Development of Iontronic Implants Using Hyperbranched Polymeric Membranes for Localized Drug Delivery in Chemotherapy

Hard-to-treat tumors (HTTs) remain an unmastered medical challenge. Very often, limited operability, as well as lacking efficiency of systemically administered chemotherapeutics in already weakened patients lead to devastating diagnosis and reduced life expectancy. Bioelectronic implants for local chemo drug delivery can optimize drug concentrations at the tumor site, the duration of treatment and the tumor suppression, while systemic effects remain at an acceptable low level.<br/>Here we present miniature devices for iontronic drug delivery able to administer chemotherapeutics via electric control with high spatiotemporal precision. Incorporated in these devices are anionic hyperbranched polyglycerol membranes (AHPGs), forming an ion selective matrix of multiple fixed negative charges. Through this polymeric ion exchange membrane, drugs electromigrate in an electric field towards a target of choice.<br/>These engineered devices, called chemotherapy ion pumps (chemoIPs), are here used for the delivery of chemotherapeutics and their performance was monitored via voltage-current measurements and evaluated based on the drug delivery rates. chemoIP treatment efficiency was evaluated in different brain tumor models with increasing complexity (from simple cell culture monolayers of cells, up to more complex <i>in vivo</i> models) and cell death, tumor suppression and drug distribution were analyzed. We furthermore observed the extent of noxious effects of chemotherapeutics in healthy populations of the brain – neurons and astrocytes - doing a whole proteome analysis with mass spectrometry.<br/>AHPG ion exchange membranes enable drug delivery with pmol*min^-1 delivery precision at currents in the nano-ampere range. The further application of this electrical and temporal control was shown in brain tumor cell culture, triggering the disintegration of targeted tumor spheroids among chemoIP treatment. Chosen chemotherapeutics furthermore trigger cellular effects suitable for the application in the brain: effectively killing brain tumor cells while being harmless for neurons and astrocytes. Additionally, we show preliminary results indicating that chemoIP treatment significantly reduces the tumor size of vascularized brain tumors.<br/>The here exemplified electrically-driven drug delivery via chemoIPs is a drug administration method that can serve as basis for further implant development, which has the potential to increase the efficacy of chemotherapy due to highly-targeted and locally-controlled drug delivery.