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Molecular Pharmaceutics Jul 2023Selective delivery of chemotherapy to the tumor site while sparing healthy cells and tissues is an attractive approach for cancer treatment. Carriers such as peptides...
Selective delivery of chemotherapy to the tumor site while sparing healthy cells and tissues is an attractive approach for cancer treatment. Carriers such as peptides can facilitate selective tumor targeting and payload delivery. Peptides with specific affinity for the overexpressed cell-surface receptors in cancer cells are conjugated to chemotherapy to afford peptide-drug conjugates (PDCs) that show selective uptake by cancer cells. Using a 10-mer linear peptide (WxEAAYQrFL) called 18-4 that targets and binds breast cancer cells, we designed a peptide 18-4-doxorubicin (Dox) conjugate with high specific toxicity toward triple-negative breast cancer (TNBC) MDA-MB-231 cells and 30-fold lower toxicity to normal breast MCF10A epithelial cells. Here, we elucidate the activity of this potent and tumor-selective peptide 18-4-Dox conjugate in mice bearing orthotopic MDA-MB-231 tumors. Mice treated with four weekly injections of the conjugate showed significantly lower tumor volumes compared to mice treated with free Dox at an equivalent Dox dose. Immunohistochemical (IHC) analysis of mice tissues revealed that treatment with a low dose of PDC (2.5 mg/kg of Dox equiv) reduced the expression of proliferation markers (PCNA and Ki-67) and increased apoptosis (evidenced by increased caspase-3 expression). At the same dose of free Dox (2.5 mg/kg), the expression of these markers was similar to that of saline treatment. Accordingly, significantly more Dox accumulated in tumors of conjugate-treated mice (7-fold) compared to the Dox-treated mice, while lower levels of Dox were observed in the liver, heart, and lungs of peptide-Dox conjugate-treated mice (up to 3-fold less) than Dox-treated mice. The IHC analysis of keratin 1 (K1), the receptor for peptide 18-4, revealed K1 upregulation in tumors and low levels in normal mammary fat pad and liver tissues from mice, suggesting preferential uptake of PDCs by TNBC to be K1 receptor-mediated. Taken together, our data support the use of a PDC approach to deliver chemotherapy selectively to the TNBC to inhibit tumor growth.
Topics: Humans; Animals; Mice; Female; Triple Negative Breast Neoplasms; Keratin-1; Drug Delivery Systems; Doxorubicin; Peptides; Cell Line, Tumor; Breast Neoplasms
PubMed: 37307328
DOI: 10.1021/acs.molpharmaceut.3c00189 -
PloS One 2023Doxorubicin (DOX) is an anthracycline antibiotic which is widely used for the treatment of various cancers, while the dose-related cardiotoxicity limits its potential...
OBJECTIVE
Doxorubicin (DOX) is an anthracycline antibiotic which is widely used for the treatment of various cancers, while the dose-related cardiotoxicity limits its potential therapeutic application. The underlying mechanism of DOX induced cardiotoxicity is complex and remains elusive. Our previous studies have shown that M2b macrophage plays an important role in reducing inflammation due to ischemic reperfusion injury in the myocardium. The purpose of this study was to investigate the potential protective role of M2b macrophages in DOX induced cardiotoxicity.
METHODS
In vivo, we conducted DOX induced cardiac injury in C57BL/6 mice and treated them with M2b macrophages. Then, the mice were examined by echocardiography. The heart specimens were harvested for histological examination, transmission electron microscope analysis, and autophagy molecules evaluation. In vitro, HL-1 cardiac cell lines treated with DOX were cocultured with or without M2b macrophages. Then, Autophagy related genes and protein expression were assessed by real-time quantitative PCR and western blot; cell proliferation was assessed by cell counting kit-8.
RESULTS
We found that M2b macrophages can improve cardiac function and alleviate cardiac injury in DOX induced cardiac injury mice. M2b macrophages can enhance cardiac autophagy levels both in vivo and in vitro in DOX induced cardiac injury model. In addition, this protective effect can be blocked by an autophagy inhibitor.
CONCLUSION
Our study shows that M2b macrophages can help attenuate the DOX induced cardiotoxicity by regulating the autophagy level of cardiomyocytes.
