Thermosensitive
liposomes (TSLs) have been widely investigated for controlled drug release at specific pathophysiological sites. Although excellent thermo-sensitivity under
hyperthermia (HT) was already realized for TSLs, their in vivo stability under physiological temperature still remains challenging. To overcome this limitation, optimized
polymer-based thermosensitive
liposomes (P-TSLs) with good thermo-sensitivity as well as satisfactory in vivo stability were developed in this study for
tumor-specific controlled delivery of
doxorubicin (DOX). In particular,
polymers including p(NIPAM-r-
HPMA) and p(
HPMA-r-APMA) were successfully synthesized based on a reversible addition-fragmentation chain transfer (RAFT) technique. Next, thermosensitive
polymer p(NIPAM-r-
HPMA) was first proposed to be inserted into the
lipid bilayer of TTSL by a postinsertion method. The resulting P-TTSL had a phase transition temperature (Tm) of around 42 °C and displayed excellent thermo-sensitivity under HT: nearly 70% of DOX was released within 1 min when only 1% p(NIPAM-r-
HPMA) was incorporated. Moreover, its stability was maintained at 37 °C. Compared with TTSL, significantly higher cellular uptake of DOX under HT was noticed in P-TTSL, indicating a burst release of DOX at 42 °C. In addition, both in vitro
tumor spheroid experiments and in vivo
tumor slices demonstrated an enhanced DOX deep penetration when treated by P-TTSL under HT. To achieve in vivo imaging and local HT under NIR, p (
HPMA-r-APMA) was labeled by Cy7.5 and coinserted into TTSL, and the best drug efficacy was observed in CY-P-TTSL with HT along with prolonged blood circulation time. We have further investigated the biocompatibility of the developed CY-P-TTSL, and reduced
cardiotoxicity was observed even under HT in comparison with free DOX, demonstrating it is a reliable thermosensitive
drug carrier for improving drug stability and therapeutic efficacy.