title: Peptide mediated active targeting and intelligent particle size reduction-mediated enhanced penetrating of fabricated nanoparticles for triple-negative breast cancer treatment.
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.
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Guanlian
authors.initials: G
authors.lastname: Hu
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Xingli
authors.initials: X
authors.lastname: Chun
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: He
authors.affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.|State Key Laboratory of Molecular Engineering of Polymers (Fudan University), Shanghai 200433, China.
authors.forename: Huile
authors.initials: H
authors.lastname: Gao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D050091:Dendrimers / Q000737:chemistry; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010316:Particle Size; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011107:Polylysine / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: C531860:Angiopep-2; D050091:Dendrimers; D010455:Peptides; D011107:Polylysine; D004317:Doxorubicin; D020778:Matrix Metalloproteinase 2
keywords: active targeting; gelatin nanoparticles; particle size reduction; triple-negative breast cancer; tumor penetration