Expression Dynamics of CA IX Epitope in Cancer Cells under Intermittent Hypoxia Correlates with Extracellular pH Drop and Cell Killing by Ureido-Sulfonamide CA IX Inhibitors.

Carbonic anhydrase IX (CA IX) is a membrane-bound CA isozyme over-expressed in many hypoxic tumor cells, where it ensures pH homeostasis and has been implicated in tumor survival, metastasis and resistance to chemotherapy and radiotherapy. Given the functional importance of CA IX in tumor biochemistry, we investigated the expression dynamics of CA IX in normoxia, hypoxia and intermittent hypoxia, which are typical conditions experienced by tumor cells in aggressive carcinomas. We correlated the CA IX epitope expression dynamics with extracellular pH acidification and with viability of CA IX-expressing cancer cells upon treatment with CA IX inhibitors (CAIs) in colon HT-29, breast MDA-MB-231 and ovarian SKOV-3 tumor cell models.

Targeted Liposomes Encapsulating miR-603 Complexes Enhance Radiation Sensitivity of Patient-Derived Glioblastoma Stem-Like Cells.

Despite potential for clinical efficacy, therapeutic delivery of microRNAs (miRNA) remains a major translational barrier. Here, we explore a strategy for miRNA delivery in the treatment of glioblastoma, the most common form of adult brain cancer, that involves complexation of miRNA with polyethylenimine (PEI) and encapsulation in targeted liposomes. miRNA 603 (miR-603) is a master regulatory miRNA that suppresses glioblastoma radiation resistance through down-regulation of insulin-like growth factor 1 (IGF1) signaling.

Effect of an alkyl spacer on the morphology and internalization of MUC1 aptamer-naphthalimide amphiphiles for targeting and imaging triple negative breast cancer cells.

Despite decades of research, there are few targeted treatment options available for triple negative breast cancer (TNBC), leaving chemotherapy, and radiation treatment regimes with poor response and high toxicity. Herein aptamer-amphiphiles were synthesized which selectively bind to the mucin-1 (MUC1) glycoprotein that is overexpressed in TNBC cells. These amphiphiles have a fluorescent tail (1,8-naphthalimide or 4-nitro-1,8-naphthalimide) which enables self-assembly of the amphiphiles and allows for easy visualization without the requirement for further conjugation of a fluorophore.

PEG Linker Length Strongly Affects Tumor Cell Killing by PEGylated Carbonic Anhydrase Inhibitors in Hypoxic Carcinomas Expressing Carbonic Anhydrase IX.

Hypoxic tumors overexpress membrane-bound isozymes of carbonic anhydrase (CA) CA IX and CA XII, which play key roles in tumor pH homeostasis under hypoxia. Selective inhibition of these CA isozymes has the potential to generate pH imbalances that can lead to tumor cell death. Since these isozymes are dimeric, we designed a series of bifunctional PEGylated CA inhibitors (CAIs) through the attachment of our preoptimized CAI warhead 1,3,4-thiadiazole-2-sulfonamide to polyethylene glycol (PEG) backbones with lengths ranging from 1 KDa to 20 KDa via a succinyl linker.

Thermosensitive and biodegradable hydrogel encapsulating targeted nanoparticles for the sustained co-delivery of gemcitabine and paclitaxel to pancreatic cancer cells.

Pancreatic cancer represents a life threatening disease with rising mortality. Although the synergistic combination of gemcitabine and albumin-bound paclitaxel has proven to enhance the median survival rates as compared to gemcitabine alone, their systemic and repeated co-administration has been associated with serious toxic side effects and poor patient compliance. For this purpose, we designed a thermosensitive and biodegradable hydrogel encapsulating targeted nanoparticles for the local and sustained delivery of gemcitabine (GEM) and paclitaxel (PTX) to pancreatic cancer.

Design of an Aptamer-Amphiphile for the Detection of β-Lactoglobulin on a Liquid Crystal Interface.

An aptamer-amphiphile was designed that binds to β-lactoglobulin (β-LG), a major allergen from cow's milk. For this work, a 23-nucleotide ssDNA aptamer β-LG-23, capable of forming antiparallel G-quadruplexes was used, and its specificity and binding affinity of 22 ± 2 nM for β-LG were evaluated via enzyme-linked apta-sorbent assay (ELASA). The β-LG-23 aptamer was synthesized as an amphiphile by conjugating it to a C double tail via different spacers, and the effect of the spacers on the binding affinity and secondary structure of the aptamer was investigated.

Carbonic anhydrases as disease markers.

Introduction: The physiologic importance of fast CO/HCO interconversion in various tissues requires the presence of carbonic anhydrase (CA, EC 4.2.1.

pH-Sensitive Multiligand Gold Nanoplatform Targeting Carbonic Anhydrase IX Enhances the Delivery of Doxorubicin to Hypoxic Tumor Spheroids and Overcomes the Hypoxia-Induced Chemoresistance.

Hypoxia is a common feature of solid tumors contributing to resistance to chemotherapy. Selective delivery of chemotherapeutic drugs to hypoxic tumor niche remains an unsolved issue. For this purpose, we constructed a gold nanoplatform targeting carbonic anhydrase IX (CA IX) epitope, which is overexpressed in hypoxic tumor cells versus in normal tissues.

PEGylated Bis-Sulfonamide Carbonic Anhydrase Inhibitors Can Efficiently Control the Growth of Several Carbonic Anhydrase IX-Expressing Carcinomas.

A series of aromatic/heterocyclic bis-sulfonamides were synthesized from three established aminosulfonamide carbonic anhydrase (CA, EC 4.2.1.