Enhancing Accumulation and Penetration of HPMA Copolymer–Doxorubicin Conjugates in 2D and 3D Prostate Cancer Cells via iRGD Conjugation with an MMP‑2 Cleavable Spacer

• Published in: Journal of the American Chemical Society 2015-06, Vol.137 (21), p.6726-6729
• Main Authors: Peng, Zheng-Hong, Kopeček, Jindřich
• Format: Article
• Language: English
• Subjects: Acrylamides - chemistry; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - metabolism; Antibiotics, Antineoplastic - pharmacology; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Doxorubicin - chemistry; Doxorubicin - metabolism; Doxorubicin - pharmacology; Drug Carriers - chemistry; Drug Screening Assays, Antitumor; Humans; Male; Matrix Metalloproteinase 2 - chemistry; Matrix Metalloproteinase 2 - metabolism; Molecular Structure; Oligopeptides - chemistry; Oligopeptides - metabolism; Polymers - chemistry; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Structure-Activity Relationship
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.5b00922

To enhance the accumulation and penetration of nanomedicines in tumor tissue, we developed and evaluated the biological properties of matrix metallo­proteinase 2 (MMP-2)-responsive N-(2-hydroxy­propyl)­meth­acryl­amide (HPMA) copolymer drugs and tumor-penetrating peptide conjugates (P-DOX-PLGLAG-iRGD). Two different spacers were used in the design: a lysosomally (cathepsin B) cleavable tetrapeptide GFLG spacer conjugated doxorubicin (DOX) to HPMA copolymer, and an MMP-2-degradable linker (PLGLAG) connected tumor-homing and -penetrating cyclic peptide iRGD to HPMA copolymer. The accumulation of DOX in P-DOX-PLGLAG-iRGD-treated monolayer (2D) and multilayer (3D) DU-145 prostate cancer cells was higher than that of control groups (P-DOX and P-DOX + iRGD). The cell cycle arrest analysis and cytotoxicity data demonstrated that P-DOX-PLGLAG-iRGD produced a higher G2/M arrest and possessed stronger cytotoxicity against DU-145 cells than P-DOX + iRGD or P-DOX, which was consistent with the drug uptake results. Similarly, P-DOX-PLGLAG-iRGD demonstrated the highest penetration ability in 3D multicellular DU-145 tumor cell spheroids. The results indicate that covalent conjugation of iRGD via MMP-2-sensitive bonds enhances accumulation and penetration of nanomedicines into tumor cell monolayers and spheroids.