| Overexpression of HER2(Human epidermal growth factor receptor 2,HER2)is presented in roughly 20～30% of breast cancer patients with a poor prognosis.HER2 is also overexpressed in approximately 20% of gastroesophageal junctions and gastric cancers with a poor prognosis.Despite great progress achieved in HER2-targeted therapies,a large number of patients eventually relapse due to primary or acquired drug resistance to Trastuzumab monotherapy.The basic strategy to address resistance is to combine Trastuzumab with other targeted or chemotherapeutic agents.Some of the chemotherapeutic drugs against HER2 therapies are faced with challenges,such as poor physiological solubility,dose-dependent toxicity,and rapid clearance from the body.Carbon nanomaterials such as carbon dots and graphene oxide,due to their unique physical,chemical,and electrical properties,have shown promising applications in targeted drug delivery,controlled drug release,reduce unwanted side-effects.Surface functionalization allows these nanomaterials to be used more safely and effectively,and ensures that they can overcome different biological barriers and selectively accumulate in tumor cells for effective treatment.This paper has carried out a multiple of combinational treatment strategies against HER2 target.The main results are as follows:(1)The combination of Trastuzumab and novel anti-HER2 antibody: A novel fully human antibody GB235-019 was screened from a single chain antibody phage library.The CHO DG44 cell line stably-expressing the mutant of GB235-019 N73D(Designated as GB235)was obtained by gene recombination technology.The antitumor activity of Trastuzumab+GB235 was verified in cell-based assays,and further evaluated in vivo efficacy in the HER2 positive ST-02-0077 and GA0060 xenograft models.Treatment of ST-02-0077 tumor-bearing mice with 6 mg/kg Trastuzumab or GB235+Trastuzumab(20+6)mg/kg for 31 days,resulted in tumor growth inhibition(TGI)by 42.6% and 77.6%,respectively.In mice bearing the GA0060 tumors,administration of GB235+Trastuzumab(20+10)mg/kg,achieving the day-38 TGI by66.1%,while treatment with 10 mg/kg Trastuzumab alone without response.(2)The combination of Trastuzumab and gene therapy: The high efficiency and low cytotoxicity gene delivery system BP-CDs was prepared by hydrothermal reaction and functionalization of polyethylenimine.BP-CDs can load and deliver gene drugs of siRNA into cells efficiently.BP-CDs/HER3 siRNA complexes demonstrated significant growth inhibition in BT-474 cells in a dose-dependent manner.Consistently,cells treated with BP-CDs/HER3 siRNA complexes(150 ng,with the optimal weight ratio of 3)or Trastuzumab each reduced the net cell growth by 39% and 51%,respectively,while the BP-CDs/HER3 siRNA complexes in combination with Trastuzumab caused69% cell death.(3)The combination of Trastuzumab and chemotherapeutic drug: The chitosanfunctionalized graphene oxide(Chr GO)nanosheets were fabricated via microwaveassisted reduction.The adriamycin loading percentage was determined to be as high as169.8%(w/w).Treatment of BT-474 cells with Trastuzumab(5 μ g/m L)or Chr GO/adriamycin complexes(Equivalent adriamycin,5 μg/m L),resulted in the proliferation inhibition of 54.5% and 59.5%,respectively,while treatment with the combination of Trastuzumab and Chr GO/adriamycin complexes induced 88.5% cell death.In conclusion,Trastuzumab therapy still serves as the backbone of HER2-positive breast cancer treatment.Trastuzumab in combination with other agents(novel antibodies,gene therapy,or anthracyclines)demonstrated synergetic antitumor activity,reversed the resistance to Trastuzumab monotherapy.To meet a variety of clinical needs of first-line(preferred),second-line(secondary),and third-line(alternative)treatment for HER2-positive breast cancer patients.This study not only provides a new strategy for the construction of carbon nanomaterials for regulating target gene expression,but also provides new evidence for the evaluation of medicinal properties of nucleic acid drug HER3 siRNA.At the same time,our work provides new research ideas for the biologically functional modification of r GO and provides new support for the targeted delivery of adriamycin and the controlled release of adriamycin for breast cancer treatment.The combination of Trastuzumab with novel HER2 antibody,HER3 siRNA,or adriamycin is a potential therapeutic option for patients with HER2-positive tumors. |
