Heparanase-Inhibiting Polymeric Heparan Sulfate Mimetic Attenuates Myeloma Tumor Growth and Bone Metastasis

Multiple myeloma (MM) is the second most common hematologic malignancy, heavily relying on the bone marrow microenvironment for its growth, leading to severe clinical complications. A critical factor of MM progression is the aberrant expression of heparanase (HPSE), an enzyme responsible for degrading heparan sulfate (HS) chains in the extracellular matrix (ECM) and cell surface. This degradation fosters tumor cell proliferation, migration, and resistance to chemotherapy. Consequently, targeting HPSE has emerged as a promising therapeutic strategy for MM, though clinical application of HPSE inhibitors remains limited. Herein, we report a HS-mimicking glycopolymer as a highly effective HPSE inhibitor that demonstrates a significant reduction in the viability of myeloma cells. Furthermore, this HS mimetic downregulates HPSE expression and prevents ECM degradation. In vivo analyses reveal that this polymeric HS mimetic significantly inhibited the growth of MPC-11 myeloma tumors, achieving a tumor growth inhibition (TGI) index of 85.77%, surpassing the clinically tested SST0001, which had a TGI value of 67.78%. Additionally, the glycopolymer exhibited promising efficacy against metastatic CAG human myeloma, comparable to bortezomib, a widely used proteasome inhibitor for MM treatment. A combined treatment further reduced tumor burden. These results highlight the remarkable potential of HS-mimicking glycopolymer as a promising therapeutic option for MM.