Abstract
Numerous strategies have been developed to treat cancer conventionally. Most importantly, chemotherapy shows its huge promise as a better treatment modality over others. Nonetheless, the very complex behavior of the tumor microenvironment frequently impedes successful drug delivery to the tumor sites that further demands very urgent and effective distribution mechanisms of anticancer drugs specifically to the tumor sites. Hence, targeted drug delivery to tumor sites has become a major challenge to the scientific community for cancer therapy by assuring drug effects to selective tumor tissue and overcoming undesired toxic side effects to the normal tissues. The application of nanotechnology to the drug delivery system pays heed to the design of nanomedicine for specific cell distribution. Aiming to limit the use of traditional strategies, the adequacy of drug-loaded nanocarriers (i.e., nanomedicine) proves worthwhile. After systemic blood circulation, a typical nanomedicine follows three levels of disposition to tumor cells in order to exhibit efficient pharmacological effects induced by the drug candidates residing within it. As a result, nanomedicine propounds the assurance towards the improved bioavailability of anticancer drug candidates, increased dose responses, and enhanced targeted efficiency towards delivery and distribution of effective therapeutic concentration, limiting toxic concentration. These aspects emanate the proficiency of drug delivery mechanisms. Understanding the potential tumor targeting barriers and limiting conditions for nanomedicine extravasation, tumor penetration, and final accumulation of the anticancer drug to tumor mass, experiments with in vivo animal models for nanomedicine screening are a key step before it reaches clinical translation. Although the study with animals is undoubtedly valuable, it has many associated ethical issues. Moreover, individual experiments are very expensive and take a longer time to conclude. To overcome these issues, nowadays, multicellular tumor spheroids are considered a promising in vitro model system that proposes better replication of in vivo tumor properties for the future development of new therapeutics. In this review, we will discuss how tumor spheroids could be used as an in vitro model system to screen nanomedicine used in targeted drug delivery, aiming for better therapeutic benefits. In addition, the recent proliferation of mathematical modeling approaches gives profound insight into the underlying physical principles and produces quantitative predictions. The hierarchical tumor structure is already well decorous to be treated mathematically. To study targeted drug delivery, mathematical modeling of tumor architecture, its growth, and the concentration gradient of oxygen are the points of prime focus. Not only are the quantitative models circumscribed to the spheroid, but also the role of modeling for the nanoparticle is equally inevitable. Abundant mathematical models have been set in motion for more elaborative and meticulous designing of nanomedicine, addressing the question regarding the objective of nanoparticle delivery to increase the concentration and the augmentative exposure of the therapeutic drug molecule to the core. Thus, to diffuse the dichotomy among the chemistry involved, biological data, and the underlying physics, the mathematical models play an indispensable role in assisting the experimentalist with further evaluation by providing the admissible quantitative approach that can be validated. This review will provide an overview of the targeted drug delivery mechanism for spheroid, using nanomedicine as an advantageous tool.
Highlights
Cancer tissues are anomalous cell mass exhibiting escalated growth and unregulated cell proliferation
The conventional 2D cultures are incapable of imitating the heterogeneity and complexity of solid tumors as in vivo tumors grow in 3D confirmation with a specific architecture that cannot be reproduced by a 2D monolayer cellular model system. 3D tumor spheroid models possess several characteristics of real tumors, such as cell-cell interactions, cellular microenvironments, drug penetration, reaction and resistance, and extracellular matrix (ECM) production/deposition
The cell signaling pathway and the physiological communications established between cells in close contact within the spheroids makes it possible to replicate the fundamental aspects of real tumor and its microenvironments, including the proliferative rates of different cells, specific gene expressions, ECM deposition, ECM-cell, and cell-cell physical interactions, and drug resistance
Summary
Cancer tissues are anomalous cell mass exhibiting escalated growth and unregulated cell proliferation. Creating the same environment artificially as the real tumor is subject to a lot of constraints in terms of progressive cell accumulation, properties that help cancer cells persist within the tissue leading to a tumor, and physicochemical traits that result in their invasiveness and drug resistance To overcome these issues, multicellular tumor spheroids are considered promising in vitro three-dimensional (3D culture) models, which are intermediate between in vitro cellular monolayer and in vivo animal models in terms of complexity, cell-cell communication, and gradients of nutrients and oxygen (Kostarelos et al, 2004; Mehta et al, 2012; Solomon et al, 2016). We conclude with an outlook of the future perspective of the dynamics of shape change of nanomedicine as a modified and efficient drug delivery system (Li et al, 2017b)
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