Chemotherapy agents have been widely used for
cancer treatment, while the insolubility, instability and toxicity seriously restrict their efficacy. Thus,
prodrug strategy was devised. Since some
prodrugs are still with poor solubility or stability, a synergy strategy is needed to enhance their efficacy.
Gemcitabine (GEM) is a prescribed anticancer drug, however, the rapid clearance, growing resistance and serious side effects limit its clinical efficacy. Conjugating GEM with d-α-
tocopherol succinate (TOS) is an effective
solution, while the GEM-TOS (GT) is unstable in aqueous
solution. d-α-
Tocopherol polyethylene glycol succinate (
TPGS) has been used to enhance the stability, but GT stabilized by
TPGS (GTT) has limited effect on
tumor metastases.
Tumor metastases lead to high mortality in patients suffering from
cancers. In order to further achieve antimetastatic effect, an amphiphilic
polymer (LT) was synthesized by connecting
low-molecular-weight heparin (
LMWH) with TOS, and eventually obtained desired self-delivery micellar NPs (GLT) by co-assembly GT with LT. The GLT not only possessed excellent stability, but also inhibited the
metastases by acting on different phases of the metastatic cascade. The hydrophobic TOS inhibited the secretion of
matrix metalloproteinase-9 (MMP-9), the hydrophilic
LMWH inhibited the interaction between
tumor cells and platelets. As a result, GLT reduced
tumor cells entering the blood and implanting at the distant organs, leading to a much more excellent inhibitory effect on the lung
metastasis than GEM and GTT.