Novel pH-sensitive zinc phthalocyanine assembled with albumin for tumor targeting and treatment

Abstract

Purpose

Zinc phthalocyanine (ZnPc) has been applied widely in photodynamic therapy (PDT) with high ROS-production capacity and intense absorption in the near-infrared region. However, weak tumor targeting and the aggregation tendency of ZnPc seriously affect the therapeutic effect of PDT. Therefore, overcoming the aggregation of ZnPc and enhancing its antitumor effect were the purpose of this study.

Methods

In this study, we first found that the aggregation behaviors of the photosensitizer ZnPc(TAP)₄, ZnPc substituted by tertiary amine groups, were regulated finely by pH and that ZnPc(TAP)₄ could be disaggregated gradually as the pH descended. ZnPc(TAP)₄ and human serum albumin (HSA) molecules were assembled into nanoparticles (NPs) for tumor targeting. Meanwhile, the chemotherapy drug paclitaxel (Ptx) was loaded into HSA NPs together with ZnPc(TAP)₄ for dual antitumor effects. HSA NPs loading both ZnPc(TAP)₄ and Ptx (NP–ZnPc[TAP]₄–Ptx) were characterized by particle size and in vitro release. Cytotoxicity, subcellular localization, tumor targeting, and anticancer effect in vivo were investigated respectively.

Results

We found that NP–ZnPc(TAP)₄–Ptx had good stability with qualifying particle size. Interestingly, ZnPc(TAP)₄ was released from the NPs and the photodynamic activity enhanced in the acidic environment of tumor. In addition, NP–ZnPc(TAP)₄–Ptx had prominent cytotoxicity and time-dependent subcellular localization characteristics. Through a three-dimensional animal imaging system, NP–ZnPc(TAP)₄–Ptx showed much-enhanced tumor targeting in tumor-bearing mice. Above all, NP–ZnPc(TAP)₄–Ptx was demonstrated to have the synergistic anticancer effect of PDT and chemotherapy.

Conclusion

NP–ZnPc(TAP)₄–Ptx had enhanced tumor targeting for the pH-sensitive property of ZnPc(TAP)₄ and the transport function of HSA. NP–ZnPc(TAP)₄–Ptx possessed a double-anticancer effect through the combination of ZnPc(TAP)₄ and Ptx. This drug-delivery system may also be used to carry chemotherapy drugs other than Ptx for improving antitumor effects.

Keywords:

• photodynamic therapy
• drug-delivery system
• controlled release
• chemotherapy
• antitumor activity
• combination therapy

Supplementary materials

Figure S1 Ultraviolet–visible spectra of NP–ZnPc(TAP)₄–Ptx and NP–ZnPc(TAP)₄ (the concentration of ZnPc[TAP]₄ was 5 µM) in PBS.

Notes: This result showed that NP–ZnPc(TAP)₄–Ptx and NP–ZnPc(TAP)₄ had almost the same spectrum, while the spectrum was different from that of ZnPc(TAP)₄ in PBS without HSA (Figure 1B). This suggested that ZnPc(TAP)₄ interacted with HSA in the NPs.

Abbreviations: NP, nanoparticle; ZnPc, zinc phthalocyanine; Ptx, paclitaxel; HSA, human serum albumin.

Figure S2 Cytotoxicity of NP–ZnPc(TAP)₄–Ptx and NP–Ptx for H1299 cells at Ptx concentrations of 0.3 µM, 0.6 µM, 3 µM, 6 µM, 12 µM, and 30 µM.

Notes: After 8,000 adherent cells in each well of 96-well plates had absorbed NP–ZnPc(TAP)₄–Ptx or NP–Ptx for 24 hours, cells were illuminated with light fluence of 1.5 J/cm² for 1 minute. Another 24 hours later, viable cells were checked by MTT. NP–ZnPc(TAP)₄–Ptx had enhanced cytotoxicity over NP–Ptx, which further demonstrated the synergistic antitumor effect. ***P<0.001.

Abbreviations: NP, nanoparticle; ZnPc, zinc phthalocyanine; Ptx, paclitaxel.

Acknowledgments

This work was supported by grants from the Qingdao Applied Postdoctoral Research Project.

Author contributions

All authors contributed to data analysis, drafting and revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.