Topics: Mice; Animals; Myocytes, Cardiac; Cardiotoxicity; Signal Transduction; Mice, Inbred C57BL; Doxorubicin; Autophagy; Macrophages; Oxidative Stress; Apoptosis
PubMed: 37498828
DOI: 10.1371/journal.pone.0288422 -
Nano Letters Nov 2023Given the key roles of cancer associated fibroblasts (CAFs) in shaping tumor stroma, this study shows a CAF-associated ITGB1-inactivating peptide-enriched membrane...
Given the key roles of cancer associated fibroblasts (CAFs) in shaping tumor stroma, this study shows a CAF-associated ITGB1-inactivating peptide-enriched membrane nanodelivery system (designated as PMNPs-D) to simultaneously target CAFs and tumor cells for boosted chemotherapy through promoted drug perfusion. In the structure of PMNPs-D, the PLGA-based inner core is loaded with the chemotherapeutic drug doxorubicin, and the outer surface is cloaked by hybrid biomembranes with the insertion of integrin β1 (ITGB1) inhibiting peptide (i.e., FNIII14). After prolonged blood circulation and actively targeting in tumor sites, PMNPs-D can respond to CAF-overexpressed fibroblast activation protein-α (FAP-α) to trigger the release of FNIII14, which will bind to ITGB1 and inhibit CAFs' biological function in producing the stromal matrix, thereby loosening the condensed stromal structure and enhancing the permeability of nanotherapeutics in tumors. As a result, this tailor-designed nanosystem shows substantial tumor inhibition and metastasis retardation in aggressive adenoid cystic carcinoma (ACC) tumor-harboring mice.
Topics: Animals; Mice; Cancer-Associated Fibroblasts; Neoplasms; Doxorubicin; Membranes; Peptides; Tumor Microenvironment; Cell Line, Tumor; Fibroblasts
PubMed: 37729438
DOI: 10.1021/acs.nanolett.3c02983 -
Biomaterials Oct 2023Taking advantage of endogenous Ca to upregulate intramitochondrial Ca level has become a powerful mean for mitochondrial dysfunction-mediated tumor therapy. However, the...
Taking advantage of endogenous Ca to upregulate intramitochondrial Ca level has become a powerful mean for mitochondrial dysfunction-mediated tumor therapy. However, the Ca entered into mitochondria is limited ascribing to the uncontrollability and non-selectivity of endogenous Ca transport. It remains a great challenge to make the maximum use of endogenous Ca to ensure sufficient Ca overloading in mitochondria. Herein, we smartly fabricate an intracellular Ca directional transport channel to selectively transport endogenous Ca from endoplasmic reticulum (ER) to mitochondria based on cascade release nanoplatform ABT-199@liposomes/doxorubicin@Fe-tannic acid (ABT@Lip/DOX@Fe-TA). In tumor acidic microenvironment, Fe ions are firstly released and reduced by tannic acid (TA) to Fe for ROS generation. Subsequently, under the NIR light irradiation, the released ABT-199 molecules combine with ROS contribute to the formation of IP3R-Grp75-VDAC1 channel between ER and mitochondria, thus Ca ions are directionally delivered and intramitochondrial Ca level is significantly upregulated. The synergetic ROS generation and mitochondrial Ca overloading effectively intensifies mitochondrial dysfunction, thereby achieving efficient tumor inhibition. This work presents a new insight and promising avenue for endogenous Ca-involved tumor therapies.
Topics: Calcium; Reactive Oxygen Species; Ferric Compounds; Mitochondria; Doxorubicin
PubMed: 37619266
DOI: 10.1016/j.biomaterials.2023.122284 -
Advanced Materials (Deerfield Beach,... Aug 2023Efficient hepatocellular carcinoma (HCC) treatment remains a significant challenge due to the inherent limitations of traditional strategies. The exploration of...
