Holo‐Lactoferrin Modified Liposome for Relieving Tumor Hypoxia and Enhancing Radiochemotherapy of Cancer

Abstract

Hypoxic microenvironments in the solid tumor play a negative role in radiotherapy. Holo‐lactoferrin (holo‐Lf) is a natural protein, which acts as a potential ligand of transferrin receptor (TfR). In this work, an anticancer drug, doxorubicin (Dox)‐loaded liposome‐holo‐Lf nanocomposites, is developed for tumor targeting and imaging guided combined radiochemotherapy. Dox‐loaded liposome‐holo‐Lf (Lf‐Liposome‐Dox) nanocomposites exhibit significant cellular uptake likely owing to the TfR receptor‐mediated targeting accumulation of Lf‐Liposome‐Dox nanocomposites. Additionally, the nanocomposites exhibit high accumulation in the tumor site after intravenous injection as evidenced from in vivo fluorescence imaging. More importantly, it is found that the holo‐Lf has the ability to catalyze the conversion of hydrogen peroxide (H2O2) to oxygen for relieving the tumor hypoxic microenvironment. Photoacoustic imaging further confirms the abundant generation of oxygen in the presence of Lf‐Liposome‐Dox nanocomposites. Based on these findings, in vivo combined radiochemotherapy is performed using Lf‐Liposome‐Dox as therapeutic agent, achieving excellent cancer treatment effect. The study further promotes the potential biomedical application of holo‐Lf in cancer treatment.

Lactoferrin’s Anti-Cancer Properties: Safety, Selectivity, and Wide Range of Action

“…In particular, bLf-containing polyethylene glycol (PEG)-modified liposomes have been employed in the targeting of Dox in in vitro and in vivo models of hepatocarcinoma, showing a relevant effect in improving Dox cellular uptake, which was associated to the presence of asialoglycoprotein receptors on cancer cell membrane, and to a significant inhibition of tumor growth in mice bearing HepG2 xenografts compared to mice injected intravenously with the sole Dox-loaded PEGylated liposomes [201]. Moreover, the intravenous injection of Dox-loaded holo-bLf-liposomes in a murine model of breast cancer resulted, along with a high accumulation of the nanocomposites in the tumor site, in tumor suppression and in a higher induction, when compared to mice treated with the sole Dox-loaded liposomes, of hydrogen peroxide conversion to oxygen, due to the release of ferric ions following holo-bLf degradation [202]. Similarly, bLf-containing micelles were used for the efficient targeting of both rapamycin and wogonin to treat breast cancer cells [203].…”

“…The use of Lf-loaded liposomes as anti-cancer drug carrier has also been tested [201,202]. In particular, bLf-containing polyethylene glycol (PEG)-modified liposomes have been employed in the targeting of Dox in in vitro and in vivo models of hepatocarcinoma, showing a relevant effect in improving Dox cellular uptake, which was associated to the presence of asialoglycoprotein receptors on cancer cell membrane, and to a significant inhibition of tumor growth in mice bearing HepG2 xenografts compared to mice injected intravenously with the sole Dox-loaded PEGylated liposomes [201].…”

Combined chemo-magnetic field-photothermal breast cancer therapy based on porous magnetite nanospheres

“…In several studies, the anti-cancer activity of Lf is associated with the capacity of apoptosis through down-regulation of Bcl-2 mRNA 23 , along with up-regulation of the pro-apoptotic Bax and Caspase 3 mRNA 24 . Besides, Lf can result in targeted delivery of NP containing Doxo to tumor site 25 as well as an increase in the blood circulation time due to ability to escape from mononuclear phagocyte system (MPS) 26 and controlling drug release 2 , whereas, the anti-cancer mechanism of Lf ' is not fully understood.…”

Lactoferrin, a multi-functional glycoprotein: Active therapeutic, drug nanocarrier & targeting ligand

“…In addition, Lf nanocarriers could increase the expression of cytokines TNF-α, and IFN-γ with anticancer activity. Interestingly, the iron saturation of Lf could be linked to its anticancer efficacy so that the iron saturated holo-Lf exhibited higher anti-tumor efficacy than apo-Lf or native Lf while the mechanism is still unclear [ 78 ].…”

“…The presence of Fe in the structure of holo-Lf can induce decomposition of H 2 O 2 to oxygen thus alleviating the hypoxic TME. Through its oxygen generation capacity, Lf-PEGylated DOX-loaded liposomes showed synergistic anticancer effect and increased survival rate of mice when combined with 4 Gy X-ray radiation in breast cancer bearing mice which could be confirmed by photoacoustic imaging [ 78 ]. Lf NPs were also used to enhance the efficacy of breast cancer photodynamic therapy by encapsulation of photosensitizer (PS) Chlorine e6 (Ce6).…”