Enzyme-sensitive biodegradable and multifunctional polymeric conjugate as theranostic nanomedicine

Abstract In this study, we designed and fabricated a novel amphiphilic biodegradable triblock N-(2-hydroxypropyl methyl) acrylamide (HPMA) copolymer-gadolinium- paclitaxel-Cyanine5.5 (pHPMA-Gd-PTX-Cy5.5) conjugate and further studied its theranostic nanomedicine for cancer treatment. The amphiphilic block polymer was synthesized through two-step RAFT polymerization, and self-assembled into a nanoparticle with a diameter of around 85 nm. The enzyme-sensitive tetrapeptide GFLG linker was introduced to the backbone of the polymer as a spacer to conjugate the anticancer drug paclitaxel (PTX) to the polymeric carrier, allowing the conjugate with a high molecular weight (MW, 92 kDa) to degrade into low MW products (44 kDa), as well as to release the drug in the cancer microenvironment. The Cy5.5 and Gd(III)-labeled nanoparticles had 5 folds T 1 relaxivity relative to the clinical magnetic resonance imaging (MRI) contrast agent Gd-DTPA, enhancing the imaging capacity of the theranostic nanomedicine. In vivo MR imaging, fluorescence imaging and Gd(III) histological distribution demonstrated that the residence time of the multifunctional conjugate-based nanoparticles has been significantly prolonged and accumulation of the conjugate at the tumor site has been increased. The conjugate-based nanoparticles therefore significantly inhibited proliferation and induced apoptosis of the 4T1 murine breast cancer cells in the xenograft tumor model and no obvious side effects were observed. Overall, the theranostic nanomedicine derived from the enzyme-sensitive biodegradable pHPMA-Gd-PTX-Cy5.5 conjugate may open a door for simultaneous therapeutic treatment and MR imaging of breast cancer.