Anti-Angiogenic Therapy: Albumin-Binding Proteins Could Mediate Mechanisms Underlying the Accumulation of Small Molecule Receptor Tyrosine Kinase Inhibitors in Normal Tissues with Potential Harmful Effects on Health

Abstract

Anti-angiogenics currently used in cancer therapy target angiogenesis by two major mechanisms: (i) neutralizing angiogenic factors or their receptors by using macromolecule anti-angiogenic drugs (e.g., therapeutic antibodies), and (ii) blocking intracellularly the activity of receptor tyrosine kinases with small molecule (Mr < 1 kDa) inhibitors. Anti-angiogenics halt the growth and spread of cancer, and significantly prolong the disease-free survival of the patients. However, resistance to treatment, insufficient efficacy, and toxicity limit the success of this antivascular therapy. Published evidence suggests that four albumin-binding proteins (ABPs) (gp18, gp30, gp60/albondin, and secreted protein acidic and cysteine-rich (SPARC)) could be responsible for the accumulation of small molecule receptor tyrosine kinase inhibitors (RTKIs) in normal organs and tissues and therefore responsible for the side effects and toxicity associated with this type of cancer therapy. Drawing attention to these studies, this review discusses the possible negative role of albumin as a drug carrier and the rationale for a new strategy for cancer therapy based on follicle-stimulating hormone receptor (FSHR) expressed on the luminal endothelial cell surface of peritumoral blood vessels associated with the major human cancers. This review should be relevant to the audience and the field of cancer therapeutics and angiogenesis/microvascular modulation-based interventions.

Why 90% of clinical drug development fails and how to improve it?

“…This hypothesis believes that only free unbound drug from plasma (not plasma protein bound drug) can distribute to disease-targeted tissues to interact with its molecular target; while free drug exposure in the plasma would be similar to the disease-targeted tissues at steady state 41 , 42 ; and thus drug exposure in the plasma can be used to predict the pharmacodynamic effect of the drug candidate. However, this “free drug” hypothesis may only apply to a limited class of drug candidates but not applicable to many other compounds since many factors can cause an asymmetric free drug distribution between plasma and tissue 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 . Therefore, drug exposure in the plasma, without knowing the exposure in disease-targeted tissue/normal tissues, may mislead the selection of drug candidate to clinical trials 51 , 52 , 53 , 65 .…”

“…In fact, albumin is actively transported from plasma to extra-cellular matrix, and to tissues through FcRn and other active transport process 45 , which carries fatty acids or drugs to different tissues. Previous study found that albumin-bound small molecules (tyrosine kinase inhibitors) interacting with albumin-binding proteins on vascular and in tissues, such as gp18, gp30, gp60/albondin, and secreted protein acidic and cysteine-rich (SPARC), which mediates tissue accumulation of these small molecules in normal tissues, which is associated with their toxicity 46 . Protein-bound drugs may also contribute higher drug accumulation in tumor tissues than that in the normal tissues 40 .…”

Counterion Tuning of Near-Infrared Organic Salts Dictates Phototoxicity to Inhibit Tumor Growth

“…43 In addition to Oatp1b2 expression, 6DT1 tumors and cells express higher levels of proteins that uptake albumin, including secreted protein acidic and rich in cysteine (Sparc), compared to surrounding breast tissues (Table S2). 44,45 These expression data show that our 6DT1 model reflects expression trends found in human breast cancer and is therefore appropriate and clinically relevant for investigating Oatp-and albuminmediated cellular uptakes of cyanine organic salts.…”