Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs.
Ontology highlight
ABSTRACT:
SUBMITTER: Sugahara KN
PROVIDER: S-EPMC2881692 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Kandela et al., 2015) that described how we intended to replicate selected experiments from the paper "Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs" (Sugahara et al., 2010). Here we report the results of those experiments. We found that coadministration with iRGD peptide did not have an impact on permeability of the chemotherapeutic agent doxorubicin (DOX) in a xenograft model of prostate cancer, whereas the original study reported that it increased the penetrance of this cancer drug (Figure 2B; Sugahara et al., 2010). Further, in mice bearing orthotopic 22Rv1 human prostate tumors, we did not find a statistically significant difference in tumor weight for mice treated with DOX and iRGD compared to DOX alone, whereas the original study reported a decrease in tumor weight when DOX was coadministered with iRGD (Figure 2C; Sugahara et al., 2010). In addition, we did not find a statistically significant difference in TUNEL staining in tumor tissue between mice treated with DOX and iRGD compared to DOX alone, while the original study reported an increase in TUNEL positive staining with iRGD coadministration (Figure 2D; Sugahara et al., 2010). Similar to the original study (Supplemental Figure 9A; Sugahara et al., 2010), we did not observe an impact on mouse body weight with DOX and iRGD treatment. Finally, we report meta-analyses for each result.
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Project description:PurposeC-end rule (CendR) peptides are found to enhance the penetration of chemotherapeutic agents into tumor cells, while GX1 is a peptide that homes to gastric cancer (GC) vasculature. This study aimed to synthesize a novel peptide GX1-RPAKPAR (GXC) and to explore the effect of GXC on sensitizing GC cells to chemotherapeutic agents.Materials and methodsIntracellular Adriamycin concentration analysis was applied to conform whether GXC peptide increases the penetration of chemotherapeutic agents into GC cells in vitro. The effect of GXC peptide on sensitizing GC cells to chemotherapeutics was validated by apoptosis assay and in vitro/vivo drug sensitivity assay. The specificity of GXC to GC tissue was validated by ex vivo fluorescence imaging.ResultsIn vitro, administration of GXC significantly increased Adriamycin concentrations inside SGC-7901 cells, and enhanced the efficacy of chemotherapeutic agents by decreasing the IC₅₀ value. In vivo, FITC-GXC specifically accumulated in GC tissue. Moreover, systemic co-injection with GXC peptide and Adriamycin statistically improved the therapeutic efficacy in SGC-7901 xenograft models, surprisingly, without obviously increasing side effects.ConclusionThese results demonstrated that co-administration of the novel peptide GXC with chemotherapeutic agents may be a potential way to enhance the efficacy of anticancer drugs in GC treatment.
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Project description:Resistance to irradiation (IR) remains a major therapeutic challenge in tumor radiotherapy. The development of novel tumor-specific radiosensitizers is crucial for effective radiotherapy against solid tumors. Here, we revealed that remodeling tumor tissue penetration via tumor-penetrating peptide internalizing arginine-glycine-aspartic acid RGD (iRGD) enhanced irradiation efficacy. The growth of 4T1 and CT26 multicellular tumor spheroids (MCTS) and tumors was delayed significantly by the treatment with IR and iRGD. Mechanistically, iRGD reduced hypoxia in MCTS and tumors, resulting in enhanced apoptosis after MCTS and tumors were treated with IR and iRGD. This is the first report that shows enhanced radiation efficacy by remodeling tumor-specific tissue penetration with iRGD, implying the potential clinical application of peptides in future tumor therapy.
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Project description:Three-dimensional (3 D) cell culture platforms are increasingly being used in cancer research and drug development since they mimic avascular tumors in vitro. In this study, we focused on the development of a novel air-grown multicellular spheroid (MCS) model to mimic in vivo tumors for understanding lung cancer biology and improvement in the evaluation of aerosol anticancer therapeutics. 3 D MCS were formed using A549 lung adenocarcinoma cells, comprising cellular heterogeneity with respect to different proliferative and metabolic gradients. The growth kinetics, morphology and 3 D structure of air-grown MCS were characterized by brightfield, fluorescent and scanning electron microscopy. MCS demonstrated a significant decrease in growth when the tumor-penetrating peptide iRGD and paclitaxel (PTX) were coadministered as compared with PTX alone. It was also found that when treated with both iRGD and PTX, A549 MCS exhibited an increase in apoptosis and decrease in clonogenic survival capacity in contrast to PTX treatment alone. This study demonstrated that coadministration of iRGD resulted in the improvement of the tumor penetration ability of PTX in an in vitro A549 3 D MCS model. In addition, this is the first time a high-throughput air-grown lung cancer tumor spheroid model has been developed and evaluated.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal; however, some improvement in overall survival has been achieved with the introduction of nanocarriers that deliver irinotecan or paclitaxel. Although it is generally assumed that nanocarriers rely principally on abnormal leaky vasculature for tumor access, a transcytosis transport pathway that is regulated by neuropilin-1 (NRP-1) has recently been reported. NRP-1-mediated transport can be triggered by the cyclic tumor-penetrating peptide iRGD. In a KRAS-induced orthotopic PDAC model, coadministration of iRGD enhanced the uptake of an irinotecan-loaded silicasome carrier that comprises lipid bilayer-coated mesoporous silica nanoparticles (MSNPs); this uptake resulted in enhanced survival and markedly reduced metastasis. Further, ultrastructural imaging of the treated tumors revealed that iRGD coadministration induced a vesicular transport pathway that carried Au-labeled silicacomes from the blood vessel lumen to a perinuclear site within cancer cells. iRGD-mediated enhancement of silicasome uptake was also observed in patient-derived xenografts, commensurate with the level of NRP-1 expression on tumor blood vessels. These results demonstrate that iRGD enhances the efficacy of irinotecan-loaded silicasome-based therapy and may be a suitable adjuvant in nanoparticle-based treatments for PDAC.
