One-pot synthesis of pH-responsive hyperbranched polymer-peptide conjugates with enhanced stability and loading efficiency for combined cancer therapy
Nanoparticles as drug delivery systems had received significant attentions due to their merits such as prolonged circulation time and passive targeting to the tumor site. Polymer-peptide conjugates (PPCs) intend to self-assemble into nanoparticles in the aqueous solution, and the resulting nanoparticles as drug carriers combine the virtues of polymers and peptides. In this paper, a simple synthetic method based on thiol-acrylate Michael addition reaction was used for one-pot synthesis of amphiphilic hyperbranched poly(β-thioester)s (PPHD-PK) conjugated with cytotoxic peptide (KLAKLAK)2 (denoted as KLAK) and poly(ethylene glycol) (PEG). In aqueous media, PPHD-PK self-assembled into nanoparticles, and the hyperbranched poly(β-thioester)s (PPHD) containing acid-labile β-thiopropionate group acted as the interior of nanoparticles, while the PEG and KLAK were employed as the outer shell. The PPHD-PK nanoparticles showed enhanced cellular uptake and favorable antitumor activity, which was attributed to the spherical structure with superficial positive charges and mitochondria-regulated apoptosis of the KLAK peptide. Compared with linear PPCs, the stability of nanoparticles and the drug loading efficiency of PPHD-PK were significantly improved, implying the stronger intermolecular interaction was generated by intertwisting branched networks in the nanoparticle core region. The doxorubicin (DOX) as a typical chemotherapeutic drug was readily released from PPHD-PK in the acidic environment of lysosome, thus leading to efficient nuclear drug translocation and resultant potent drug efficacy. Furthermore, the DOX-loaded PPHD-PK nanoparticles showed higher cytotoxic activity than DOX-loaded PPHD-P (without KLAK) and blank PPHD-PK nanoparticles, indicating the combined treatment of DOX and KLAK werewas effective to kill HeLa cells. Therefore, the DOX-loaded PPHD-PK nanoparticles with enhanced stability and loading efficiency exhibit great potential as anti-tumor nanodrugs for efficient cancer therapy.