While commonly known for degradation of the extracellular matrix, matrix metalloproteinases (MMPs) exhibit broad potential for use in targeting of bioactive and imaging agents in cancer treatment. MMPs are upregulated at all stages of expression in cancers. A comprehensive analysis of published literature on expression of all MMP subtypes at the genetic, protein, and activity levels in normal and diseased tissues indicate targeting applicability in a variety of cancers. This expression significantly increases at advanced cancer stages, providing an improved opportunity for controlled release in higher-stage patients. Since MMPs are integral at every stage of metastasis, MMP roles in cancer are discussed with a focus on MMP distribution and mobility within cells and tumors for cancer targeting applications. Several strategies for MMP utilization in targeting – such as matrix degradation, MMP cleavage, MMP binding, and MMP-induced environmental changes – are addressed.
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.
Combination of polymer therapeutics and hyperthermia has been shown to enhance accumulation in selectively heated tumor tissue. The additional use of heat shock (HS)-targeting towards tumor tissues can further enhance accumulation and retention, and improve therapeutic outcomes. In this work, high intensity focused ultrasound (HIFU) was used to generate hyperthermia in prostate tumor tissue. Upregulation of the cell surface HS receptor glucose regulated protein 78 kDa (GRP78) was observed after treatment with HIFU hyperthermia which was then targeted by specific HS-targeting peptides. We used the peptide sequence WDLAWMFRLPVG attached to the side chains of water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing docetaxel (DOC) conjugated via a lysosomally degradable linker. It was shown that HIFU-mediated HS-targeted copolymer-DOC conjugates improved treatment efficacy in a murine prostate tumor xenograft model. These results show that the use of HIFU hyperthermia in combination with HS-targeted polymer-drug conjugates has potential to improve therapeutic outcomes in prostate cancer treatment.
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