Cinobufagin-Loaded and Folic Acid-Modified Polydopamine Nanomedicine Combined With Photothermal Therapy for the Treatment of Lung Cancer

Abstract

Cinobufagin is used as a traditional Chinese medicine for cancer therapy. However, it has some disadvantages, such as poor water solubility, short circulating half-life, and low bioavailability. In the present study, a targeted delivery and smart responsive polydopamine (PDA)-based nanomedicine for delivering cinobufagin was rationally designed to improve the anticancer efficacy of the compound for the treatment of lung cancer. The modification of the nanomedicine using folic acid first mediated tumor targeting via the interaction between folic acid and its receptors on tumor cells. After lysosomes escape, the PDA nanomedicine was triggered by the low pH and released its cargo into the tumor microenvironment. The nanomedicine had a better therapeutic effect against lung cancer when used in combination with photothermal therapy. Compared with other nanomedicines used with photothermal therapy, this nanocarrier was not only sensitive to biologically low pH levels for on-demand drug release, but was also biodegradable, breaking down into biocompatible terminal products. Therefore, the proposed drug delivery system with targeted delivery and smart release demonstrated potential as a multifunctional nanoplatform that can enhance the bioavailability and reduce the side effects of chemotherapeutic agents.

Keywords: anticancer nanomedicine; biodegradation; photothermal therapy; stimuli response; targeted delivery.

FIGURE 1

Schematic diagram of Cino nanomedicine with targeted delivery and smart response. Cino, cinobufagin; PDA, polydopamine; FA, folic acid; FR, folate receptor; NIR, near infrared.

FIGURE 2

Characterization of synthesized PDA NPs. (A) TEM image of PDA NPs (scale bar = 200 nm). (B) Particle size distribution using dynamic light scattering (DLS).

FIGURE 3

Targeted effect of DOX-loaded FA-modified nanomedicine. (A) Fluorescence microscopy images of normal Beas2B, lung cancer A549, and LLC cells after treatment with DOX-loaded FA-modified nanomedicine (0.5 mg/ml) for 4 h. The red color indicates DOX, and the blue color indicates Hoechst; scale bar = 25 μm. (B) Flow cytometry analysis of the above samples at PE (red) channel.

FIGURE 4

Controlled release and optothermal response of the PDA nanomedicine. (A) Cino release from Cino-loaded PDA nanomedicine (0.5 mg/ml) after treatment with pH = 5.0 PBS buffer, without or with an 808 laser (2 W cm⁻², 5 min). Data are presented as the mean ± SD (standard deviation, n = 3). The temperature curves (B) and pictures (C) of PBS buffer, blank PDA NPs, and Cino-loaded PDA nanomedicine after treatment with the 808 laser.

FIGURE 5

In vitro anti-tumor efficacy of Cino-loaded PDA nanomedicine in lung cancer cells. (A) Viability of A549 cells after incubation with various concentrations of free Cino, Cino-loaded PDA nanomedicine, and Cino-loaded PDA nanomedicine with NIR treatment. Data are presented as mean ± SD (standard deviation, n = 4). (B) Viability of LLC cells after incubation with various concentrations of free Cino, Cino-loaded PDA nanomedicine, and PDA nanomedicine with NIR treatment (2 W cm⁻², 5 min). Data are presented as the mean ± SD (standard deviation, n = 4).

FIGURE 6

In vivo anti-tumor efficacy of Cino-loaded PDA nanomedicine. (A) Tumor volume growth curves (B) optothermal response (C) tumor photo, and (D) tumor weight of LLC tumor-bearing mice after systemic administration of saline, blank NPs, free Cino (1 mg/kg), Cino-loaded PDA nanomedicine (1 mg/kg of Cino), and Cino-loaded PDA nanomedicine (1 mg/kg of Cino) treated with 808 NIR laser (2 W cm⁻², 5 min). Data are presented as the mean ± SD (standard deviation, n = 6), *p < 0.05, **p < 0.01.

FIGURE 7

Immunohistochemical staining. (A) Cleaved caspase-3 immunohistochemical staining of LLC tumor-bearing mice after systemic administration of saline, blank NPs, free Cino, Cino loaded nanomedicine, and Cino loaded nanomedicine with NIR laser (scale bar = 50 μm). (B) Statistical analysis of immunohistochemical staining. Data are presented as the mean ± SD (standard deviation, n = 15), **p < 0.01, ***p < 0.001.