Abstract
The extracellular matrix (ECM) plays an active role in cell life through a tightly controlled reciprocal relationship maintained by several fibrous proteins, enzymes, receptors, and other components. It is also highly involved in cancer progression. Because of its role in cancer etiology, the ECM holds opportunities for cancer therapy on several fronts. There are targets in the tumor-associated ECM at the level of signaling molecules, enzyme expression, protein structure, receptor interactions, and others. In particular, the ECM is implicated in invasiveness of tumors through its signaling interactions with cells. By capitalizing on the biology of the tumor microenvironment and the opportunities it presents for intervention, the ECM has been investigated as a therapeutic target, to facilitate drug delivery, and as a prognostic or diagnostic marker for tumor progression and therapeutic intervention. This review summarizes the tumor ECM biology as it relates to drug delivery with emphasis on design parameters targeting the ECM.
Highlights
An example of priming the matrix to enhance drug delivery is in the use of pulsed high intensity focused ultrasound (HIFU) to alter the collagen structure of the extracellular matrix (ECM) to allow for better penetration of chemotherapeutic drugs [68]
Macromolecular drug carriers have been employed to improve the pharmacokinetics of small molecule drugs. Both passive targeting by the enhanced permeability and retention effect (EPR) and active targeting through use of targeting ligands have been proposed for tumor targeting
A key merit of ECM-based approaches is that they move away from oversimplifying the tumor microenvironment, by considering the specific location of different ECM components as well as the limits to migration and diffusion within the site. It takes into consideration the supportive and responsive nature of the tumor environment, including for example pancreatic stellate cells, which critically limit the efficacy of drugs
Summary
Many drug carriers are modified to target specific upregulated biomarkers, proteins, receptors, and other epitopes within the tumor ECM in order to increase localization by capitalizing on a biological change in the tumor microenvironment compared to healthy tissue. We summarize both drug delivery and cancer biology literature to understand the local dynamics that influence drug delivery. Examine efforts to employ it as a therapeutic target and as a diagnostic and prognostic marker, as well as strategies to prime the ECM to improve drug delivery through small molecule approaches and mechanical or enzymatic strategies. We examine efforts to further improve delivery through the use of drug carriers by ECM targeting or modulation
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