A Human Anti-c-Met Fab Fragment Conjugated with Doxorubicin as Targeted Chemotherapy for Hepatocellular Carcinoma

Abstract

c-Met is over-expressed in hepatocellular carcinoma(HCC) but is absent or expressed at low levels in normal tissues. Therefore we generated a novel conjugate of a human anti-c-Met Fab fragment (MetFab) with doxorubicin (DOX) and assessed whether it had targeted antitumor activity against HCC and reduced the side-effects of DOX. The MetFab was screened from human phage library, conjugated with DOX via chemical synthesis, and the conjugation MetFab-DOX was confirmed by HPLC. The drug release patterns, the binding efficacy, and cellular distribution of MetFab-DOX were assessed. MetFab-DOX was stable at pH7.2 PBS while release doxorubicin quickly at pH4.0, the binding efficacy of MetFab-DOX was similarly as MetFab, and the cellular distribution of the MetFab-DOX is distinct from free DOX. The cytotoxicity of MetFab-DOX was analyzed by the MTT method and the nude mouse HCC model. The MetFab-DOX demonstrated cytotoxic effects on c-Met expressing-tumor cells, but not on the cells without c-Met expression. MetFab-DOX exerted anti-tumor effect and significantly reduced the side effect of free DOX in mice model. Furthermore, the localization of conjugate was confirmed by immunofluorescence staining of tumor tissue sections and optical tumor imaging, respectively, and the tissue-distribution of drug was compared between free DOX and MetFab-DOX treatment by spectrofluorometer. MetFab-DOX can localize to the tumor tissue, and the concentration of doxorubicin in the tumor was higher after MetFab-DOX administration than after DOX administration. In summary, MetFab-DOX can target c-Met expressing HCC cells effectively and have obvious antitumor activity with decreased side-effects in preclinical models of HCC.

Lactoferrin-modified PEGylated liposomes loaded with doxorubicin for targeting delivery to hepatocellular carcinoma

“…[2][3][4] Currently, doxorubicin (DOX), an anthracycline antibiotic, is one of the most important chemotherapeutic agents for HCC. [6][7][8] DOX exerts its cytotoxicity by inhibiting the synthesis of nucleic acids within cancer cells. 8 However, the systemic administration of DOX is severely obstructed by its limited therapeutic responses and undesirable systemic toxicities.…”

“…[6][7][8] DOX exerts its cytotoxicity by inhibiting the synthesis of nucleic acids within cancer cells. 8 However, the systemic administration of DOX is severely obstructed by its limited therapeutic responses and undesirable systemic toxicities. [6][7][8] Therefore, improving the selective accumulation of DOX in HCC tumor cells might be an effective method to enhance its antitumor efficacies and minimize its systemic toxicities.…”

“…8 However, the systemic administration of DOX is severely obstructed by its limited therapeutic responses and undesirable systemic toxicities. [6][7][8] Therefore, improving the selective accumulation of DOX in HCC tumor cells might be an effective method to enhance its antitumor efficacies and minimize its systemic toxicities. 7 Polyethylene glycol (PEG)ylated liposomes (PLSs) are widely considered as potential anticancer chemotherapeutic agent carriers for cancer treatment.…”

Oil-in-water biocompatible microemulsion as a carrier for the antitumor drug compound methyl dihydrojasmonate

“…The main problem of most antineoplastic therapeutic compounds is their severe side effects. [1][2][3] Drug delivery systems, which have the ability to compartmentalize drugs in nanostructures, are one of the technological strategies that can enable parenteral administration and reduce potential toxic effects. Doxorubicin (DOX), a widely used antitumor compound, generates heart and kidney toxicity.…”

“…Doxorubicin (DOX), a widely used antitumor compound, generates heart and kidney toxicity. In addition to myelosuppression, 1 cisplatin, another important antineoplastic agent, may cause nephrotoxicity. 2 On the other hand, the monoclonal antibody bevacizumab may induce gastrointestinal hemorrhage and perforation.…”