Overcoming key biological barriers to cancer drug delivery and efficacy
Susy M Kim1, Peggy H Faix1, Jan E Schnitzer1
1Proteogenomics Research Institute for Systems Medicine, 505 Coast Blvd. South, La Jolla, CA 92037, United States.
Abstract:
Poor delivery efficiency continues to hamper the effectiveness of cancer therapeutics engineered to destroy solid tumors using different strategies such as nanocarriers, targeting agents, and matching treatments to specific genetic mutations. All contemporary systemic anti-cancer agents are dependent upon passive transvascular mechanisms for their delivery into solid tumors. The therapeutic efficacies of our current drug arsenal could be significantly improved with an active delivery strategy. Here, we discuss how drug delivery and therapeutic efficacy are greatly hindered by barriers presented by the vascular endothelial cell layer and by the aberrant nature of tumor blood vessels in general. We describe mechanisms by which molecules cross endothelial cell (EC) barriers in normal tissues and in solid tumors, including paracellular and transcellular pathways that enable passive or active transport. We also discuss specific obstacles to drug delivery that make solid tumors difficult to treat, as well strategies to overcome them and enhance drug penetration. Finally, we describe the caveolae pumping system, a promising active transport alternative to passive drug delivery across the endothelial cell barrier. Each strategy requires further testing to define its therapeutic applicability and clinical utilities.
Insights
Poor drug delivery limits cancer therapeutics targeting solid tumors. This study explores overcoming tumor vascular barriers with active transport strategies, like the caveolae pumping system, to improve treatment efficacy.
Area of Science:
- Oncology
- Nanotechnology
- Biomedical Engineering
Background:
- Cancer therapeutics often fail due to poor delivery efficiency into solid tumors.
- Current systemic anti-cancer agents rely on passive transvascular delivery, which is insufficient.
- Tumor blood vessels present significant barriers to drug penetration and efficacy.
Purpose of the Study:
- To discuss the challenges hindering drug delivery into solid tumors.
- To explore mechanisms of molecule transport across endothelial cell barriers.
- To identify and evaluate strategies for enhancing drug penetration and therapeutic efficacy.
Main Methods:
- Review of passive and active transport mechanisms across endothelial cells (ECs) in normal tissues and tumors.
- Analysis of obstacles to drug delivery in solid tumors.
- Discussion of potential strategies to overcome these obstacles.
Main Results:
- Endothelial cell barriers and aberrant tumor vasculature impede drug delivery.
- Both paracellular and transcellular pathways are involved in molecule transport.
- The caveolae pumping system is presented as a promising active transport strategy.
Conclusions:
- Active drug delivery strategies are needed to improve cancer therapeutic efficacy.
- Overcoming endothelial barriers is crucial for effective solid tumor treatment.
- Further research is required to validate therapeutic applicability and clinical utility of novel delivery systems.
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