PEG-PAEs is about 6.3 μg/mL). The pH-sensitive PAEs endowed PDANs both pH-triggered drug release characteristics and enhanced endo/lysosomal escape ability, thus improving the localization and cytotoxicity of DOX. AS1411 Apt conjugated PDANs precisely targeted nucleolin and their uptake correlates to a significant activity enhancement only in tumor cells (MCF-7) but not in normal cells (MCF-10A). Thus, PDANs can be a very promising targeted drug delivery platform for effective breast cancer therapy. [ABSTRACT FROM AUTHOR]

A superparamagnetic iron oxide nanoparticles (SPIONs)/doxorubicin (Dox) co-loaded poly(lactic- co -glycolic acid) (PLGA)-based nanoparticles targeted with AS1411 aptamer (Apt) against murine C26 colon carcinoma cells is successfully developed via a modified multiple emulsion solvent evaporation method for theranostic purposes. The mean size of SPIO/Dox-NPs (NPs) was 130 nm with a narrow particle size distribution and Dox loading of 3.0%. The SPIO loading of 16.0% and acceptable magnetic properties are obtained and analyzed using thermogravimetric and vibration simple magnetometer analysis, respectively. The best release profile from NPs was observed in PBS at pH 7.4, in which very low burst release was observed. Nucleolin is a targeting ligand to facilitate anti-tumor delivery of AS1411-targeted NPs. The Apt conjugation to NPs (Apt-NPs) enhanced cellular uptake of Dox in C26 cancer cells. Apt-NPs enhance the cytotoxicity effect of Dox followed by a significantly higher tumor inhibition and prolonged animal survival in mice bearing C26 colon carcinoma xenografts. Furthermore, Apt-NPs enhance the contrast of magnetic resonance images in tumor site. Altogether, these Apt-NPs could be considered as a powerful tumor-targeted delivery system for their potential as dual therapeutic and diagnostic applications in cancers. [ABSTRACT FROM AUTHOR]

In this project, synergistic cancer cell death was achieved by a targeted delivery system comprising Bcl-xL-specific shRNA and a very low DOX content, which simultaneously activated an intrinsic apoptotic pathway. A modified branched polyethylenimine (PEI 10 kDa) was grafted through polyethylene glycol (PEG) linker to carboxylated single-walled carbon nanotubes (SWCNT) to serve as a vehicle for shRNA delivery. The SWNT-PEG-PEI conjugate was covalently attached to AS1411 aptamer as the nucleolin ligand to target the co-delivery system to the tumor cells overexpressing nucleolin receptors on their surface. The final vehicle was eventually obtained after intercalation of DOX with pBcl-xL shRNA-SWCNT-PEG-10-10%PEI-Apt. Cell viability assay, GFP expression and transfection experiment against L929 (-nucleolin) and AGS (+nucleolin) cells illustrated that the tested targeted delivery system inhibited the growth of nucleolin-abundant gastric cancer cells with strong cell selectivity. Subsequently, we illustrated that the combination treatment of the selected shRNAs and DOX had excellent tumoricidal efficacy as verified by MTT assay. Furthermore, very low concentration of DOX, approximately 58-fold lower than its IC50 concentration, was used which could mitigate toxic side effects of DOX. Overall, our work revealed that combination of shRNA-mediated gene-silencing strategy with chemotherapeutic agents constitutes a valuable and safe approach for antitumor activity. [ABSTRACT FROM AUTHOR]

[Display omitted] • The MnO 2 -based nanoplatform can constantly consume GSH and generate O 2 to enhance the efficiency of photodynamic therapy. • The multifunctional nanoplatform exhibits excellent photothermal effects and achieves significant in vivo synergistic photodynamic and photothermal therapy. • CBDM nanoplatform can effectively inhibit the growth of tumor and fight against tumor metastasis. Photodynamic therapy (PDT) as emerging phototherapy has attracted extensive attention in cancer therapy. However, the overexpressed glutathione (GSH) and hypoxic conditions of the tumor microenvironment (TME) sevely limit the therapeutic efficiency of PDT. Herein, we design a multifunctional nanoplatform (CBDM) for cancer therapy consisting of photosensitizer (Ce6), bovine serum albumin (BSA), and polydopamine-manganese dioxide (MnO 2) nanocomplex, which is simultaneously modified by nucleolin-targeting AS1411 aptamer. This MnO 2 -based nanoplatform ameliorates tumor hypoxia and promotes oxygen production via the reaction between MnO 2 and endogenous H 2 O 2 and acid H+ in the TME. Besides, this biocompatibility nanoplatform exhibits an augmented PDT effect and high photothermal conversion efficiency under 808 nm laser irradiation. Importantly, the MnO 2 -based nanoplatform achieves a significant in vivo synergistic therapeutic effect and fights against liver metastasis of breast cancer. As a result, the excellent biocompatibility, especially the superior anticancer efficacy, and suppression of tumor metastasis make the MnO 2 -based nanoplatform a promising candidate for cancer therapy. [ABSTRACT FROM AUTHOR]

Nucleolin protein expression is higher on the ovarian cancer cell surface. AS1411, a DNA aptamer, can bind with nucleolin protein specifically. In this study, we developed HA and ST DNA tiles to assemble six AS1411 aptamers to deliver doxorubicin. In addition, to superior serum stability and drug loading, HA-6AS and ST-6AS outperformed TDN-AS in cellular uptake. HA-6AS and ST-6AS exhibited satisfactory targeted cytotoxicity and achieved resounding lysosomal escape. Moreover, when injected into nude mice subcutaneous xenograft models, HA-6AS reached the peak in tumor more quickly than ST-6AS, and better expressed the active targeting ability of AS1411. Our study suggests that designing appropriate DNA tiles to assemble different aptamers to deliver different chemotherapeutic drugs is a promising treatment for ovarian cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ruan, Han, Li, Chen, Sun, Wang, Luo, Gu and Shi.)

In this study, double shelled NIR CdSeTe/CdS/C quantum dots (QDs) were synthesized by a liquid phase method. The as-prepared QDs showed low cytotoxicity and good biocompatibility due to the formation of carbon shell. The imaging of targeted Human cervical carcinoma cells (HeLa cells) indicates that the CdSeTe/CdS/C QDs have excellent optical properties and cell viability. These results clearly shows that the CdSeTe/CdS/C QDs can be a good candidate for bioapplications. [ABSTRACT FROM AUTHOR]