Fabrication of amphiphilic random copolymers as efficient chemotherapeutic nano-carriers for doxorubicin delivery in metastatic experimental murine lymphoma.

Abstract

Developing efficient and stable amphiphilic polymeric nanocarriers faces challenges, including the trade-off between nano-particle size, drug loading capacity, cellular uptake efficiency, as well as the overall cytotoxicity. In this context, the synthesis of well-defined diblock or triblock copolymers via controlled radical polymerization techniques, which often involve multiple steps and poor scalability, has become a widely adopted approach for designing polymeric nanostructures with tailored properties. This study presents a facile strategy for preparing a series of random copolymer systems via reversible addition-fragmentation chain transfer (RAFT) polymerization and demonstrates their excellent performance as nano-drug carriers. First, a homopolymer of a newly synthesized monomer, namely, N-n-propyl-N-(3-(isopropylamino)-3-oxopropyl)acrylamide (M3), was synthesized, followed by the preparation of a series of random copolymers of this monomer with the macromonomer poly(ethylene glycol) methyl ether acrylate (PEGA, Mn = 480) having variable compositions. By systematic variation of PEGA, the lower critical solution temperature (LCST) of the random copolymer poly(M3-ra-PEGA) at only 17 mol% reached 34 °C, which is below the physiological temperature. Doxorubicin (DOX) was loaded into the micelles of this copolymer with a drug loading content (DLC) of 9% and a drug loading efficiency (DLE) of 45%. The DOX-loaded random copolymer demonstrated significant tumoricidal potential against Dalton's lymphoma (DL) tumor cells with dose-dependent reduction in cell viability, direct cytotoxicity and long-term growth inhibition upon treatment. The DOX-loaded copolymer significantly protected the DL tumor-bearing animals by enhancing their life span, reducing the tumor volume and preventing metastasis.