Abstract
Lung cancer ranks among the most common malignancies, and is the leading cause of cancer-related mortality worldwide. Chemotherapy for lung cancer can be made more specific to tumor cells, and less toxic to normal tissues, through the use of ligand-mediated drug delivery systems. In this study, we investigated the targeting mechanism of the ligand-mediated drug delivery system using a peptide, SP5-2, which specifically binds to non-small cell lung cancer (NSCLC) cells. Conjugation of SP5-2 to liposomes enhanced the amount of drug delivered directly into NSCLC cells, through receptor-mediated endocytosis. Functional SP5-2 improved the therapeutic index of Lipo-Dox by enhancing therapeutic efficacy, reducing side effects, and increasing the survival rate of tumor-bearing mice in syngenic, metastatic and orthotopic animal models. Accumulation of SP5-2-conjugated liposomal doxorubicin (SP5-2-LD) in tumor tissues was 11.2-fold higher than that of free doxorubicin, and the area under the concentration-time curve (AUC0–72 hours) was increased 159.2-fold. Furthermore, the experiment of bioavailability was assessed to confirm that SP5-2 elevates the uptake of the liposomal drugs by the tumor cells in vivo. In conclusion, the use of SP5-2-conjugated liposomes enhances pharmacokinetic properties, improves efficacy and safety profiles, and allows for controlled biodistribution and drug release.
Highlights
Lung cancer continues to be the leading cause of cancer deaths in the United States, and a major cause of death worldwide [1,2]
Our result showed that incubation of H460 cells with SP5-2-LS at 37uC for 30 minutes resulted in cytoplasmic fluorescence surrounding the nuclei (Figure 1)
Doxorubicin treatment has been shown to be associated with severe cardiotoxicity and hepatotoxicity; these side effects could be reduced with PEGylated liposomes, which increased the tumor localization of the nanoparticle formulation (Table 1) [17]
Summary
Lung cancer continues to be the leading cause of cancer deaths in the United States, and a major cause of death worldwide [1,2]. The two main types of lung cancer are non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). 80% of all primary pulmonary tumors are of the NSCLC type [3]; these have a limited response rate to current chemotherapeutic agents, and afflicted patients have a two-year survival rate of 21% [4]. A major factor contributing to poor chemotherapeutic efficacy in the treatment of lung cancer is the high interstitial fluid pressure (IFP) within tumors. Immature vasculature and high IFP hinder drug delivery into solid tumors, and reduce the therapeutic efficacy of systemically administered chemotherapy [8,9]. Only 5– 10% of drugs accumulated in normal viscera enter into tumor tissues [10,11]
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