as-1411 and Colonic-Neoplasms

Severe side effects of chemotherapy agents on vital organs are the major causes of cancer-related mortality, not merely cancer disease. Encapsulating chemotherapeutic molecules in nanocarriers is a justifiable solution in decreasing the risk of their side effects and boosting the efficiency of treatment. The present study has developed the doxorubicin (DOX)-loaded AS1411 (anti-nucleolin) aptamer surface-functionalized exosome (DOX-Apt-Exo) to treat colorectal cancer in both in-vitro and in-vivo experimental models. HEK293-derived exosomes were loaded with DOX through the incubation method with a nearly 13% encapsulation efficiency. Afterwards, the 5-terminal carboxyl group of AS1411-aptamer was converted into amine-reactive NHS esters with EDC/NHS amide coupling chemistry before being conjugated to the amine groups on the exosome surface. DLS and TEM estimated the designed formulation (DOX-Apt-Exo) size of about 200 nm. Aptamer-binding affinity and cellular uptake of DOX-Apt-Exo by nucleolin-overexpressing cancer cells were depicted through fluorescence microscopy. Comparing the in-vitro cytotoxicity impact of DOX-loaded exosomes, either targeted or non-targeted by MTT assay, clearly verified a high effectiveness of ligand-receptor mediated target therapy. Subsequently, in-vivo experiments which were conducted on four groups of ectopic mouse models of colon cancer (5 in each group) demonstrated the tumor growth suppression through professional long-term accumulation and retention of DOX-Apt-Exo at the tumor site by ligand-receptor interaction. The results suggested that AS1411 aptamer-functionalized exosomes can be recommended as a safe and effective system to site-specific drug delivery in possible clinical applications of colon cancer.

Topics: Amides; Amines; Animals; Cell Line, Tumor; Colonic Neoplasms; Doxorubicin; Drug Delivery Systems; Exosomes; HEK293 Cells; Humans; Ligands; Mice; Nanoparticles

Chemotherapy is the primary treatment for advanced colon cancer, but its efficacy is often limited by severe toxicities. Targeted therapy in the form of selectively drug delivery system (SDDS) is an important strategy to reduce adverse effects. Here, we aim to design a novel SDDS with potential for practical application using biocompatible components and scalable production process, for targeted delivery of doxorubicin (Dox) to colon cancer cells.. The SDDS was made of a self-assembled DNA nano-cross (Holliday junction, or HJ) functionalized by four AS1411 aptamers (Apt-HJ) and loaded with Dox.. Apt-HJ had an average size of 12.45 nm and a zeta potential of -11.6 mV. Compared with the monovalent AS1411 aptamer, the quadrivalent Apt-HJ showed stronger binding to target cancer cells (CT26). A complex of Apt-HJ and doxorubicin (Apt-HJ-Dox) was formed by intercalating Dox into the DNA structure of Apt-HJ, with each complex carrying approximately 17 Dox molecules. Confocal microscopy revealed that Apt-HJ-Dox selectively delivered Dox into CT26 colon cancer cells but not the control cells. Moreover, Apt-HJ-Dox achieved targeted killing of CT26 cancer cells in vitro and reduced the damage to control cells. Importantly, compared with free Dox, Apt-HJ-Dox significantly enhanced the antitumor efficacy in vivo without boosting the adverse effects.. These results suggest that Apt-HJ-Dox has application potential in targeted treatment of colon cancer.

Topics: Animals; Antibiotics, Antineoplastic; Aptamers, Nucleotide; Cell Line, Tumor; CHO Cells; Colonic Neoplasms; Cricetulus; DNA, Cruciform; Doxorubicin; Drug Delivery Systems; Mice; Mice, Inbred BALB C; Microscopy, Fluorescence; Nanostructures; Neoplasms, Experimental; Oligodeoxyribonucleotides

Nanotechnology has shown advantages for cancer treatment. Multimodal nanoparticles (NPs) combining chemotherapy and photothermal therapy are promising and elicit synergetic benefit. However, there were still less multifunctional nanomaterials with good targeting and anti-tumor property applied as the colon cancer therapeutic strategy. In this study, we designed the gold NPs modified with AS1411 and DNA riched of GC intercalation (hairpin DNA) with doxorubicin (DOX) for targeted chemotherapy and NIR laser-triggered chemo-photothermal effect (PTT). We took advantage of PTT effect to realize DOX release from hairpin DNA. We also demonstrated AS1411 based NPs exhibited remarkable targeted binding towards SW480 colon cancer cells in vitro and enhanced uptake inside the cells. Strikingly, AS1411 based NPs exhibited the most efficient cytotoxicity and markedly enhanced inhibition effect on cells proliferation to SW480 cells under laser exposure when compared to the NPs merely with PTT or chemotherapy. Our study appears to provide an alternative nanoplatform with good targeted and chemo-photothermal therapy against colon cancer.

