Engineered liver-derived decellularized extracellular matrix-based three-dimensional tumor constructs for enhanced drug screening efficiency

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Abstract

The decellularized extracellular matrix (dECM) has emerged as an effective medium for replicating the in vivo-like conditions of the tumor microenvironment (TME), thus enhancing the screening accuracy of chemotherapeutic agents. However, recent dECM-based tumor models have exhibited challenges such as uncontrollable morphology and diminished cell viability, hindering the precise evaluation of chemotherapeutic efficacy. Herein, we utilized a tailor-made microfluidic approach to encapsulate dECM from porcine liver in highly poly(lactic- co-glycolic acid) (PLGA) porous microspheres (dECM-PLGA PMs) to engineer a three-dimensional (3D) tumor model. These dECM-PLGA PMs-based microtumors exhibited significant promotion of hepatoma carcinoma cells (HepG2) proliferation compared to PLGA PMs alone, since the infusion of extracellular matrix (ECM) microfibers and biomolecular constituents within the PMs. Proteomic analysis of the dECM further revealed the potential effects of these bioactive fragments embedded in the PMs. Notably, dECM-PLGA PMs-based microtissues effectively replicated the drug resistance traits of tumors, showing pronounced disparities in half-maximal inhibitory concentration (IC ₅₀) values, which could correspond with certain aspects of the TME. Collectively, these dECM-PLGA PMs substantially surmounted the prevalent challenges of unregulated microstructure and suboptimal cell viability in conventional 3D tumor models. They also offer a sustainable and scalable platform for drug testing, holding promise for future pharmaceutical evaluations.

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Influence of tumour micro-environment heterogeneity on therapeutic response.

Melissa Junttila, Frederic de Sauvage (2013)

Tumour formation involves the co-evolution of neoplastic cells together with extracellular matrix, tumour vasculature and immune cells. Successful outgrowth of tumours and eventual metastasis is not determined solely by genetic alterations in tumour cells, but also by the fitness advantage such mutations confer in a given environment. As fitness is context dependent, evaluating tumours as complete organs, and not simply as masses of transformed epithelial cells, becomes paramount. The dynamic tumour topography varies drastically even throughout the same lesion. Heterologous cell types within tumours can actively influence therapeutic response and shape resistance.

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Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity.

Giorgio Minotti, Pierantonio Menna, Emanuela Salvatorelli … (2004)

The clinical use of anthracyclines like doxorubicin and daunorubicin can be viewed as a sort of double-edged sword. On the one hand, anthracyclines play an undisputed key role in the treatment of many neoplastic diseases; on the other hand, chronic administration of anthracyclines induces cardiomyopathy and congestive heart failure usually refractory to common medications. Second-generation analogs like epirubicin or idarubicin exhibit improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not abated. It is because of their janus behavior (activity in tumors vis-à-vis toxicity in cardiomyocytes) that anthracyclines continue to attract the interest of preclinical and clinical investigations despite their longer-than-40-year record of longevity. Here we review recent progresses that may serve as a framework for reappraising the activity and toxicity of anthracyclines on basic and clinical pharmacology grounds. We review 1) new aspects of anthracycline-induced DNA damage in cancer cells; 2) the role of iron and free radicals as causative factors of apoptosis or other forms of cardiac damage; 3) molecular mechanisms of cardiotoxic synergism between anthracyclines and other anticancer agents; 4) the pharmacologic rationale and clinical recommendations for using cardioprotectants while not interfering with tumor response; 5) the development of tumor-targeted anthracycline formulations; and 6) the designing of third-generation analogs and their assessment in preclinical or clinical settings. An overview of these issues confirms that anthracyclines remain "evergreen" drugs with broad clinical indications but have still an improvable therapeutic index.

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Gergely Szakács, Jill K Paterson, Joseph A Ludwig … (2006)

Effective treatment of metastatic cancers usually requires the use of toxic chemotherapy. In most cases, multiple drugs are used, as resistance to single agents occurs almost universally. For this reason, elucidation of mechanisms that confer simultaneous resistance to different drugs with different targets and chemical structures - multidrug resistance - has been a major goal of cancer biologists during the past 35 years. Here, we review the most common of these mechanisms, one that relies on drug efflux from cancer cells mediated by ATP-binding cassette (ABC) transporters. We describe various approaches to combating multidrug-resistant cancer, including the development of drugs that engage, evade or exploit efflux by ABC transporters.

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Author and article information

Contributors

Shengchang Luo

Qingqing Wang

Miaoting Li

Peiyao Xu

Yicheng Wang

Ying Wang:

ORCID: https://orcid.org/0000-0001-6749-3848

Ranjith Kumar Kankala:

ORCID: https://orcid.org/0000-0003-4081-9179

Shibin Wang

Aizheng Chen:

ORCID: https://orcid.org/0000-0002-5840-3406

Journal

Journal ID (nlm-ta): Regen Biomater

Journal ID (iso-abbrev): Regen Biomater

Journal ID (publisher-id): rb

Title: Regenerative Biomaterials

Publisher: Oxford University Press

ISSN (Print): 2056-3418

ISSN (Electronic): 2056-3426

Publication date Collection: 2024

Publication date (Electronic): 06 September 2024

Publication date PMC-release: 06 September 2024

Volume: 11

Electronic Location Identifier: rbae113