Abstract
An amphiphilic copolymer, folic acid (FA) modified poly(ethylene glycol)-poly(lactic-co-glycolic acid) (FA-PEG-PLGA) was prepared and explored as a nanometer carrier for the co-delivery of cisplatin (cis-diaminodichloroplatinum, CDDP) and paclitaxel (PTX). CDDP and PTX were encapsulated inside the hydrophobic inner core and chelated to the middle shell, respectively. PEG provided the outer corona for prolonged circulation. An in vitro release profile of the CDDP + PTX-encapsulated nanoparticles revealed that the PTX chelation cross-link prevented an initial burst release of CDDP. After an incubation period of 24 hours, the CDDP+PTX-encapsulated nanoparticles exhibited a highly synergistic effect for the inhibition of A549 (FA receptor negative) and M109 (FA receptor positive) lung cancer cell line proliferation. Pharmacokinetic experiment and distribution research shows that nanoparticles have longer circulation time in the blood and can prolong the treatment times of chemotherapeutic drugs. For the in vivo treatment of A549 cells xeno-graft lung tumor, the CDDP+PTX-encapsulated nanoparticles displayed an obvious tumor inhibiting effect with an 89.96% tumor suppression rate (TSR). This TSR was significantly higher than that of free chemotherapy drug combination or nanoparticles with a single drug. For M109 cells xeno-graft tumor, the TSR was 95.03%. In vitro and in vivo experiments have all shown that the CDDP+PTX-encapsulated nanoparticles have better targeting and antitumor effects in M109 cells than CDDP+PTX-loaded PEG-PLGA nanoparticles (p < 0.05). In addition, more importantly, the enhanced anti-tumor efficacy of the CDDP+PTX-encapsulated nanoparticles came with reduced side-effects. No obvious body weight loss or functional changes occurred within blood components, liver, or kidneys during the treatment of A549 and M109 tumor-bearing mice with the CDDP+PTX-encapsulated nanoparticles. Thus, the FA modified amphiphilic copolymer-based combination of CDDP and PTX may provide useful guidance for effective and safe cancer chemotherapy, especially in tumors with high FA receptor expression.
Highlights
In small-molecule-based chemotherapy, the use of a single agent often cannot achieve complete tumor remission due to the rapid development of drug resistance of tumor cells
[32] The aforementioned is indicative of the successful synthesis of PLGA, Poly(ethylene glycol) (PEG)-PLGA and folic acid (FA)-PEG-PLGA copolymer
We present an FA modified amphiphilic copolymerbased CDDP and PTX combination strategy for greater chemotherapeutic response and lessened side-effects
Summary
In small-molecule-based chemotherapy, the use of a single agent often cannot achieve complete tumor remission due to the rapid development of drug resistance of tumor cells. The combination therapy of multiple drugs with different action mechanisms, has proven to be an effective strategy in clinical cancer treatments. The combination of free drugs often brought more serious toxic side effects to humans, which has been a serious problem in clinical cancer treatments. Their different biochemical properties and pharmacokinetic characteristics affect synergistic therapeutic efficacy. The combination of free-CDDP and free-PTX drugs has become the first-line chemotherapeutic agent for advanced breast cancer, advanced non-small-cell lung cancer (NSCLC), advanced gastric cancer, ovarian cancer, etc. The additional clinical benefit gained from the combination chemotherapy of free-CDDP and free-PTX was discounted because of the increased side effects
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