Topics: Antineoplastic Agents; Aptamers, Nucleotide; Cell Line, Tumor; Colonic Neoplasms; Combined Modality Therapy; Doxorubicin; Drug Delivery Systems; Humans; Laser Therapy; Metal Nanoparticles; Oligodeoxyribonucleotides; Photothermal Therapy

Chemotherapy of colon cancer needs improvement to mitigate the severe adverse effects (AEs) associated with the cytotoxic drugs. The aim of this study is to develop a novel targeted drug delivery system (TDDS) with practical application potential for colon cancer treatment.. The TDDS was built by loading docetaxel (DTX) in albumin nanoparticles (NPs) that were functionalized with nucleolin-targeted aptamers (AS1411).. The TDDS (Apt-NPs-DTX) had an average size of 62 nm and was negatively charged with a zeta potential of -31.2 mV. DTX was released from the albumin NP with a typical sustained release profile. Aptamer-guided NPs were preferentially ingested by nucleolin-expressing CT26 colon cancer cells vs the control cells. In vitro cytotoxicity study showed that Apt-NPs-DTX significantly enhanced the killing of CT26 colon cancer cells. Importantly, compared with non-targeted drug delivery, Apt-NPs-DTX treatment significantly improved antitumor efficacy and prolonged the survival of CT26-bearing mice, without raising systemic toxicity.. The results suggest that Apt-NPs-DTX has potential in the targeted treatment of colon cancer.

Topics: Animals; Antineoplastic Agents; Aptamers, Nucleotide; Cell Line, Tumor; CHO Cells; Colonic Neoplasms; Cricetulus; Docetaxel; Drug Carriers; Drug Delivery Systems; Drug Liberation; Female; Mice, Inbred BALB C; Nanoparticles; Neoplasms, Experimental; Oligodeoxyribonucleotides; Serum Albumin, Bovine

One of the major abundant proteins in the nucleous is nucleolin that overexpressed on the cytoplasmic membrane of malignant and endothelial cells and makes it as a promising condidate for targeted drug delivery.. In this study, doxorubicin (Dox) as a chemotherapy drug was entrapped into the Poly lacticco- glycolic acid (PLGA)-based nanoparticles (NPs). Then, the targeting ability of anti nucleolin AS1411 aptamer-targeted Dox-encapsulated PLGA-based NPs (AS1411-NPs) was investigated in high nucleolin-expressing C26 colon carcinoma and rat C6 glioma cell lines compared with low nucleolinexpressing mouse L929 cell line.. We recently first assessed the existence of cell surface nucleolin of these three different cell lines by immunocytochemistry method. We found that a large amount of nucleolin was localized in the cytoplasmic membrane of C26 and C6 cell lines, with a very smaller amount on the surface of L929 cell line.. As a result, more rapidly internalization of AS1411-NPs into the C26 and C6 cells compared with L929 cells was verified.. We think that AS1411-NPs, as a ligand, first bind to nucleolin, as a receptor, and then the receptor-ligand complex is more efficiently incorporated into the high nucleolin-expressing cell lines through receptor-mediated endocytosis pathway.

Topics: Animals; Antibiotics, Antineoplastic; Aptamers, Nucleotide; Cell Line; Cell Proliferation; Colonic Neoplasms; Doxorubicin; Drug Delivery Systems; Drug Screening Assays, Antitumor; Glioma; Humans; Ligands; Mice; Nanoparticles; Nucleolin; Oligodeoxyribonucleotides; Particle Size; Phosphoproteins; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; RNA-Binding Proteins; Surface Properties

In the current study camptothecin-loaded pegylated PAMAM dendrimer were synthesized and were functionalized with AS1411 anti-nucleolin aptamers for site-specific targeting against colorectal cancer cells which over expresses nucleolin receptors. The morphological properties and size dispersity of the prepared nanoparticles were evaluated using transmission electron microscope (TEM) and DLS. The drug-loading content and encapsulation efficiency were obtained 8.1% and 93.67% respectively. The in vitro release of camptothecin from the formulation was provided the sustained release of encapsulated camptothecin during 4days. Comparative in vitro cytotoxicity experiments demonstrated that the targeted camptothecin loaded-pegylated dendrimers had higher antiproliferation activity, towards nucleolin-positive HT29 and C26 colorectal cancer cells than nucleolin-negative CHO cell line. Fluorscence microscopy and flow cytometry also confirmed the enhanced cellular uptake of AS1411 targeted pegylated-dendrimer. In vivo study in C26 tumor-bearing BALB/C mice revealed that the AS1411-functionalized camptothecin loaded pegylated dendrimers improved antitumor activity and survival rate of the encapsulated camptothecin. Conjugation of AS1411 aptamer to the camptothecin loaded-pegylated dendrimer surface provides site-specific delivery of camptothecin, inhibit C26 tumor growth in vivo and significantly decrease systemic toxicity. These results suggested that the new nucleolin-targeted pegylated PAMAM dendrimer as a delivery system for camptothecin have the potential for the treatment of nucleolin-overexpressed colorectal cancer.

Topics: Adenocarcinoma; Animals; Aptamers, Nucleotide; Camptothecin; Cell Line, Tumor; CHO Cells; Colon; Colonic Neoplasms; Cricetulus; Dendrimers; Drug Carriers; Drug Delivery Systems; HT29 Cells; Humans; Mice; Mice, Inbred BALB C; Nanoparticles; Nucleolin; Oligodeoxyribonucleotides; Phosphoproteins; RNA-Binding Proteins