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.
o ‐Aminoazotoluene (OAT), capable of photoisomerization, and o ‐vanillin, a potent comutagen, have been used to synthesize a new ligand, HL, [C 6 H 4 (CH 3 )N=NC 6 H 3 (CH 3 )N=CHC 6 H 3 (OH)(OCH 3 )], which, upon complexation with copper(II), results in a new copper(II) complex‐Cu(L) 2 , [Cu{C 6 H 4 (CH 3 )N=NC 6 H 3 (CH 3 )N=CHC 6 H 3 (OCH 3 )O} 2 ]. Both HL and Cu(L) 2 have been characterized by single‐crystal X‐ray diffraction measurements along with other analytical techniques, for example, IR spectroscopy, NMR spectroscopy, UV–Vis spectroscopy, elemental analysis and mass spectrometry. These compounds were tested with different in vitro anticancer assay as well as with in silico studies. A comparative study has been demonstrated on anticancer activity of HL and Cu(L) 2 with the ligand HAZ, {C 6 H 5 N=NC 6 H 4 N=CHC 6 H 3 (OH)(OCH 3 )} and its Cu‐complex, [Cu(AZ) 2 , Cu{C 6 H 5 N=NC 6 H 4 N=CHC 6 H 3 (OCH 3 )O} 2 ]. The sensing properties of HAZ, along with the synthesis and structural properties of both HAZ and Cu(AZ) 2 , have been reported by our group earlier. Cytotoxicity measurements on MCF7 cell lines show that Cu(L) 2 and Cu(AZ) 2 have higher anticancer activity than their corresponding ligands. The apoptotic effect of Cu‐complex was studied through nuclear fragmentation assay and AO/EB dual‐staining assay on MCF7 cell line. The IC 50 value of Cu(L) 2 in 0.01% DMSO/water after 24‐h treatment was found 4.2 μM, which is one of the lowest values with this response time compared to the other analogous anticancer compounds. Finally, we have evaluated the expression of h ERα protein with respect to Cu‐complexes, and it was observed that Cu(L) 2 caused more down‐regulation of h ERα as compared to Cu(AZ) 2 .
Nanoparticle-based cellular probes are emerging as an alternative for molecular probes. However, cellular interaction and uptake of nanoprobes strongly depends on their surface chemistry, and the delivery of anionic nanoparticles is relatively difficult. Herein, we report cholesterol-modified chitosan oligosaccharide as a nontoxic reagent that is able to deliver different anionic nanoparticles into the cell. The cationic chitosan backbone of the reagent assists their electrostatic binding with the anionic nanoparticle, and the hydrophobic cholesterol component induces cellular interaction/uptake. The optimum amount of cholesterol is decisive as an effective reagent—high cholesterol per chitosan reduces their water solubility, while low cholesterol per chitosan provides poor performance, similar to chitosan. Different anionic nanoparticles of hydrodynamic diameter 20−50 nm such as polyacrylate coated anionic quantum dot (QD) and iron oxide nanoparticle are effectively delivered into cells. The developed chitosan−cholesterol reagent is easy to prepare, is nontoxic, requires a low dose for nanoparticle delivery, and can be used for the cellular delivery of other anionic nanoparticles.
Abstract Folate‐functionalized quantum dots, gold/silver nanoparticles, and magnetic quantum dots have been synthesized and used as fluorescence, dark‐field, and dual‐imaging probes for the detection of cancer cells and tissues. A very efficient and generalized folate‐functionalization method has been developed for various amine‐terminated nanoparticles. The advantages of the presented approach are that it can be used to synthesize a wide range of folate‐functionalized nanoparticles and the number of folate molecules per nanoparticle can be controlled easily to tune their interaction with folate receptors present at the cell surface. These folate‐functionalized nanoparticles have been used as cellular and tissue‐imaging bioprobes. Results show that folate‐functionalized nanoparticles act as efficient and selective imaging probes in targeting cancer cells and tissues and labeled cells/tissues can be detected by using different imaging modalities.
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