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Project description:Peritoneal carcinomatosis is a major source of morbidity and mortality in patients with advanced abdominal neoplasms. Intraperitoneal chemotherapy (IPC) is an area of intense interest given its efficacy in ovarian cancer. However, IPC suffers from poor drug penetration into peritoneal tumors. As such, extensive cytoreductive surgery is required prior to IPC. Here, we explore the utility of iRGD, a tumor-penetrating peptide, for improved tumor-specific penetration of intraperitoneal compounds and enhanced IPC in mice. Intraperitoneally administered iRGD significantly enhanced penetration of an attached fluorescein into disseminated peritoneal tumor nodules. The penetration was tumor-specific, circulation-independent, and mediated by the neuropilin-binding RXXK tissue-penetration peptide motif of iRGD. Q-iRGD, which fluoresces upon cleavage, including the one that leads to RXXK activation, specifically labeled peritoneal metastases displaying different growth patterns in mice. Importantly, iRGD enhanced intratumoral entry of intraperitoneally co-injected dextran to approximately 300% and doxorubicin to 250%. Intraperitoneal iRGD/doxorubicin combination therapy inhibited the growth of bulky peritoneal tumors and reduced systemic drug toxicity. iRGD delivered attached fluorescein and co-applied nanoparticles deep into fresh human peritoneal metastasis explants. These results indicate that intraperitoneal iRGD co-administration serves as a simple and effective strategy to facilitate tumor detection and improve the therapeutic index of IPC for peritoneal carcinomatosis.
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Project description:A serious limitation of numerous antitumor drugs is the incapacity to penetrate solid tumors. However, addition of an RGD fragment to peptide drugs might solve this problem. In this study, we explored whether the introduction of a permeability-enhancing sequence, such as iRGD (CRGDK/RGPD/EC) fragments, would enhance the activity of thymosin alpha 1 (Tα1). The modified Tα1 (Tα1-iRGD) was successfully expressed and purified, and the in vitro assay showed that Tα1-iRGD presented a similar activity as Tα1 in promoting proliferation of mouse splenocytes. Meanwhile, cell adhesion analysis revealed that Tα1-iRGD exhibited more specific and greater binding with tumor cells compared with Tα1. Furthermore, the iRGD fragment evidently enhanced the basal ability of Tα1 to inhibit proliferation of cancer cells in vitro, particularly of mouse melanoma cell line B16F10 and human lung cancer cell line H460. Our findings indicated that the addition of an iRGD fragment increased the anti-proliferative activity of Tα1 against cancer cells by improving the ability of Tα1 to penetrate the tumor cells. This study highlighted the important roles of an iRGD sequence in the therapeutic strategy of Tα1-iRGD. Thus, Tα1-iRGD could be a novel drug candidate for cancer treatment.
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Project description:Tumor penetrating peptides contain a cryptic (R/K)XX(R/K) CendR element that must be C-terminally exposed to trigger neuropilin-1 (NRP-1) binding, cellular internalization and malignant tissue penetration. The specific proteases that are involved in processing of tumor penetrating peptides identified using phage display are not known. Here we design de novo a tumor-penetrating peptide based on consensus cleavage motif of urokinase-type plasminogen activator (uPA). We expressed the peptide, uCendR (RPARSGR↓SAGGSVA, ↓ shows cleavage site), on phage or coated it onto silver nanoparticles and showed that it is cleaved by uPA, and that the cleavage triggers binding to recombinant NRP-1 and to NPR-1-expressing cells. Upon systemic administration to mice bearing uPA-overexpressing breast tumors, FAM-labeled uCendR peptide and uCendR-coated nanoparticles preferentially accumulated in tumor tissue. We also show that uCendR phage internalization into cultured cancer cells and its penetration in explants of murine tumors and clinical tumor explants can be potentiated by combining the uCendR peptide with tumor-homing module, CRGDC. Our work demonstrates the feasibility of designing tumor-penetrating peptides that are activated by a specific tumor protease. As upregulation of protease expression is one of the hallmarks of cancer, and numerous tumor proteases have substrate specificities compatible with proteolytic unmasking of cryptic CendR motifs, the strategy described here may provide a generic approach for designing proteolytically-actuated peptides for tumor-penetrative payload delivery.
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Project description:DNA vaccination holds great promise for the prevention and treatment of cancer and infectious diseases. However, the clinical ability of DNA vaccines is still controversial due to the limited immune response initially observed in humans. We hypothesized that electroporation of a plasmid encoding the HIV-1 Gag viral capsid protein would enhance cancer DNA vaccine potency. DNA electroporation used to deliver plasmids in vivo, induced type I interferons, thereby supporting the activation of innate immunity. The coadministration of ovalbumin (OVA) and HIV-1 Gag encoding plasmids modulated the adaptive immune response. This strategy favored antigen-specific Th1 immunity, delayed B16F10-OVA tumor growth and improved mouse survival in both prophylactic and therapeutic vaccination approaches. Similarly, a prophylactic DNA immunization against the melanoma-associated antigen gp100 was enhanced by the codelivery of the HIV-1 Gag plasmid. The adjuvant effect was not driven by the formation of HIV-1 Gag virus-like particles. This work highlights the ability of both electroporation and the HIV-1 Gag plasmid to stimulate innate immunity for enhancing cancer DNA vaccine immunogenicity and demonstrates interesting tracks for the design of new translational genetic adjuvants to overcome the current limitations of DNA vaccines in humans.
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