Abstract
Triple-negative breast cancer (TNBC) is one of the most invasively malignant human cancers and its incidence increases year by year. Effective therapeutics against them needs to be developed urgently. In this study, a kind of angiopep-2 modified and intelligently particle size-reducible NPs, Angio-DOX-DGL-GNP, was designed for accomplishing both high accumulation and deep penetration within tumor tissues. On one hand, for improving the cancerous targeting efficiency of NPs, angiopep-2 was anchored on the surface of NPs to facilitate their accumulation via binding with low density lipoprotein-receptor related protein (LRP) overexpressed on TNBC. On the other hand, for achieving high tumor retention and increasing tumor penetration, an intelligently particle size-reducible NPs were constructed through fabricating gelatin NPs (GNP) with doxorubicin (DOX) loaded dendrigraft poly-lysine (DGL). In vitro cellular uptake and ex-vivo imaging proved the tumor targeting effect of Angio-DOX-DGL-GNP. Additionally, the degradation of large-sized Angio-DOX-DGL-GNP by matrix metalloproteinase-2 (MMP-2) led to the size reduction from 185.7 nm to 55.6 nm. More importantly, the penetration ability of Angio-DOX-DGL-GNP after incubation with MMP-2 was dominantly enhanced in tumor spheroids. Due to a combinational effect of active targeting and deep tumor penetration, the tumor growth inhibition rate of Angio-DOX-DGL-GNP was 74.1% in a 4T1 breast cancer bearing mouse model, which was significantly higher than other groups. Taken together, we successfully demonstrated a promising and effective nanoplatform for TNBC treatment.
Highlights
Triple-negative breast cancer (TNBC), which does not express or express low levels of estrogen receptor, progesterone receptor and HER2/neu, is one of the most invasively malignant human cancers and its incidence increases year by year [1, 2]
The activated carboxyl groups of cis-aconitic anhydride-doxorubicin (CAD) were grafted on the amino groups of Angio-dendrigraft poly-lysine (DGL)-PEG via amide linkage to obtain the final product: Angio-DOX-DGL-PEG
The results showed that the size of Angio-DOX-DGL-gelatin NPs (GNP) could reduce from 185.7 nm to 55.6 nm, indicating GNP could be degraded into small fragments by matrix metalloproteinase-2 (MMP-2) as previous study showed [41, 42]
Summary
Triple-negative breast cancer (TNBC), which does not express or express low levels of estrogen receptor, progesterone receptor and HER2/neu, is one of the most invasively malignant human cancers and its incidence increases year by year [1, 2]. After accumulating around tumors, NPs faced vastly diffusional hinderance due to the presence of the compressed intratumoral blood and lymphatic vessels and the dense collagenrich extracellular matrix (ECM) They were always unable to access into the nonvascularized and anoxic regions within deep tumor parenchyma, and the cancerous cells of core area are still aggressively survived, resulting in chemotherapeutic bland and latent crisis for tumor metastasis and regeneration [8, 9]. Angio-DOX-DGL-GNP could effectively accumulate around in tumor sites through passive and active tumor targeting [22, 23]. Our in vitro and in vivo results indicated that Angio-DOX-DGLGNP possessed notable tumor accumulation and penetration abilities, maximizing antitumor effect
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