To overcome the strong negative charge and improve the endocytosis of poly-β-
malic acid (PMLA) as a
drug carrier, a pH-sensitive
nanoconjugate of PMLA/hyd-PEG5000/
PEG2000-TAT/DOX (PHPTD) was developed. The
trans activator of transcription (TAT) modified with
polyethylene glycol2000(
PEG2000) was conjugated with the PMLA backbone which improved the endocytosis of PMLA. PEG5000 was utilized to shield TAT by a pH-sensitive
hydrazone (Hyd) bond. In order to decrease the potential risk of accelerated blood clearance (ABC) phenomenon by anti-PEG
IgM, the minimal content of TAT for penetrating
tumor cells and the optimal protecting layer density of PEG5000 were screened. The result showed that 0.3 mol% TAT was enough to efficiently improve cellular uptake of PMLA (30 kda). The cytotoxicity and the 1H-NMR results indicated that 3.6 mol% PEG5000-modified
nanoconjugates could shield 0.3 mol% TAT. The antitumor effect in
breast cancer cells (MDA-MB-231) in
tumor-bearing BALB/C mice demonstrated that this
nanoconjugates exhibits high therapeutic efficiency in artificial solid
tumors and low toxicity to normal tissues. It is indicated that TAT could be hidden in the long chain of PEG5000 at a neutral pH, when arrival to the
tumor extracellular microenvironment, PEG5000 was cleaved from the
nanoconjugates through the
hydrazone bond due to the acidic
tumor environment. Then, TAT was exposed, allowing the
nanoconjugates to be transported into
tumor cells. Our findings provide important and detailed information regarding the optimal content of TAT and the shielded density of PEG5000 and reveal their abilities of
tumor penetration and potential for the efficient
drug carrier.