Semi-interpenetrated, dendritic, dual-responsive nanogels with cytochrome c corona induce controlled apoptosis in HeLa cells

ENRICO MICELI; STEFANIE WEDEPOHL; ERNESTO RAFAEL OSORIO BLANCO; GUIDO NOÉ RIMONDINO; MARISA MARTINELLI; MIRIAM STRUMIA; MARIA MOLINA; MRITYUNJOY KAR; CALDERON MARCELO

EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2018 vol. 130 p. 115 - 122

0939-6411

The use of thermoresponsive nanogels (NGs) allows the controlled release of therapeutic molecules upon athermal switch. Usually, this strategy involves the use of temperature increase to activate cargo expulsion fromshrinking NGs. In this study, poly(N-isopropylacrylamide) (pNIPAM)-based NGs were involved in the release of atherapeutic protein corona by temperature decrease. NGs based on dendritic polyglycerol (dPG) and thermoresponsivepNIPAM were semi-interpenetrated with poly(4-acryloylamine-4-(carboxyethyl)heptanodioic acid)(pABC). The resulting semi-interpenetrated NGs retain the thermoresponsive properties of pNIPAM, togetherwith pH-responsive, dendritic pABC as a secondary network, in one single nanoparticle. Semi-interpenetratedpolymer network (SIPN) NGs are stable in physiological conditions, exhibit a reversible phase transition at 35 °C,together with tunable electrophoretic mobilities around the body temperature. The binding of cytochrome c (cytc) was successful on SIPN NGs in their collapsed state at 37 °C. Upon cooling of the samples to room temperature,the swelling of the NG effectively boosted the release of cyt c, as compared with the same kept at constant 37 °C.These responsive SIPN NGs were able to deliver cyt c to cancer cells and specifically induce apoptosis at 30 °C,while the cells remained largely unaffected at 37 °C. In this way, we show therapeutic efficacy of thermoresponsiveNGs as protein carriers and their efficacy triggered by temperature decrease. We envision the use ofsuch thermal trigger as relevant for the treatment of superficial tumors, in which induction of apoptosis can becontrolled by the application of local cooling agents.