Drug delivery to solid tumors: the predictive value of the multicellular tumor spheroid model for nanomedicine screening

Abstract

The increasing number of publications on the subject shows that nanomedicine is an attractive field for investigations aiming to considerably improve anticancer chemotherapy. Based on selective tumor targeting while sparing healthy tissue, carrier-mediated drug delivery has been expected to provide significant benefits to patients. However, despite reduced systemic toxicity, most nanodrugs approved for clinical use have been less effective than previously anticipated. The gap between experimental results and clinical outcomes demonstrates the necessity to perform comprehensive drug screening by using powerful preclinical models. In this context, in vitro three-dimensional models can provide key information on drug behavior inside the tumor tissue. The multicellular tumor spheroid (MCTS) model closely mimics a small avascular tumor with the presence of proliferative cells surrounding quiescent cells and a necrotic core. Oxygen, pH and nutrient gradients are similar to those of solid tumor. Furthermore, extracellular matrix (ECM) components and stromal cells can be embedded in the most sophisticated spheroid design. All these elements together with the physicochemical properties of nanoparticles (NPs) play a key role in drug transport, and therefore, the MCTS model is appropriate to assess the ability of NP to penetrate the tumor tissue. This review presents recent developments in MCTS models for a better comprehension of the interactions between NPs and tumor components that affect tumor drug delivery. MCTS is particularly suitable for the high-throughput screening of new nanodrugs.

Surface Functionalization and Targeting Strategies of Liposomes in Solid Tumor Therapy: A Review

“…The complex biology of solid tumors with various biological barriers, e.g., mononuclear-phagocyte system uptake and extravasation through vascular-endothelial layer, and physiological factors, e.g., hypoxia, low pH and raised interstitial-fluid pressure, highlights the need to design and formulate an efficient delivery system for anticancer agents [ 1 ]. The clinical application of many anticancer drugs have been hindered due to their limited water solubility, pharmacokinetics and potential adverse effects [ 2 ]. It has been estimated that in the USA during 2017 about 0.6 million deaths may occur due to all forms of cancers [ 3 ].…”

Temoporfin-in-Cyclodextrin-in-Liposome—A New Approach for Anticancer Drug Delivery: The Optimization of Composition

“…Understanding the PS distribution processes in target tissues is a primary factor that is responsible for prediction of antitumor efficiency of photodynamic agents. MCTSs represent avascular regions found in many solid tumor tissues and allow for simulating the penetration and intratumor transport of anticancer nanomedicines, including photoactive NPs [ 38 , 39 ]. In the present work, HT-29 MCTSs were generated by spinner technique and filtered by the size from 380 to 520 µM for further experiments.…”

Defined Mathematical Relationships Among Cancer Cells Suggest Modular Growth in Tumor Progression and Highlight Developmental Features Consistent With a Para-Embryonic Nature of Cancer

“…These would be presumably similar to in vivo initial avascular tumors ( Vinnitsky, 2014 ), which could survive as such (dormant) in the absence of suitable implantation conditions or progress in the presence of such conditions. Multicellular tumor spheroid models closely mimic small avascular tumors in vivo , with the presence of proliferative cells (about 40%) surrounding quiescent cells and a necrotic core, and with similar gradients of oxygen, pH, and nutrients ( Millard et al, 2017 ; Hamilton and Rath, 2019 ) ( Figure 4B ). It has been proposed that tumor spheres fulfill the precondition for a protected niche for dormant tumor cells as an hypoxic niche protected by the outer layers, which exhibit continuous shedding of tumor cells and fragments ( Johnson et al, 2013 ; Hamilton and Rath, 2019 ).…”

“…In such a way, an advanced avascular tumor mass could be a sphere made of (a) an anoxic central zone with necrotic tumor cells, presumably the earlier tumor modules; (b) a sub-central hypoxic zone with the later generated quiescent CSC 3 s that try to migrate externally ( Staneva et al, 2019 ) in search of niches to self-seed around or for metastasizing elsewhere ( Norton and Popel, 2014 ); and (c) a peripheral normoxic zone with the earlier generated proliferating CSC 3 s and their numerous progeny of CPCs and CDCs, resulting together in a cord-finger morphology ( Norton and Popel, 2014 ; Figures 2 , 3 ). Thus, this tumor proliferation model would generate structures that appear to be very similar to real initial avascular tumors and multicellular tumor spheroids (MCTS) ( Millard et al, 2017 ; Hamilton and Rath, 2019 ; Scientific Reports and Nature Research, 2019 ; Figure 4 ).…”

“…Tumor-sphere cultivation is widely used to analyze the self-renewal capability of CSCs and to enrich these cells from bulk CCs, thus providing a reliable platform for screening potential anti-CSC agents ( Knoblich, 2008 ; Nunes et al, 2018 ). Large spheroids (400–500 microns in diameter) display a layered cell distribution, also observed in solid avascular tumors: the outer layers are enriched with highly proliferating cells, the middle zone exhibits quiescent cells, and the core contains necrotic cells and acellular regions with hypoxia and nutrient depletion ( Norton and Popel, 2014 ; Galateanu et al, 2016 ; Millard et al, 2017 ). Very large tumor spheroids can reach 650 microns in diameter ( Zanoni et al, 2016 ).…”