Periodic Reporting for period 1 - bioSWITCH (Bioorthogonal Implantable Iontronic Switch to Temporally Control the Local Release of Chemotherapeutics)
Période du rapport: 2023-03-01 au 2024-02-29
Our vision for a new type of cancer treatment is based on an implantable therapeutic system capable of ‘programmable’ on-demand delivery of drugs directly to the tumor. We conceive an implantable iontronic switch (bioSWITCH) to enable a spatiotemporally controlled administration of highly potent chemotherapeutics, without the need for systemic administration of (pro)drugs or drug conjugates.
This radically new technology will be realized by a combination of next-level tools: An i) iontronic pump enables electrophoretic transport of a ii) bioorthogonal chemical trigger (T) into a ii) chemogel modified with a iv) click-activatable drug (D) to release chemotherapeutics with electronic precision and full control of the local concentration/time profile. As a result, bioSWITCH can generate previously unobtainable discrete as well as continuous drug concentration profiles at the tumor site, and thus allows for the use of highly potent drugs that are otherwise not applicable due to high cytotoxicity. The goal is to demonstrate the technology’s potential to effectively interfere with tumor progression using a xenograft pancreas cancer mouse model. Efficiently shrinking tumors in size allows for surgical resection of previously non-operable tumors and dramatically increases survival rates. Ultimately, the combination of local drug delivery (space) and chronopharmacological aspects (time) elevates medicine to the 4th dimension and will initiate an evolutionary leap in the field of cancer therapies and medicine by delivering optimized drug doses, precisely tuned to the individual’s chronotype to maximize treatment efficacy while substantially minimizing, if not completely preventing, severe off-target effects.
Our consortium of world leading academics and pioneering SMEs will ensure the translation of this disruptive technology into the market to maximize the socioeconomic impact.
This radically new technology will be realized by a combination of next-level tools: An i) iontronic pump enables electrophoretic transport of a ii) bioorthogonal chemical trigger (T) into a ii) chemogel modified with a iv) click-activatable drug (D) to release chemotherapeutics with electronic precision and full control of the local concentration/time profile. As a result, bioSWITCH can generate previously unobtainable discrete as well as continuous drug concentration profiles at the tumor site, and thus allows for the use of highly potent drugs that are otherwise not applicable due to high cytotoxicity. The goal is to demonstrate the technology’s potential to effectively interfere with tumor progression using a xenograft pancreas cancer mouse model. Efficiently shrinking tumors in size allows for surgical resection of previously non-operable tumors and dramatically increases survival rates. Ultimately, the combination of local drug delivery (space) and chronopharmacological aspects (time) elevates medicine to the 4th dimension and will initiate an evolutionary leap in the field of cancer therapies and medicine by delivering optimized drug doses, precisely tuned to the individual’s chronotype to maximize treatment efficacy while substantially minimizing, if not completely preventing, severe off-target effects.
Our consortium of world leading academics and pioneering SMEs will ensure the translation of this disruptive technology into the market to maximize the socioeconomic impact.
#1: Implantable iontronic devices
An 8-channel, well-plate compatible platform utilizing a semi-automated measurement system was created to optimization and investigate device performance, geometry, and switching speeds. We successfully developed planar- and capillary device designs which are used for extensive testing the chemical compounds and guide design aspects of the implant devices. The planar platform enables accurate patterning and multiple ion pump outlets on flexible substrates, while capillary ion pumps benefit from a straightforward, durable design utilizing proven 3D-printing methods but are limited to a single ion pump outlet. Tetrazine pumping speeds of ~7 and ~ 30 pmol/min were achieved for capillary devices using 20 nA and 100 nA settings respectively.
#2: Drug-loaded chemogels
A click-cleavable bioorthogonal linker was successfully modified with several fluorophores. Therefore, synthetic procedures were developed to obtain fluorescent and fluorogenic conjugates. Respective dye-loaded hydrogels were prepared via incorporation of these compounds to obtain the target materials required for further investigations towards the assembly of drug-loaded hydrogels (chemogels).
#3: bioSWITCH in vitro
Preliminary iontronic prodrug toxicity experiments using pancreatic tumor cells yielded the desired outcome; i.e. the iontronically activated prodrug is as effective as the parent drug. This result confirms our hypothesis that the bioSWITCH concept will allow drug delivery with electronic precision and control.
#4: Iontronic in vivo chemistry
Preliminary tests using chorioallantoic membrane of chick embryos as tumor models demonstrated the bioSWITCH effect in vivo.
An 8-channel, well-plate compatible platform utilizing a semi-automated measurement system was created to optimization and investigate device performance, geometry, and switching speeds. We successfully developed planar- and capillary device designs which are used for extensive testing the chemical compounds and guide design aspects of the implant devices. The planar platform enables accurate patterning and multiple ion pump outlets on flexible substrates, while capillary ion pumps benefit from a straightforward, durable design utilizing proven 3D-printing methods but are limited to a single ion pump outlet. Tetrazine pumping speeds of ~7 and ~ 30 pmol/min were achieved for capillary devices using 20 nA and 100 nA settings respectively.
#2: Drug-loaded chemogels
A click-cleavable bioorthogonal linker was successfully modified with several fluorophores. Therefore, synthetic procedures were developed to obtain fluorescent and fluorogenic conjugates. Respective dye-loaded hydrogels were prepared via incorporation of these compounds to obtain the target materials required for further investigations towards the assembly of drug-loaded hydrogels (chemogels).
#3: bioSWITCH in vitro
Preliminary iontronic prodrug toxicity experiments using pancreatic tumor cells yielded the desired outcome; i.e. the iontronically activated prodrug is as effective as the parent drug. This result confirms our hypothesis that the bioSWITCH concept will allow drug delivery with electronic precision and control.
#4: Iontronic in vivo chemistry
Preliminary tests using chorioallantoic membrane of chick embryos as tumor models demonstrated the bioSWITCH effect in vivo.
First iontronically controlled bioorthogonal reaction, capable of achieving produg activation with electronic precision.