Peptide-Functionalized Hydrogel Cubes for Active Tumor Cell Targeting

• Published in: Biomacromolecules 2018-10, Vol.19 (10), p.4084-4097
• Main Authors: Xue, Bing, Kozlovskaya, Veronika, Sherwani, Mohammad Asif, Ratnayaka, Sithira, Habib, Shahriar, Anderson, Theron, Manuvakhova, Marina, Klampfer, Lidija, Yusuf, Nabiha, Kharlampieva, Eugenia
• Format: Article
• Language: English
• Subjects: Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - chemistry; Cell Survival; Doxorubicin - administration & dosage; Doxorubicin - chemistry; Drug Carriers - chemistry; Drug Delivery Systems; Humans; Hydrogels - chemistry; Neoplasms - drug therapy; Neoplasms - pathology; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Polymers - chemistry; Polymethacrylic Acids - chemistry; Serine Endopeptidases - chemistry; Serine Endopeptidases - metabolism; Tumor Cells, Cultured
• ISSN: 1525-7797; 1526-4602
• DOI: 10.1021/acs.biomac.8b01088

Conjugation of bioactive targeting molecules to nano- or micrometer-sized drug carriers is a pivotal strategy to improve their therapeutic efficiency. Herein, we developed pH- and redox-sensitive hydrogel particles with a surface-conjugated cancer cell targeting ligand for specific tumor-targeting and controlled release of the anticancer drug doxorubicin. The poly­(methacrylic acid) (PMAA) hydrogel cubes of 700 nm and 2 μm with a hepsin-targeting (IPLVVPL) surface peptide are produced through multilayer polymer assembly on sacrificial cubical mesoporous cores. Direct peptide conjugation to the disulfide-stabilized hydrogels through a thiol-amine reaction does not compromise the structural integrity, hydrophilicity, stability in serum, or pH/redox sensitivity but does affect internalization by cancer cells. The cell uptake kinetics and the ultimate extent of internalization are controlled by the cell type and hydrogel size. The peptide modification significantly promotes the uptake of the 700 nm hydrogels by hepsin-positive MCF-7 cells due to ligand–receptor recognition but has a negligible effect on the uptake of 2 μm PMAA hydrogels. The selectivity of 700 nm IPLVVPL-PMAA hydrogel cubes to hepsin-overexpressing tumor cells is further confirmed by a 3–10-fold higher particle internalization by hepsin-positive MCF-7 and SK-OV-3 compared to that of hepsin-negative PC-3 cells. This work provides a facile method to fabricate enhanced tumor-targeting carriers of submicrometer size and improves the general understanding of particle design parameters for targeted drug delivery.