3D tumor tissue analogs and their orthotopic implants for understanding tumor-targeting of microenvironment-responsive nanosized chemotherapy and radiation

Sethi, Pallavi; Jyoti, Amar; Swindell, Elden P.; Chan, Ryan; Langner, U. W.; Feddock, Jonathan; Nagarajan, Radhakrishnan; O’Halloran, Thomas V.; Upreti, Meenakshi

doi:10.1016/j.nano.2015.07.013

Cited by 27 publications

(43 citation statements)

References 56 publications

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“…We have demonstrated the usefulness of the 3D TNBC model in in vivo setting by implantation of the TTA in the mammary fat pad of nude mice [24, 25]. This preclinical tumor model incorporates aspects of the tumor microenvironment and the neovascular architecture, critical for evaluating nanoparticles and stroma-directed molecular targeting.…”

Section: Resultsmentioning

confidence: 99%

“…Studies, including our own, have demonstrated the potential of galectin-1 as a therapeutic target by identifying the overexpression of galectin-1 in various human cancers and enrichment in tumor stroma [23, 24]. In addition, we have reported a further induction of galectin-1 expression in tumor stroma as a response to radiation therapy, suggesting that targeting galectin-1 may synergize with radiation therapy [23–25]. A number of novel compounds and approaches to block galectin-1 or its activity are currently being evaluated [23].…”

Section: Introductionmentioning

confidence: 97%

“…However, developing nanotherapeutic regimens that target the tumor stroma implicitly demand reliable tumor models that replicate the stromal characteristics of the human cancer. Using a murine in vitro/in vivo TNBC tumor model system with galectin-1 enriched stroma we have reported that conjugation of anginex to liposomes enables preferential targeting of the unique mix of dual chemotherapy released at the irradiated tumor endothelium in a controlled manner over time, beyond that expected from enhanced tumor permeability and retention [25]. This novel therapeutic approach is designed to destabilize the tumor microenvironment which sensitizes and primes the tumor cells for cell death, maximizing the therapeutic gain of the antitumor strategy in selective and effective inhibition of tumor growth and metastasis in contrast to conventional systemic approaches.…”

Section: Introductionmentioning

confidence: 99%

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Radiation-enhanced therapeutic targeting of galectin-1 enriched malignant stroma in triple negative breast cancer

et al. 2016

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Currently there are no FDA approved targeted therapies for Triple Negative Breast Cancer (TNBC). Ongoing clinical trials for TNBC have focused primarily on targeting the epithelial cancer cells. However, targeted delivery of cytotoxic payloads to the non-transformed tumor associated-endothelium can prove to be an alternate approach that is currently unexplored. The present study is supported by recent findings on elevated expression of stromal galectin-1 in clinical samples of TNBC and our ongoing findings on stromal targeting of radiation induced galectin-1 by the anginex-conjugated arsenic-cisplatin loaded liposomes using a novel murine tumor model. We demonstrate inhibition of tumor growth and metastasis in response to the multimodal nanotherapeutic strategy using a TNBC model with orthotopic tumors originating from 3D tumor tissue analogs (TTA) comprised of tumor cells, endothelial cells and fibroblasts. The ‘rigorous’ combined treatment regimen of radiation and targeted liposomes is also shown to be well tolerated. More importantly, the results presented provide a means to exploit clinically relevant radiation dose for concurrent receptor mediated enhanced delivery of chemotherapy while limiting overall toxicity. The proposed study is significant as it falls in line with developing combinatorial therapeutic approaches for stroma-directed tumor targeting using tumor models that have an appropriate representation of the TNBC microenvironment.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Radiation-enhanced therapeutic targeting of galectin-1 enriched malignant stroma in triple negative breast cancer

et al. 2016

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“…Therefore, we established a tumor cell spheroid model for evaluating the penetration of Cur-NPs into tumor tissue in vitro. 29 In this experiment, curcumin is not suitable for observing drug penetration into compact cell spherical entities because of its weak fluorescence. Therefore, coumarin was used as an indicator instead of curcumin in these experiments.…”