Efficient hepatocellular carcinoma (HCC) treatment remains a significant challenge due to the inherent limitations of traditional strategies. The exploration of polysaccharides' natural immunity for HCC immunotherapy is rarely explored. For this purpose, facile construction of a multifunctional nanoplatform, biotinylated aldehyde alginate-doxorubicin nano micelle (BEACNDOXM) is reported in this study for synergistic chemo-immunotherapy by using constant β-D-mannuronic acid (M) units and modulated α-L-guluronic acid (G) units in the alginate (ALG) structure. The M units show natural immunity and specific binding ability with mannose receptors (MRs) via strong receptor-ligand interactions, and the G units serve as highly reactive conjugation sites for biotin (Bio) and DOX. Therefore, this formulation not only integrates the natural immunity of ALG and the immunogenic cell death (ICD) triggering function of DOX, but also shows dual targeting properties to HCC cells via MRs and Bio receptors (BRs)-mediated endocytosis. Notably, BEACNDOXM mediates a tumor inhibitory efficiency 12.10% and 4.70% higher than free DOX and single targeting aldehyde alginate-doxorubicin nano micelle controls, respectively, at an equivalent DOX dose of 3 mg kg in Hepa1-6 tumor-bearing mice. This study reports the first example of integrating the natural immunity of ALG and the ICD effect of anticancer drugs for enhanced chemo-immunotherapy of HCC.
Topics: Animals; Mice; Carcinoma, Hepatocellular; Liver Neoplasms; Alginates; Doxorubicin; Immunotherapy; Cell Line, Tumor; Nanoparticles
PubMed: 37216573
DOI: 10.1002/adma.202301352 -
Journal of Clinical Oncology : Official... Jun 2024
Topics: Humans; Breast Neoplasms; Female; Doxorubicin; Antibiotics, Antineoplastic; Follow-Up Studies
PubMed: 38478798
DOI: 10.1200/JCO.23.02763 -
Advanced Healthcare Materials Nov 2023Micro-sized magnetic particles (also known as microrobots [MRs]) have recently been shown to have potential applications for numerous biomedical applications like drug...
Micro-sized magnetic particles (also known as microrobots [MRs]) have recently been shown to have potential applications for numerous biomedical applications like drug delivery, microengineering, and single cell manipulation. Interdisciplinary studies have demonstrated the ability of these tiny particles to actuate under the action of a controlled magnetic field that not only drive MRs in a desired trajectory but also precisely deliver therapeutic payload to the target site. Additionally, optimal concentrations of therapeutic molecules can also be delivered to the desired site which is cost-effective and safe especially in scenarios where drug dose-related side effects are a concern. In this study, MRs are used to deliver anticancer drugs (doxorubicin) to cancer cells and subsequent cell death is evaluated in different cell lines (liver, prostate, and ovarian cancer cells). Cytocompatibility studies show that MRs are well-tolerated and internalized by cancer cells. Doxorubicin (DOX) is chemically conjugated with MRs (DOX-MRs) and magnetically steered toward cancer cells using the magnetic controller. Time-lapsed video shows that cells shrink and eventually die when MRs are internalized by cells. Taken together, this study confirms that microrobots are promising couriers for targeted delivery of therapeutic biomolecules for cancer therapy and other non-invasive procedures that require precise control.
Topics: Male; Humans; Doxorubicin; Drug Delivery Systems; Antineoplastic Agents; Cell Line; Cell Death
PubMed: 37378647
DOI: 10.1002/adhm.202300939 -
Cell Death & Disease Aug 2023In breast cancer, dysregulated TP53 expression signatures are a better predictor of chemotherapy response and survival outcomes than TP53 mutations. Our previous studies...
In breast cancer, dysregulated TP53 expression signatures are a better predictor of chemotherapy response and survival outcomes than TP53 mutations. Our previous studies have shown that high levels of Δ40p53 are associated with worse disease-free survival and disruption of p53-induced DNA damage response in breast cancers. Here, we further investigated the in vitro and in vivo implications of Δ40p53 expression in breast cancer. We have shown that genes associated with cell differentiation are downregulated while those associated with stem cell regulation are upregulated in invasive ductal carcinomas expressing high levels of Δ40p53. In contrast to p53, endogenous ∆40p53 co-localised with the stem cell markers Sox2, Oct4, and Nanog in MCF-7 and ZR75-1 cell lines. ∆40p53 and Sox2 co-localisation was also detected in breast cancer specimens. Further, in cells expressing a high ∆40p53:p53 ratio, increased expression of stem cell markers, greater mammosphere and colony formation capacities, and downregulation of miR-145 and miR-200 (p53-target microRNAs that repress stemness) were observed compared to the control subline. In vivo, a high ∆40p53:p53 ratio led to increased tumour growth, Ki67 and Sox2 expression, and blood microvessel areas in the vehicle-treated mice. High expression of ∆40p53 also reduced tumour sensitivity to doxorubicin compared to control tumours. Enhanced therapeutic efficacy of doxorubicin was observed when transiently targeting Δ40p53 or when treating cells with OTSSP167 with concomitant chemotherapy. Taken together, high Δ40p53 levels induce tumour growth and may promote chemoresistance by inducing a stemness phenotype in breast cancer; thus, targeting Δ40p53 in tumours that have a high Δ40p53:p53 ratio could enhance the efficacy of standard-of-care therapies such as doxorubicin.
