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

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

EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2018

0939-6411

The use of thermoresponsive nanogels (NGs) allows the controlled release oftherapeutic molecules upon a thermal switch. Usually, this strategy involves the use of temperatureincrease to activate cargo expulsion from shrinking NGs. In this study, poly(Nisopropylacrylamide)(pNIPAM)-based NGs were involved in the release of a therapeutic proteincorona 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 ofpNIPAM, together with pH-responsive, dendritic pABC as a secondary network, in one singlenanoparticle. Semi-interpenetrated polymer network (SIPN) NGs are stable in physiologicalconditions, exhibit a reversible phase transition at 35 °C, together with tunable electrophoreticmobilities around the body temperature. The binding of A cytochrome c (cyt c) corona wassuccessful formed on SIPN NGs in their collapsed state at (37 °C). Upon cooling of the samples toroom temperature, the swelling of the NG effectively boosted the release of cyt c, as compared withthe same kept at constant 37 °C. These responsive SIPN NGs were able to deliver cyt c to cancercells and specifically induce apoptosis at 30 °C, while the cells remained largely unaffected at 37°C. In this way, we show therapeutic efficacy of thermoresponsive NGs as protein carriers and theirefficacy triggered by temperature decrease. We envision the use of such thermal trigger as relevantfor the treatment of superficial tumors, in which induction of apoptosis can be controlled by theapplication of local cooling agents.