Nanomedicine Penetration to Tumor: Challenges, and Advanced Strategies to Tackle This Issue

Abstract

Nanomedicine has been under investigation for several years to improve the efficiency of chemotherapeutics, having minimal pharmacological effects clinically. Ineffective tumor penetration is mediated by tumor environments, including limited vascular system, rising cancer cells, higher interstitial pressure, and extra-cellular matrix, among other things. Thus far, numerous methods to increase nanomedicine access to tumors have been described, including the manipulation of tumor micro-environments and the improvement of nanomedicine characteristics; however, such outdated approaches still have shortcomings. Multi-functional convertible nanocarriers have recently been developed as an innovative nanomedicine generation with excellent tumor infiltration abilities, such as tumor-penetrating peptide-mediated transcellular transport. The developments and limitations of nanomedicines, as well as expectations for better outcomes of tumor penetration, are discussed in this review.

Nano-drug delivery system for pancreatic cancer: A visualization and bibliometric analysis

“…The low tumor penetration dominated by TME is the core factor hindering the clinical efficacy of NDDS, mainly because of the complex arrangement and distribution of blood vessels in tumors ( Jain and Stylianopoulos, 2010 ; Matsumoto et al, 2016 ), which is mainly manifested in, on the one hand, the rapid diffusion of tumor cells leads to the lack of oxygen and nutrition, which leads to vascular abnormalities and heterogeneity ( Chauhan et al, 2011 ), and ultimately inhibits the penetration of NPs ( Jain, 2003 ); The uneven distribution of blood vessels from the periphery to the center of the tumor further hinders the deep penetration of NPs into the tumor ( Munir, 2022 ). On the other hand, the ECM has very narrow pores, which hinders the delivery of NPs by electrostatic interactions and steric restriction ( Stylianopoulos et al, 2010 ; Sriraman et al, 2014 ).…”

“…On the other hand, the ECM has very narrow pores, which hinders the delivery of NPs by electrostatic interactions and steric restriction ( Stylianopoulos et al, 2010 ; Sriraman et al, 2014 ). Therefore, destroying tumor ECM and complex blood vessel distribution becomes one of the main methods to improve the penetration of NPs ( Munir, 2022 ). However, forcefully destroying the matrix barrier and the blood vessels in the tumor may lead to the imbalance of signal transduction and dependence in TME, and uncontrolled PC growth and metastasis ( Chen et al, 2022 ).…”

Biodistribution of therapeutic extracellular vesicles

“…In addition, the mesh-like structure of ECM generates steric hindrance for larger nanoparticles such as EVs and partially restricts their diffusion across the tissue [136] . Apart from steric hindrance, nanoparticles also experience electrostatic repulsions due to highly polar and negatively charged proteoglycans in ECM [137] . These physical forces impose a significant barrier for any nanoparticulate to diffuse into ECM and achieve cellular targeting.…”

Sonoprinting nanoparticles on cellular spheroids via surface acoustic waves for enhanced nanotherapeutics delivery

“…Given that the compactness of the spheroids and therefore the penetration of NPs is significantly influenced by ECM, further studies are necessary to investigate the performance of the SAW delivery in co-culture models and spheroids with ECM-depositing fibroblasts where the ECM is more abundant. Moreover, the ECM composition and concentration, the mechanical characteristics of the components such as collagen and their network mesh size, the mechanism of compaction, and the presence of different integrins and cadherins that govern cell junctions can significantly influence the extent of nanoparticle penetration into tissues, [55][56][57] and ultimately impact the functionality of the SAW systems as suggested by the difference of results in the two cell types discussed above.…”