Tracking of multimodal therapeutic nanocomplexes targeting breast cancer in vivo.
Ontology highlight
ABSTRACT:
SUBMITTER: Bardhan R
PROVIDER: S-EPMC4089981 | biostudies-literature | 2010 Dec
REPOSITORIES: biostudies-literature
Publications
Tracking of multimodal therapeutic nanocomplexes targeting breast cancer in vivo.
Bardhan Rizia R Chen Wenxue W Bartels Marc M Perez-Torres Carlos C Botero Maria F MF McAninch Robin Ward RW Contreras Alejandro A Schiff Rachel R Pautler Robia G RG Halas Naomi J NJ Joshi Amit A
Nano letters 20101122 12
Nanoparticle-based therapeutics with local delivery and external electromagnetic field modulation holds extraordinary promise for soft-tissue cancers such as breast cancer; however, knowledge of the distribution and fate of nanoparticles in vivo is crucial for clinical translation. Here we demonstrate that multiple diagnostic capabilities can be introduced in photothermal therapeutic nanocomplexes by simultaneously enhancing both near-infrared fluorescence and magnetic resonance imaging (MRI). W ...[more]
Similar Datasets
Project description:Background:Cationic solid lipid nanoparticles (SLN) have attracted intensive interest as an effective gene delivery system for its high biocompatibility, stability and low cytotoxicity. In our previous study, we successfully prepared SLN-STAT3 decoy ODN complexes and made a primary study on its antitumor behavior in ovarian cancer cells in vitro. However, there is little information available so far about the effect of SLN-STAT3 decoy ODN complexes on ovarian cancer in vivo, either little information about the pharmacological toxicology in vivo. Material and Methods:We applied nanotechnology to improve the gene delivery system and synthesize SLN-STAT3 decoy ODN complexes. Xenograft mouse models were established to assess the antitumor effects of SLN-STAT3 decoy ODN on the tumor growth of ovarian cancer in vivo. To analyze the mechanisms of SLN-STAT3 decoy ODN, we investigated apoptosis, autophagy, epithelial-mesenchymal transition (EMT) in tumor tissues of nude mice and investigated the effects and toxicology of SLN-STAT3 decoy ODN complexes on the vital organs of nude mice. Results:The results showed that SLN-STAT3 decoy ODN complexes markedly inhibited tumor growth in vivo. SLN-STAT3 decoy ODN complexes could induce cell apoptosis through downregulating Bcl-2, survivin and pro caspase 3, but upregulating Bax and cleaved caspase 3. These complexes could also regulate autophagy through upregulating LC3A-II, LC3B-II and beclin-1, but downregulating p-Akt and p-mTOR. Moreover, these complexes could inhibit cancer cell invasion through reversing EMT. Besides, SLN-STAT3 decoy ODN complexes showed no obvious toxicity on vital organs and hematological parameters of nude mice. Conclusion:The molecular mechanisms that SLN-STAT3 decoy ODN complexes inhibit tumor growth involved activating the apoptotic cascade, regulating autophagy, and reversing EMT program; and these complexes showed no obvious toxicity on nude mice. Our study indicated that the nanocomplexes SLN-STAT3 decoy ODN might be a promising therapeutic approach for ovarian cancer treatment.
| S-EPMC7292488 | biostudies-literature
Project description:Targeted nanomedicines offer many advantages over macromolecular therapeutics that rely only on passive accumulation within the tumour environment. The aim of this work was to investigate the in vivo anticancer efficiency of polymeric nanomedicines that were conjugated with peptide aptamers that show high affinity for receptors on many cancer cells. In order to assess the ability for the nanomedicine to treat cancer and investigate how structure affected the behavior of the nanomedicine, three imaging modalities were utilized, including in vivo optical imaging, multispectral optoacoustic tomography (MSOT) and ex vivo confocal microscopy. An 8-mer (A8) or 13-mer (A13) peptide aptamer that have been shown to exhibit high affinity for heat shock protein 70 (HSP70) was covalently-bound to hyperbranched polymer (HBP) nanoparticles with the purpose of both cellular targeting, as well as the potential to impart some level of chemo-sensitization to the cells. Furthermore, doxorubicin was bound to the polymeric carrier as the anticancer drug, and Cyanine-5.5 (Cy5.5) was incorporated into the polymer as a monomeric fluorophore to aid in monitoring the behavior of the nanomedicine. Enhanced tumour regression was observed in nude mice bearing MDA-MB-468 xenografts when the nanocarriers were targeted using the peptide ligands, compared to control groups treated with free DOX or HBP without aptamer. The accumulated DOX level in solid tumours was 5.5 times higher in mice treated with the targeted therapeutic, than mice treated with free DOX, and 2.6 times higher than the untargeted nanomedicine that relied only on passive accumulation. The results suggest that aptamer-targeted therapeutics have great potential for improving accumulation of nanomedicines in tumours for therapy.
