The drug delivery systems improve the efficacy of chemotherapeutics through enhanced targeting and controlled release however,
biological barriers of tumor microenvironment greatly impede the penetration of nanomedicine within the
tumor. We report herein the fabrication of a PEG-detachable
silybin (SLB) pH-sensitive
liposome decorated with TAT-
peptide. For this, Acyl
hydrazide-activated
PEG2000 was prepared and linked with
ketone-derivatized
DPPE via an
acid-labile
hydrazone bond to form mPEG2000-HZ-DPPE. TAT
peptide was conjugated with a shorter -PEG1000-DSPE spacer and post-inserted into PEGylated
liposome (DPPC: mPEG2000-
DSPE: Chol). To prepare nanoliposomes (around 100 nm), first, a novel method was used to prepare SLB-Soya PC (SLB-
SPC) complex, then this complex was incorporated into nanoliposomes. The pH-sensitivity and shielding effect of long PEG chain on TAT
peptide was investigated using DiI
liposome and FACS analysis. Pre-treatment to the lowered pH enhanced cellular association of TAT-modified pH-sensitive
liposome due to the cleavage of
hydrazone bond and TAT exposure. Besides, TAT-modified pH-sensitive
liposomes significantly reduced cell viability compared to the plain
liposome. In vivo results were very promising with pH-sensitive
liposome by detaching PEG moieties upon exposure to the acidic tumor microenvironment, enhancing cellular uptake, retarding
tumor growth, and prolonging the survival of 4T1
breast tumor-bearing BALB/c mice. TAT modification of pH-sensitive
liposome improved
cancer cell association and cytotoxicity and demonstrated potential intracellular delivery upon exposure to acidic pH. However, in in vivo studies, TAT as a targeting
ligand significantly decreased the therapeutic efficacy of the formulation attributed to an inefficient
tumor accumulation and higher release rate in the circulation. The results of this study indicated that pH-sensitive
liposome containing SLB, which was prepared with a novel method with a significant SLB loading efficiency, is very effective in the treatment of 4T1
breast tumor-bearing BALB/c mice and merits further investigation.