Topics: Animals; Mice; Tumor Suppressor Protein p53; Cell Line, Tumor; Doxorubicin; MicroRNAs; Protein Isoforms; Neoplasms
PubMed: 37553320
DOI: 10.1038/s41419-023-06031-4 -
Nature Nanotechnology Aug 2023Although cyclodextrin-based renal-clearable nanocarriers have a high potential for clinical translation in targeted cancer therapy, their designs remain to be optimized...
Although cyclodextrin-based renal-clearable nanocarriers have a high potential for clinical translation in targeted cancer therapy, their designs remain to be optimized for tumour retention. Here we report on the design of a tailored structure for renal-clearable zwitterionic cyclodextrin for colorectal cancer-selective drug delivery. Twenty cyclodextrin derivatives with different charged moieties and spacers are synthesized and screened for colloidal stability. The resulting five candidates are evaluated for biodistribution and an optimized structure is identified. The optimized cyclodextrin shows a high tumour accumulation and is used for delivery of doxorubicin and ulixertinib. Higher tumour accumulation and tumour penetration facilitates tumour elimination. The improved antitumour efficacy is demonstrated in heterotopic and orthotopic colorectal cancer models.
Topics: Humans; Cyclodextrins; Tissue Distribution; Drug Delivery Systems; Doxorubicin; Colorectal Neoplasms; Drug Carriers
PubMed: 37106052
DOI: 10.1038/s41565-023-01381-8 -
Cell Death & Disease Dec 2023Given the lack of therapeutic targets, the conventional approach for managing triple-negative breast cancer (TNBC) involves the utilization of cytotoxic chemotherapeutic...
Given the lack of therapeutic targets, the conventional approach for managing triple-negative breast cancer (TNBC) involves the utilization of cytotoxic chemotherapeutic agents. However, most TNBCs acquire resistance to chemotherapy, thereby lowering the therapeutic outcome. In addition to oncogenic mutations in TNBC, microenvironment-induced mechanisms render chemoresistance more complex and robust in vivo. Here, we aimed to analyze whether depletion of Munc18-1 interacting protein 3 (Mint3), which activates hypoxia-inducible factor 1 (HIF-1) during normoxia, sensitizes TNBC to chemotherapy. We found that Mint3 promotes the chemoresistance of TNBC in vivo. Mint3 depletion did not affect the sensitivity of human TNBC cell lines to doxorubicin and paclitaxel in vitro but sensitized tumors of these cells to chemotherapy in vivo. Transcriptome analyses revealed that the Mint3-HIF-1 axis enhanced heat shock protein 70 (HSP70) expression in tumors of TNBC cells. Administering an HSP70 inhibitor enhanced the antitumor activity of doxorubicin in TNBC tumors, similar to Mint3 depletion. Mint3 expression was also correlated with HSP70 expression in human TNBC specimens. Mechanistically, Mint3 depletion induces glycolytic maladaptation to the tumor microenvironment in TNBC tumors, resulting in energy stress. This energy stress by Mint3 depletion inactivated heat shock factor 1 (HSF-1), the master regulator of HSP expression, via the AMP-activated protein kinase/mechanistic target of the rapamycin pathway following attenuated HSP70 expression. In conclusion, Mint3 is a unique regulator of TNBC chemoresistance in vivo via metabolic adaptation to the tumor microenvironment, and a combination of Mint3 inhibition and chemotherapy may be a good strategy for TNBC treatment.
Topics: Humans; Carrier Proteins; Cell Line, Tumor; Doxorubicin; Paclitaxel; Triple Negative Breast Neoplasms; Tumor Microenvironment
PubMed: 38081808
DOI: 10.1038/s41419-023-06352-4