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Biological Events and Barriers to Effective Delivery of Cancer Therapeutics

  • Erica N. Bozeman
  • Lily YangEmail author
Chapter
Part of the Bioanalysis book series (BIOANALYSIS, volume 5)

Abstract

The development and progression of human cancer are multistage processes that involve a variety of genetic mutations, epigenetic alterations, and interactions between tumor cells and their microenvironment. The genetic and epigenetic abnormalities lead to the selective growth of tumor cells that are highly resistant to apoptotic cell death and capable of avoiding immune surveillance. Those aggressive biological characteristics contribute to intrinsic and acquired resistance to cancer therapeutics. Intrinsic drug resistance refers to a poor therapeutic response of tumors to the initial chemotherapy, while acquired resistance is developed during drug treatment through additional genetic changes and dysregulation of signal pathways in tumor cells. Cross talk between cancer cells and tumor-associated stromal cells promotes infiltration and proliferation of tumor-associated fibroblasts and macrophages, accumulation of extracellular matrix (the supporting framework around the tumor cells), and dysfunctional tumor vasculatures, which create physical barriers for efficient delivery of therapeutic and diagnostic agents into tumor cells. Additional biological barriers include the overexpression of drug efflux pumps, upregulation of signal pathways associated with resistance, and the presence of cancer stem cells within the tumor. Targeting proteins that are overexpressed in the tumors such as human epidermal growth factor 2 (HER-2) aids in enhancing the overall efficiency of therapeutic delivery. While early detection of cancer cells is critical to effective treatment, clinically validated biomarkers of presymptomatic and early-stage disease are typically limited to serum or urine biomarker detection. Although conventional contrast-enhanced imaging approaches have been used for cancer detection, it has been difficult to detect small tumors due to their lack of specificity and sensitivity. Moreover, extensive stromal response in early tumors creates a delivery barrier for targeted imaging contrasts to reach tumor cells for production of specific imaging signals. In this chapter, we will focus on the key biological events in tumor development that result in heterogeneous therapeutic responses in cancer patients.

Keywords

Tumor heterogeneity Drug delivery barriers Drug resistance Tumor stroma Targeted cancer therapy Nanoparticles Chemotherapy Tumor biomarkers Tumor microenvironment Immune surveillance Drug resistance Cancer Immune cells Tumor vasculature Enhanced permeability and retention (EPR) effect Reticuloendothelial system (RES) Drug clearance Extracellular matrix Fibroblasts Macrophages Multidrug resistance (MDR) Detection Diagnosis Routes of administration Cancer stem cells Pancreatic cancer 

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© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019

Authors and Affiliations

  1. 1.Department of SurgeryEmory University School of MedicineAtlantaUSA

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