Co-delivery of paclitaxel and TOS-cisplatin via TAT-targeted solid lipid nanoparticles with synergistic antitumor activity against cervical cancer

Abstract

Background: Cervical cancer is a major world health problem for women. Currently, cancer research focuses on improving therapy for cervical cancer using various treatment options such as co-delivery of chemotherapeutic agents by nanocarriers.

Purpose: The aim of this study was to develop trans-activating transcriptional activator (TAT)-modified solid lipid nanoparticles (SLNs) for co-delivery of paclitaxel (PTX) and α-tocopherol succinate-cisplatin prodrug (TOS-CDDP) (TAT PTX/TOS-CDDP SLNs) in order to achieve synergistic antitumor activity against cervical cancer.

Methods: Lipid prodrug of CDDP (TOS-CDDP) and TAT-containing polyethylene glycol-distearoyl-phosphatidylethanolamine (TAT-PEG-DSPE) were synthesized. TAT PTX/TOS-CDDP SLNs were prepared by emulsification and solvent evaporation method. Physicochemical characteristics of SLNs such as size, morphology, and release profiles were explored. In vitro and in vivo studies were carried out to assess the efficacy of their antitumor activity in target cells.

Results: TAT PTX/TOS-CDDP SLNs could be successfully internalized by HeLa cells and showed a synergistic effect in the suppression of cervical tumor cell growth. They exhibited high tumor tissue accumulation, superior antitumor efficiency, and much lower toxicity in vivo.

Conclusion: The present study indicates that the co-delivery system provides a promising platform as a combination therapy for the treatment of cervical cancer, and possibly other types of cancer as well.

Keywords: cell-penetrating peptide; cervical cancer; combination therapy; lipid-based prodrug; solid lipid nanoparticles.

Figure 1

Schematic diagram of synthesis of TOS-CDDP. Abbreviations: DMAP, 4-dimethylaminopyridine; DCC, N,N′-dicyclohexyl-carbodimide; TOS-CDDP, α-tocopherol succinate-cisplatin prodrug.

Figure 2

Structural diagram of TAT PTX/TOS-CDDP SLNs. Abbreviations: CDDP, cisplatin; DSPE, distearoyl-phosphatidyleth anolamine; PEG, polyethylene glycol; PTX, paclitaxel; SLNs, solid lipid nanoparticles; TAT, trans-activating transcriptional activator; TOS-CDDP, α-tocopherol succinate-cisplatin prodrug.

Figure 3

¹H-NMR spectra of TOS-CDDP. Abbreviation: TOS-CDDP, α-tocopherol succinate-cisplatin prodrug.

Figure 4

TEM images of TAT PTX/TOS-CDDP SLNs. Abbreviations: PTX, paclitaxel; SLNs, solid lipid nanoparticles; TAT, trans-activating transcriptional activator; TEM, transmission electron microscopy; TOS-CDDP, α-tocopherol succinate-cisplatin prodrug.

Figure 5

PTX and CDDP encapsulation ability of TAT PTX/TOS-CDDP SLNs in the presence of plasma during 24 h. The data are shown as mean ± SD (n=3). Abbreviations: CDDP, cisplatin; EE, encapsulation efficiency; h, hours; PTX, paclitaxel; SD, standard deviation; SLNs, solid lipid nanoparticles; TAT, trans-activating transcriptional activator; TOS-CDDP, α-tocopherol succinate-cisplatin prodrug.

Figure 6

In vitro release profile of PTX from SLNs. The data are shown as mean ± SD (n=3). Abbreviations: CDDP, cisplatin; h, hours; PTX, paclitaxel; SD, standard deviation; SLNs, solid lipid nanoparticles; TAT, trans-activating transcriptional activator; TOS-CDDP, α-tocopherol succinate-cisplatin prodrug.

Figure 7

In vitro release profile of CDDP from SLNs. The data are shown as mean ± SD (n=3). Abbreviations: CDDP, cisplatin; h, hours; PTX, paclitaxel; SD, standard deviation; SLNs, solid lipid nanoparticles; TAT, trans-activating transcriptional activator; TOS-CDDP, α-tocopherol succinate-cisplatin prodrug.

Figure 8

Cellular uptake efficiency of the SLNs. The data are shown as mean ± SD (n=3). Abbreviations: CDDP, cisplatin; h, hours; PTX, paclitaxel; SD, standard deviation; SLNs, solid lipid nanoparticles; TAT, trans-activating transcriptional activator; TOS-CDDP, α-tocopherol succinate-cisplatin prodrug.

Figure 9

Cytotoxicity of the blank SLNs evaluated in HeLa cells. The evaluation time of exposure is 48 h. The data are shown as mean ± SD (n=3). Abbreviations: h, hours; HeLa, human cervix adenocarcinoma cell line; SD, standard deviation; SLNs, solid lipid nanoparticles.

Figure 10

In vivo antitumor efficacy of different formulations on cervical cancer-bearing mice. The data are shown as mean ± SD (n=8). Note: *P<0.05. Abbreviations: CDDP, cisplatin; PTX, paclitaxel; SD, standard deviation; SLNs, solid lipid nanoparticles; TAT, trans-activating transcriptional activator; TOS-CDDP, α-tocopherol succinate-cisplatin prodrug.

Figure 11

In vivo tumor inhibition rates of different formulations on cervical cancer-bearing mice. The data are shown as mean ± SD (n=8). Abbreviations: CDDP, cisplatin; PTX, paclitaxel; SD, standard deviation; SLNs, solid lipid nanoparticles; TAT, trans-activating transcriptional activator; TIR, tumor inhibition rate; TOS-CDDP, α-tocopherol succinate-cisplatin prodrug.

Figure 12

In vivo PTX tissue distribution results of PTX/TOS-CDDP solution (A) and TAT PTX/TOS-CDDP SLNs (B). The data are shown as mean ± SD (n=8). Abbreviations: PTX, paclitaxel; SD, standard deviation; SLNs, solid lipid nanoparticles; TAT, trans-activating transcriptional activator; TOS-CDDP, α-tocopherol succinate-cisplatin prodrug.

Figure 13

In vivo CDDP tissue distribution results of PTX/TOS-CDDP solution (A) and TAT PTX/TOS-CDDP SLNs (B). The data are shown as mean ± SD (n=8). Abbreviations: CDDP, cisplatin; h, hours; PTX, paclitaxel; SD, standard deviation; SLNs, solid lipid nanoparticles; TAT, trans-activating transcriptional activator; TOS-CDDP, α-tocopherol succinate-cisplatin prodrug.