Temperature/pH/Enzyme Triple-Responsive Cationic Protein/PAA‑b‑PNIPAAm Nanogels for Controlled Anticancer Drug and Photosensitizer Delivery against Multidrug Resistant Breast Cancer Cells

• Published in: Molecular pharmaceutics Vol. 14; no. 12; pp. 4648 - 4660
• Main Authors: Don, Trong-Ming, Lu, Kun-Ying, Lin, Li-Jie, Hsu, Chun-Hua, Wu, Jui-Yu, Mi, Fwu-Long
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 04.12.2017
• Subjects: Acrylic Resins - chemistry; Antineoplastic Agents - administration & dosage; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell Membrane Permeability; Doxorubicin - administration & dosage; Drug Carriers - chemistry; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Gels - chemistry; Humans; Hydrogen-Ion Concentration; MCF-7 Cells; Nanoparticles - chemistry; Photochemotherapy - methods; Photosensitizing Agents - administration & dosage; Protamines - chemistry; Temperature; Tumor Microenvironment - drug effects; thermoresponsive; N-isopropylacrylamide; protamine; enzymatic digestion; nanogels; pH-responsive
• ISSN: 1543-8384; 1543-8392; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.7b00737

The tumor microenvironments are often acidic and overexpress specific enzymes. In this work, we synthesized a poly­(AA-b-NIPAAm) copolymer (PAA-b-PNIPAAm) using a reversible addition–fragmentation chain transfer (RAFT) polymerization method. PAA-b-PNIPAAm and a cationic protein (protamine) were self-assembled into nanogels, which effectively reduced the cytotoxicity of protamine. The protamine/PAA-b-PNIPAAm nanogels were responsive to the stimuli including temperature, pH, and enzyme due to disaggregation of PAA-b-PNIPAAm, change in random coil/α-helix conformation of protamine, and enzymatic hydrolysis of the protein. Changing the pH from 7.4 to a lowered pHe (6.5–5.0) resulted in an increase in mean particle size and smartly converted surface charge from negative to positive. The cationic nanogels easily passed through the cell membrane and enhanced intracellular localization and accumulation of doxorubicin-loaded nanogels in multidrug resistant MCF-7/ADR breast cancer cells. Cold shock treatment triggered rapid intracellular release of doxorubicin against P-glycoprotein (Pgp)-mediated drug efflux, showing significantly improved anticancer efficacy as compared with free DOX. Furthermore, the nanogels were able to carry a rose bengal photosensitizer and caused significant damage to the multidrug resistant cancer cells under irradiation. The cationic nanogels with stimuli-responsive properties show promise as drug carrier for chemotherapy and photodynamic therapy against cancers.