| S-EPMC6170333 | biostudies-other
Project description:BackgroundThere is increasing evidence that solid cancers contain cancer-initiating cells (CICs) that are capable of regenerating a tumor that has been surgically removed and/or treated with chemotherapy and/or radiation therapy. Currently, cell surface markers, like CD133 or CD44, are used to identify CICs in vitro; however, these markers cannot be used to identify and track CICs in vivo. The 26S proteasome is the main regulator of many processes within a proliferating cell, and its activity may be altered depending on the phenotype of a cell.MethodsHuman glioma and breast cancer cells were engineered to stably express ZsGreen fused to the carboxyl-terminal degron of ornithine decarboxylase, resulting in a fluorescent fusion protein that accumulates in cells in the absence of 26S proteasome activity; activities of individual proteases were monitored in a plate reader by detecting the cleavage of fluorogenic peptide substrates. Proteasome subunit expression in cells expressing the fusion protein was assessed by quantitative reverse transcription-polymerase chain reaction, and the stem cell phenotype of CICs was assessed by a sphere formation assay, by immunohistochemical staining for known stem cell markers in vitro, and by analyzing their tumorigenicity in vivo. CICs were tracked by in vivo fluorescence imaging after radiation treatment of tumor-bearing mice and targeted specifically via a thymidine kinase-degron fusion construct. All P values were derived from two-sided tests.ResultsCancer cells grown as sphere cultures in conditions, which enrich for cancer stem cells (CSCs), had decreased proteasome activity relative to the respective monolayers (percent decrease in chymotryptic-like activity of sphere cultures relative to monolayers--U87MG: 26.64%, 95% confidence interval [CI] = 10.19 to 43.10, GL261, 52.91%, 95% CI = 28.38 to 77.43). The cancer cells with low proteasome activity can thus be monitored in vitro and in vivo by the accumulation of a fluorescent protein (ZsGreen) fused to a degron that targets it for 26S proteasome degradation. In vitro, ZsGreen-positive cells had increased sphere-forming capacity, expressed CSC markers, and lacked differentiation markers compared with ZsGreen-negative cells. In vivo, ZsGreen-positive cells were approximately 100-fold more tumorigenic than ZsGreen-negative cells when injected into nude mice (ZsGreen positive, 30 mice per group; ZsGreen negative, 31 mice per group), and the number of CICs in tumors increased after 72 hours post radiation treatment. CICs were selectively targeted via a proteasome-dependent suicide gene, and their elimination in vivo led to tumor regression.ConclusionOur results demonstrate that reduced 26S proteasome activity is a general feature of CICs that can easily be exploited to identify, track, and target them in vitro and in vivo.
| S-EPMC2727141 | biostudies-literature
Project description:Integrin ?v?6 promotes migration, invasion, and survival of cancer cells; however, the relevance and role of ?v?6 has yet to be elucidated in breast cancer.Protein expression of integrin subunit beta6 (?6) was measured in breast cancers by immunohistochemistry (n > 2000) and ITGB6 mRNA expression measured in the Molecular Taxonomy of Breast Cancer International Consortium dataset. Overall survival was assessed using Kaplan Meier curves, and bioinformatics statistical analyses were performed (Cox proportional hazards model, Wald test, and Chi-square test of association). Using antibody (264RAD) blockade and siRNA knockdown of ?6 in breast cell lines, the role of ?v?6 in Human Epidermal Growth Factor Receptor 2 (HER2) biology (expression, proliferation, invasion, growth in vivo) was assessed by flow cytometry, MTT, Transwell invasion, proximity ligation assay, and xenografts (n ? 3), respectively. A student's t-test was used for two variables; three-plus variables used one-way analysis of variance with Bonferroni's Multiple Comparison Test. Xenograft growth was analyzed using linear mixed model analysis, followed by Wald testing and survival, analyzed using the Log-Rank test. All statistical tests were two sided.High expression of either the mRNA or protein for the integrin subunit ?6 was associated with very poor survival (HR = 1.60, 95% CI = 1.19 to 2.15, P = .002) and increased metastases to distant sites. Co-expression of ?6 and HER2 was associated with worse prognosis (HR = 1.97, 95% CI = 1.16 to 3.35, P = .01). Monotherapy with 264RAD or trastuzumab slowed growth of MCF-7/HER2-18 and BT-474 xenografts similarly (P < .001), but combining 264RAD with trastuzumab effectively stopped tumor growth, even in trastuzumab-resistant MCF-7/HER2-18 xenografts.Targeting ?v?6 with 264RAD alone or in combination with trastuzumab may provide a novel therapy for treating high-risk and trastuzumab-resistant breast cancer patients.
