ABSTRACT
Aberrant sialylation of cancer cells is emerging as an attractive method for generating effective antitumor strategies. However, as sialic acid (SA) is also present in healthy tissues, systems targeting SA in tumors must be strategically designed to be specifically activated in an intratumoral environment while avoiding systemic interaction. Phenylboronic acid (PBA) and its derivatives have shown potential for developing such smart ligands based on its triggered binding to SA at intratumoral pH. Because the affinity of PBAs against SA can be structurally controlled, the approach may further offer the possibility to enhance tumor targeting by molecularly engineering PBAs. Thus, to demonstrate that the modification of the chemical structure of PBAs can promote tumor targeting, we compared nanomedicines installed with the standard PBA or 5-boronopicolinic acid (5-BPA), which shows an exceptionally high binding affinity to SA in acidic pH. Platinum anticancer drugs were loaded into these nanomedicines and evaluated against orthotopic head and neck tumors, featuring a large fraction of SA-rich cancer stem-like cells (CSCs) that are resistant to platinum drugs. The 5-BPA ligands increased intracellular drug delivery of nanomedicines at intratumoral pH (pH 6.5) and enhanced the accumulation of nanomedicines in tumors to efficaciously eliminate the malignant CSCs, suppress tumor growth, and prolong mice survival. These findings indicate the potential of engineered PBA ligands for developing effective strategies targeting SA in tumors.
ABSTRACT
Eventual relapse of tumor growth is commonly observed in head and neck cancer patients, following treatment with platinum-based chemotherapies. This occurrence is believed to be related to the failure to eradicate drug resistant, cancer stem cell (CSC) niches, thereby enriching their population in tumors after treatment. In this study, we show that in contrast to free cisplatin (CDDP), the polymer micelle-based nanomedicine incorporating cisplatin (CDDP/m), can eradicate both the undifferentiated cell and the differentiated cancer cell populations within a head and neck tumor model. Immunohistochemistry of treated tumors showed that opposing to CDDP treatment, CDDP/m could reduce tumor growth without concentrating the CSC-like population. We further showed that CDDP/m, but not CDDP, can localize into hypoxic regions, possibly CSC-rich areas, in the tumors, and can overcome their detoxification mechanism based-on high cellular expression of glutathione to successfully deliver Pt to nuclear DNA. Our data suggests CDDP/m to be a replacement for current platinum therapies, for its ability to eradicate both bulk and CSC-like populations, and in turn to prevent recurrence of tumor growth.
Subject(s)
Antineoplastic Agents/administration & dosage , Cisplatin/administration & dosage , Drug Carriers/administration & dosage , Head and Neck Neoplasms/drug therapy , Hyaluronan Receptors/metabolism , Aldehyde Dehydrogenase/metabolism , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Survival/drug effects , Cisplatin/pharmacology , Cisplatin/therapeutic use , DNA/metabolism , Drug Carriers/pharmacology , Drug Carriers/therapeutic use , Female , Head and Neck Neoplasms/metabolism , Humans , Mice, Inbred BALB C , Micelles , Nanomedicine , Platinum/metabolismABSTRACT
Common reed (Phragmites australis) is a phytoremediator tolerant to heavy metals. In this study, we found that 70% of the cadmium (Cd) found in the stem of common reed exists in a soluble form, with more than half of the soluble Cd in the 10- to 50-kDa fraction. Based on an enzyme degradation assay, the major component of the Cd-associated molecule is assumed to be an amylopectin-like α-glucan. This molecule may associate with Cd via the carboxyl group, rather than the thiol group. The conditions required for the disengagement of Cd from the 10- to 50-kDa fraction indicated that disulfide bonds and other intramolecular interactions may contribute to maintaining the proper conformation of the molecule and to stabilizing its association with Cd. Accumulation of the Cd-associated molecule was induced by Cd stress, and the molecule was found to be also associated with Cu and Fe. Thus, we have identified a novel mechanism of Cd-pooling, namely, the association of Cd with an α-glucan-like molecule in reed stem.
