The microenvironment characteristics of solid tumors, renowned as barriers that harshly impeded many drug-delivery approaches, were precisely studied, investigated, categorized, divided, and subdivided into a complex diverse of barriers. These categories were further studied with a particular perspective, which makes all barriers found in solid-tumor micromilieu turn into different types of stimuli, and were considered triggers that can increase and hasten drug-release targeting efficacy. This review gathers data concerning the nature of solid-tumor micromilieu. Past research focused on the treatment of such tumors, the recent efforts employed for engineering smart nanoarchitectures with the utilization of the specified stimuli categories, the possibility of combining more than one stimuli for much-greater targeting enhancement, examples of the approved nanoarchitectures that already translated clinically as well as the obstacles faced by the use of these nanostructures, and, finally, an overview of the possible future implementations of smart-chemical engineering for the design of more-efficient drug delivery and theranostic systems and for making nanosystems with a much-higher level of specificity and penetrability features.

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This research purposed to formulate an optimized imatinib mesylate (IM)-loaded niosomes to improve its chemotherapeutic efficacy. The influence of 3 formulation factors on niosomal vesicular size (Y), zeta potential (Y), entrapment capacity percentage (Y), the percentage of initial drug release after 2 h (Y), and the percentage of cumulative drug release after 24 h (Y) were studied and optimized using Box-Behnken design. Optimum desirability was specified and the optimized formula was prepared, stability tested, morphologically examined, checked for vesicular bilayer formation and evaluated for its in vitro cytotoxicity on 3 different cancer cell lines namely MCF-7, HCT-116, and HepG-2 in addition to 1 normal cell line to ensure its selectivity against cancer cells. The actual responses of the optimized IM formulation were 425.36 nm, -62.4 mV, 82.96%, 18.93%, and 89.45% for Y, Y, Y, Y, and Y, respectively. The optimized IM-loaded niosomes confirmed the spherical vesicular shape imaged by both light and electron microscopes and further proven by differential scanning calorimetry. Moreover, the optimized formula exhibited improved stability on storage at 4 ± 2°C and superior efficacy on MCF7, HCT-116, and HepG2 as IC values were 6.7, 16.4, and 7.3 folds less than those of free drug, respectively. Interestingly, IC of the optimized formula against normal cell line was ranged from 3 to 11 folds higher than in different cancer cells indicating a higher selectivity of the optimized formula to cancer cells. In conclusion, the incorporation of IM in niosomes enhanced its efficacy and selectivity toward cancer cells, presenting a promising tool to fight cancer using this approach.

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