| S-EPMC4151855 | biostudies-other
Project description:Subunit vaccines have been investigated in over 1000 clinical trials of cancer immunotherapy, but have shown limited efficacy. Nanovaccines may improve efficacy but have rarely been clinically translated. By conjugating molecular vaccines with Evans blue (EB) into albumin-binding vaccines (AlbiVax), here we develop clinically promising albumin/AlbiVax nanocomplexes that self-assemble in vivo from AlbiVax and endogenous albumin for efficient vaccine delivery and potent cancer immunotherapy. PET pharmacoimaging, super-resolution microscopies, and flow cytometry reveal almost 100-fold more efficient co-delivery of CpG and antigens (Ags) to lymph nodes (LNs) by albumin/AlbiVax than benchmark incomplete Freund's adjuvant (IFA). Albumin/AlbiVax elicits ~10 times more frequent peripheral antigen-specific CD8+ cytotoxic T lymphocytes with immune memory than IFA-emulsifying vaccines. Albumin/AlbiVax specifically inhibits progression of established primary or metastatic EG7.OVA, B16F10, and MC38 tumors; combination with anti-PD-1 and/or Abraxane further potentiates immunotherapy and eradicates most MC38 tumors. Albumin/AlbiVax nanocomplexes are thus a robust platform for combination cancer immunotherapy.
| S-EPMC5715147 | biostudies-literature
Project description:Breast carcinogenesis is a multistep process involving both genetic and epigenetic changes. Epigenetics is defined as a reversible and heritable change in gene expression that is not accompanied by alteration in gene sequence. DNA methylation and histone modifications are the two major epigenetic changes that influence gene expression in cancer. The interaction between methylation and histone modification is intricately orchestrated by the formation of repressor complexes. Several genes involved in proliferation, antiapoptosis, invasion and metastasis have been shown to be methylated in various malignant and premalignant breast neoplasms. The histone deacetylase inhibitors (HDi) have emerged as an important class of drugs to be used synergistically with other systemic therapies in the treatment of breast cancer. Since epigenetic changes are potentially reversible processes, much effort has been directed toward understanding this mechanism with the goal of finding novel therapies as well as more refined diagnostic and prognostic tools in breast cancer.
| S-EPMC3658161 | biostudies-other
Project description:Recent investigations have highlighted that therapeutic artificial microRNAs could be promising candidates for cancer therapy through the modulation of tumor promoter or suppressor. MEK kinase 1 (MEKK1) is expressed by mitogen-activated kinase kinase kinase 1 (MAP3K1), an important kinase that links Ras activation to MAPK signaling. In the present study, we showed that synthetic MAP3K1-targeting artificial miRNA may provide considerable beneficial effects in the prevention of breast cancer growth and metastasis. We showed that MEKK1 was highly expressed in human breast cancer specimens, compared with adjacent normal tissues. Using a miRNA-expressing lentivirus system, we delivered a artificial miRNA (Map3k1 amiRNA) that targets MAP3K1 into 4T1 breast cancer cells and investigated the impact of MAP3K1-targeting miRNA on the growth and invasive behavior of breast cancer in vitro and in vivo. We found that overexpression of Map3k1 amiRNA led to impaired activities of p-ERK and p-p38. In addition, Map3k1 amiRNA induced marked proliferative impairment and invasive attenuation in breast cancer cells. However, Map3k1 amiRNA did not have evident influence on the apoptotic response of 4T1 cells. Moreover, using in vivo nude mice model, we identified that Map3k1 amiRNA attenuated tumor growth and lung metastasis of breast cancer cells. Taken together, our findings explicitly indicated that MEKK1 exerted important oncogenic property in breast cancer development, and MAP3K1-targeting artificial miRNA may provide promising therapeutic effects in the treatment of breast cancer.
