The tumour site has a special microenvironment that provides the necessary conditions for the development and metastasis of the tumour, for example, maintaining growth-promoting signals, maintaining neovascularization, counteracting apoptosis and growth-inhibitory signals, tumour cell metastasis and infinite proliferation, genome instability and mutagenesis, energy metabolism reintegration, inflammation which promotes tumour growth, and escaping the identification and killing from immune system. (Hanahan D, Weinberg R A. Hallmarks of cancer: the next generation. Cell 2011, 144, 647-674.)
With the rapid development of biomedical technology, tumor-targeting therapy has become the main development direction of current cancer treatment. The development of drug delivery vector technology offers the possibility of specific, targeted delivery of anti-tumour drugs. The use of specific tumour-targeting ligands to modify anti-tumour drugs or drug delivery vectors can effectively increase the distribution and accumulation of drugs or drug delivery vectors in tumour sites and reduce the distribution of drugs in non-target organs and tissues, thereby achieving enhanced antitumour efficacy and reduced side effects.
Integrin is a type of cell adhesion receptor that exists on the cell membrane. It is a tumour-penetrating peptide, and its main function is to mediate the adhesion among cells, and between cells and extracellular matrix. Integrins form heterodimers by the non-covalent bonding of the α and β subunits. In vertebrate bodies, 18 α subunits and 8 β subunits form 24 different heterodimers. Among them, αvβ3 integrins are highly expressed on the surface of many tumour cells, such as ovarian cancer, melanoma, breast cancer, glioma and tumour-associated vascular endothelial cells, and are closely related to tumour neovascularization and metastasis.
Studies have confirmed that tripeptide sequence containing arginine-glycine-aspartic acid (RGD) can specifically recognize and bind integrins. At present, the commonly used tumour-penetrating peptide iRGD has the characteristics of simultaneously targeting tumour blood vessels and tumour cells, through tightly binding with the highly expressed integrin receptor proteins αvβ3 and αvβ5 on the membrane of tumour neovascular endothelial cells to achieve tumour targeting of anticancer drugs. (Sugahara K N, Teesalu T, Karmali P P, Kotamraju V R, Agemy L, Greenwald D R, Ruoslahti E. Coadministration of a tumour-penetrating peptide enhances the efficacy of cancer drugs. Science 2010 May 21; 328(5981):1031-5.)
The prior art discloses that tumour cells interact with organisms during the development of malignant tumours. Tumour cells use their own high mutability, on the one hand, to down-regulate the expression of immunorecognition and attack related proteins to achieve immune escape; on the other hand, to express abnormal or over-express immunosuppressive related proteins, thereby directly inhibiting tumour immune responses, or inducing the differentiation and infiltration of immunosuppressive cells. In this process, tumour cells not only overcome the recognition and killing by the immune system, but also establish a tumour immune microenvironment that can provide sufficient nutrition for its rapid growth. (Dunn G P, Bruce A T, Ikeda H, Old L J, Schreiber R D. Cancer immunoediting: from immunosurveillance to tumour escape. Nat Immunol. 2002 November; 3(11):991-8.)
It can be seen that although RGD peptides target tumour blood vessels and tumour cells, thereby enhancing the antitumour efficacy. Biological treatment of tumours is also an nonnegligible aspect. Tumour cells establish their own immune barriers, so that the body cannot recognize or kill the tumour cells. As long as there are residual tumour cells, the tumour may recur. Moreover, the ideal therapeutic effect cannot be achieved merely through a single cancer therapy.
In order to solve at least one of the aforementioned problems, the present invention provides a more effective novel tumour-targeting polypeptide.