Silk-based Microneedles For Intracranial Drug Delivery

Glioblastoma(GBM)is currently one of the most common and deadly intracranial malignant tumors,which is characterized by invasive growth leading to no borders with normal tissues.Standard treatment of aggressive GBM mainly relies on surgical resection within a safe range,in combination with radiotherapy and/or chemotherapy.However,chemotherapeutic drugs are difficult to reach the tumor area because of the blood-brain barrier.During the treatment process,the drugs often damage normal tissues more than tumor tissues,which will bring great side effects to the human body.Local chemotherapy has received widespread attention for its ability to overcome limitations of the blood-brain barrier and maintain a longer effective drug dose at the tumor site while greatly reducing systemic toxicity.However,many challenges still remain,such as the deep penetration required for drugs to reach infiltrating tumor cells,the lack of multi-drug delivery capacity with different release kinetics in a single device,occurrence of neurological disorders arising from mismatch between the rigid intracerebral implant and soft brain issues,and side effects caused by degradation products.To accomplish these challenges,we report a heterogenous silk fibroin microneedle(SMN)patch for circumventing the blood-brain barrier and releasing multiple drugs directly to the tumor site for synergistic treatment.The main work of this paper are presented below:1.Silk protein is a natural biopolymer renowned for its excellent biocompatibility,controllable degradation,adjustable mechanical properties and the ability to be compatible with micro-nano processing technology.In this study,silk protein was used as the carrier material,combined with advanced inkjet printing technology to integrate thrombin(hemostatic drug),bevacizumab(angiogenesis inhibitor),and temozolomide(anticancer drug)into a microneedle patch.Compared with other intracranial drug delivery devices,the microneedle patch can not only directly penetrate deep into the tissue for drug delivery,but also realize the combined delivery of multiple drugs and enhance the therapeutic effect.In addition,the use of inkjet printing technology facilitates the precise integration of multiple drug molecules in the silk protein microneedle array according to requirements-different drug types and dosages.2.The aqueous solubility of silk protein can be regulated by ethanol annealing,which can regulate the degradation rate of SMNs for temporally controllable multi-drug release.In this work,the conformation of silk substrate and microneedles in the center and surrounding region were respectively administrated by ethanol annealing,which is based on the character of silk protein.In addition,thanks to its superior mechanical properties,the flexible silk protein microneedle patch can penetrate the brain tissue firmly and conformally adhere to the curved brain surface.3.We established a method that uses NIR light to trigger photo-thermal effects and activate enzyme-induced silk protein degradation,ultimately allowing remotely controlled drug delivery,which is based on the objective requirement that the tissues need a certain time to recover and regenerate after surgical operation.This method achieves the programmable release of bevacizumab at two weeks after surgery,which inhibits the proliferation of blood vessels in the tumor area without affecting tissue recovery,and leads to its apoptosis by cutting off the nutrient supply of the tumor.4.We further evaluated therapeutic efficacy of the SMN patch with multiple drugs in vivo by using the human xenograft GBM model with immune-deficient mice.The reduction in tumor volume and the prolong survival period of mice confirmed the good therapeutic effect of the heterogeneous silk protein microneedle patch.The study indicated that the multi-drug SMN patch provides a promising pathway for the in situ treatment of GBM with improved efficiency.