Section: In Vitro Cellular Penetration Of Nps To C6 Spheroidsmentioning

confidence: 99%

Cyclic hexapeptide-conjugated nanoparticles enhance curcumin delivery to glioma tumor cells and tissue

Zhang¹,

Li²,

Hua³

et al. 2017

IJN

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Glioma has one of the highest mortality rates among primary brain tumors. The clinical treatment for glioma is very difficult due to its infiltration and specific growth locations. To achieve improved drug delivery to a brain tumor, we report the preparation and in vitro and in vivo evaluation of curcumin nanoparticles (Cur-NPs). The cyclic hexapeptide c(RGDf(N-me) VK)-C (cHP) has increased affinity for cells that overexpress integrins and was designed to target Cur-NPs to tumors. Functional polyethyleneglycol-modified poly( d , l -lactide-co-glycolide) (PEG-PLGA) conjugated to cHP was synthesized, and targeted Cur-NPs were prepared using a self-assembly nanoprecipitation process. The physicochemical properties and the in vitro cytotoxicity, accuracy, and penetration capabilities of Cur-NPs targeting cells with high levels of integrin expression were investigated. The in vivo targeting and penetration capabilities of the NPs were also evaluated against glioma in rats using in vivo imaging equipment. The results showed that the in vitro cytotoxicity of the targeted cHP-modified curcumin nanoparticles (cHP/Cur-NPs) was higher than that of either free curcumin or non-targeted Cur-NPs due to the superior ability of the cHP/Cur-NPs to target tumor cells. The targeted cHP/Cur-NPs, c(RGDf(N-me)VK)-C-modified Cur-NPs, exhibited improved binding, uptake, and penetration abilities than non-targeting NPs for glioma cells, cell spheres, and glioma tissue. In conclusion, c(RGDf(N-me)VK)-C can serve as an effective targeting ligand, and cHP/Cur-NPs can be exploited as a potential drug delivery system for targeting gliomas.

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“…Various non-tumorigenic cell lines have been grown as hollow acini, including those originating from the breast [12], kidney [13], lung [14], pancreas [15] or prostate [16]. Such 3D cultures have also been used to examine changes in both the growth and morphology of non-tumorigenic cells in altered microenvironments [17,18], to delineate the oncogenetic mechanisms of mutated cells [19,20] and to test the response of tumour cells to various treatments [21,22].…”

Section: Introductionmentioning

confidence: 99%

Towards personalized computational oncology: from spatial models of tumour spheroids, to organoids, to tissues

Karolak

Markov

McCawley

et al. 2018

J. R. Soc. Interface.

112

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A main goal of mathematical and computational oncology is to develop quantitative tools to determine the most effective therapies for each individual patient. This involves predicting the right drug to be administered at the right time and at the right dose. Such an approach is known as precision medicine. Mathematical modelling can play an invaluable role in the development of such therapeutic strategies, since it allows for relatively fast, efficient and inexpensive simulations of a large number of treatment schedules in order to find the most effective. This review is a survey of mathematical models that explicitly take into account the spatial architecture of three-dimensional tumours and address tumour development, progression and response to treatments. In particular, we discuss models of epithelial acini, multicellular spheroids, normal and tumour spheroids and organoids, and multicomponent tissues. Our intent is to showcase how these in silico models can be applied to patient-specific data to assess which therapeutic strategies will be the most efficient. We also present the concept of virtual clinical trials that integrate standard-of-care patient data, medical imaging, organ-on-chip experiments and computational models to determine personalized medical treatment strategies.

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3D tumor tissue analogs and their orthotopic implants for understanding tumor-targeting of microenvironment-responsive nanosized chemotherapy and radiation

Cited by 27 publications

References 56 publications

Radiation-enhanced therapeutic targeting of galectin-1 enriched malignant stroma in triple negative breast cancer

Radiation-enhanced therapeutic targeting of galectin-1 enriched malignant stroma in triple negative breast cancer

Cyclic hexapeptide-conjugated nanoparticles enhance curcumin delivery to glioma tumor cells and tissue

Towards personalized computational oncology: from spatial models of tumour spheroids, to organoids, to tissues

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