In Search of Advanced Tumor Diagnostics and Treatment: Achievements and Perspectives of Carbonic Anhydrase IX Targeted Delivery

Abstract

The research of how cells sense and adapt the oxygen deficiency has been recognized as worth winning a Nobel Prize in 2019. Understanding hypoxiadriven molecular machinery paved a path for novel strategies in fighting hypoxia-related diseases including cancer. The oxygen depletion inside the tumor provokes HIF-1 dependent gene and protein expression which helps the tumor to survive. For this reason, tumor related molecules are in the spotlight for scientists developing anticancer agents. One such target is carbonic anhydrase IX (CA IX)a protein located on the outer cell membrane of most hypoxic tumor cells. This offers the opportunity to exploit it as a target for delivery of cytotoxic drugs, dyes, or radioisotopes to cancer cells. Therefore, researchers investigate CA IX specific small molecules and antibodies as tumortargeting moieties in nanosystems and conjugates which are expected to overcome the limitations of some existing diagnostic and treatment strategies. This review covers the vast majority of CA IX-targeted systems (nanoparticle and conjugate based) for both therapeutic and imaging purposes published up to now. Furthermore, it shows their stage of development and gives an assessment of their clinical translation possibilities.

A photo-responsive fluorescent amphiphile for target-specific and image-guided drug delivery applications

“…Condensation of compound 6 with triethyl orthoformate provided the Cy3 derivative, 3-dodecyl-2-((E)-3-((E)-3-dodecyl-3methylindolin-2-ylidene)prop-1-en-1-yl)-3-methyl-3H-indole (7). Subsequent ring-closing reaction via nucleophilic substitution between compound 7 and 3,5-bis(bromomethyl)-4-nitrobenzoic acid (11) resulted in the 12-membered macrocyclic compound (5 2 Z,7E)-3 5 -carboxy-1 3,53 -didodecyl-1 3,53 -dimethyl-3 2nitro-1 3 H-1,5(1,2)-diindol-1-iuma-3(1,3)-benzenacyclooctaphan-7-en-1 1 -ium (Cy3L).…”

“…CA-IX is known to be overexpressed in MCF-7 and MDA-MB-468 cell lines. 7,24 Whereas, HEK293 is a CA-IX negative cell line. The MTT analysis revealed that MCF-7 cells were viable in the presence of control amphiphile Cy3L (without or with NIR-light treatment).…”

“…Malignant tumor cells upregulate the expression of various tumor-associated molecules, such as lactate dehydrogenase and carbonic anhydrase-IX (CA-IX), due to the activity of hypoxia-inducible factors. 7 Recent studies revealed that these surface-exposed proteins could be used to selectively deliver chemotherapeutic drug molecules to cancer cells over healthy ones. [7][8][9] In particular, the overexpression of CA-IX is directly associated with the multidrug resistance and aggressiveness of the tumor cells.…”

“…7 Recent studies revealed that these surface-exposed proteins could be used to selectively deliver chemotherapeutic drug molecules to cancer cells over healthy ones. [7][8][9] In particular, the overexpression of CA-IX is directly associated with the multidrug resistance and aggressiveness of the tumor cells. Consequently, inhibition of CA-IX or targeting CA-IX to deliver drug molecules to cancer cells is considered to have fewer side effects and higher therapeutic efficacy.…”

“…Consequently, inhibition of CA-IX or targeting CA-IX to deliver drug molecules to cancer cells is considered to have fewer side effects and higher therapeutic efficacy. [7][8][9] Recently, various CA-IX targeting and endogenous stimuliresponsive DDSs have been developed. 9,10 However, endogenous stimuli (such as pH, redox potential, hypoxic environment, and protein/enzyme levels) show an insignificant tumor selectivity due to the unwanted release of drugs within the blood circulation system and off-target release to normal cells.…”