Clicked Chloroquine Terpolymers as Macromolecular Inhibitors of Cancer Cell Migration
Introductions: Antimalarial agents, chloroquine (CQ) and hydroxychloroquine (HCQ), have been studied for their anticancer and antimetastatic activities in different types of malignancies. The non-degradable polymeric CQ (NpCQ), which is synthesized by copolymerization of methacrylamido methyl triazole chloroquine (MA-tCQ) and N-(2-hydroxypropyl)methacrylamide (HPMA), has been reported as macromolecular inhibitor of cancer cell migration. However, the NpCQ is unsafe in vivo because itrsquo;s positive charged, causing lethal combination with proteins in serum. In this study, wersquo;ll synthesize a series of terpolymers of MA-tCQ, HPMA and MAA, to obtain a neutral polymer that is both safe and effective.
Dissertation Methodology: Click chemistry, reversible addition-fragmentation chain transfer (RAFT) polymerization, H NMR, mass spectrum
Aims and Objectives: 1. To obtain terpolymers by polymerization of MA-tCQ, HPMA, MAA;
2. To determine net charge of polymers and albumin binding;
3. To determine ability to inhibit cancer cell invasion.
Literature Review: Chloroquine (CQ) and its derivative, hydroxychloroquine (HCQ), are widely used as antimalarial agents with emerging potential in anticancer therapies due to their inhibitory effects on autophagy and CXCR4/CXCL12 signaling pathway, as well as their abilities to normalize tumor vessel structure and reset tumor-associated macrophages. They are able to inhibit cancer cell metastasis, which is the leading cause of the cancer-related deaths. However, high and often toxic concentrations of CQ are required to achieve desired therapeutic effect. Chloroquine containing HPMA copolymers (pCQs) were synthesized for the first time by copolymerization of methacryloylated hydroxychloroquine (MA-HCQ) and HPMA. The copolymers showed lower cytotoxicity when compared with HCQ.
Though CQ has multiple antimetastatic mechanisms, treatment of cancer cells with pCQ at least partly resulted from its inhibitory effect on surface expression of CXCR4. And intracellular trafficking of pCQ shows that it does not seem to accumulate in the lysosomes, which leads to poor inhibition of autophagy. Chemokines and chemokine receptors play a prominent role in facilitating the metastatic spread and in determining the sites to which specific cancers preferentially metastasize. CXCR4 is the most widely over-expressed chemokine receptor in human cancers. Binding of CXCR4 and its ligand CXCL12 triggers activation of various signaling cascades, leading to cancer cell migration. Primary tumor cells that overexpress CXCR4 have increased tendency to metastasize to distant organs where the levels of the CXCL12 are elevated. Inhibition of CXCR4 prevents macrophage infiltration into tumors, induces tumor growth arrest and apoptosis, and prevents metastatic spread. CQ and HCQ are also CXCR4 antagonists, but they have poor inhibitory effects. The pCQ can improve CXCR4-inhibiting activity of CQ.
Scheme1 Chemical structure of pCQ
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