| S-EPMC4700027 | biostudies-literature
Project description:Identification of specific drivers of human cancer is required to instruct the development of targeted therapeutics. We demonstrate that CSNK1D is amplified and/or overexpressed in human breast tumors and that casein kinase 1? (CK1?) is a vulnerability of human breast cancer subtypes overexpressing this kinase. Specifically, selective knockdown of CK1?, or treatment with a highly selective and potent CK1? inhibitor, triggers apoptosis of CK1?-expressing breast tumor cells ex vivo, tumor regression in orthotopic models of triple-negative breast cancer, including patient-derived xenografts, and tumor growth inhibition in human epidermal growth factor receptor 2-positive (HER2(+)) breast cancer models. We also show that Wnt/?-catenin signaling is a hallmark of human tumors overexpressing CK1?, that disabling CK1? blocks nuclear accumulation of ?-catenin and T cell factor transcriptional activity, and that constitutively active ?-catenin overrides the effects of inhibition or silencing of CK1?. Thus, CK1? inhibition represents a promising strategy for targeted treatment in human breast cancer with Wnt/?-catenin involvement.
| S-EPMC4809734 | biostudies-literature
Project description:Pancreatic cancer is one of the leading causes of cancer-related death, with 5-year survival of 8.5%. The lack of significant progress in improving therapy reflects our inability to overcome the desmoplastic stromal barrier in pancreatic ductal adenocarcinoma (PDAC) as well as a paucity of new approaches targeting its genetic underpinnings. RNA interference holds promise in targeting key mutations driving PDAC; however, a nucleic acid delivery vehicle that homes to PDAC and breaches the stroma does not yet exist. Noting that the cyclic peptide iRGD mediates tumor targeting and penetration through interactions with ?v?3/5 integrins and neuropilin-1, we hypothesized that "tandem" peptides combining a cell-penetrating peptide and iRGD can encapsulate siRNA to form tumor-penetrating nanocomplexes (TPN) capable of delivering siRNA to PDAC. The use of directly conjugated iRGD is justified by receptor expression patterns in human PDAC biopsies. In this work, we optimize iRGD TPNs with polyethylene glycol (PEG)-peptide conjugates for systemic delivery to sites of disease. We show that TPNs effectively knockdown siRNA targets in PDAC cell lines and in an immunocompetent genetically engineered mouse model of PDAC. Furthermore, we validate their tumor-penetrating ability in three-dimensional organoids and autochthonous tumors. In murine therapeutic trials, TPNs delivering anti-Kras siRNA significantly delay tumor growth. Thus, iRGD TPNs hold promise in treating PDAC by not only overcoming physical barriers to therapy, but by leveraging the stroma to achieve knockdown of the gold-standard genetic target. Moreover, the modular construction of this delivery platform allows for facile adaptation to future genetic target candidates in pancreatic cancer. Mol Cancer Ther; 17(11); 2377-88. ©2018 AACR.
| S-EPMC6298224 | biostudies-literature
Project description:In this study, we reported a simple polydopamine (pD)-based surface modification method to prepare novel nanoparticle-aptamer bioconjugates (Apt-pD-DTX/NPs) for in vivo tumor targeting and enhanced therapeutic effects of breast cancer. With simple preparation procedures, the new functionalized Apt-pD-DTX/NPs could maximumly increase the local effective drug concentration on tumor sites, achieving enhanced treatment effectiveness and minimizing side effects. The dopamine polymerization and aptamer conjugation barely changed the characters of NPs. Both in vitro cell experiments (i.e. endocytosis of fluorescent NPs, in vitro cellular targeting and cytotoxicity assays) and in vivo animal studies (i.e. in vivo imaging, biodistribution and antitumor effects of NPs) demonstrated that the Apt-pD-DTX/NPs could achieve significantly high targeting efficiency and enhanced therapeutic effects compared with clinical Taxotere(®) and NPs without functional modification. Above all, the Apt-pD-DTX/NPs showed great potential as a promising nanoformulation for in vivo breast cancer therapy and the construction of pD-modified NP-aptamer bioconjugates could be of great value in medical use.
| S-EPMC4775858 | biostudies-other