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CN-122005422-A - Phase-change controlled-release multi-order implantable brain drug delivery device and preparation method thereof

CN122005422ACN 122005422 ACN122005422 ACN 122005422ACN-122005422-A

Abstract

The invention relates to the technical fields of biomedical engineering and brain drug delivery, in particular to a phase-change controlled-release multi-order implantable brain drug delivery device and a preparation method thereof. The system is specially designed for postoperative treatment of brain malignant tumor, and comprises a fibroin nanofiber substrate, a phase change material nanoparticle layer loaded with drugs, a degradable packaging layer and a wireless heating module. The fatty acid mixture with different melting points is used as a phase change matrix to respectively wrap a chemotherapeutic drug (such as temozolomide) and an anti-aging drug (such as ABT-263) so as to construct a nano-drug carrier with specific thermal response temperatures (such as 39 ℃ and 42 ℃). After the system is implanted into a brain tumor excision cavity, under the action of an external radio frequency magnetic field, accurate heat is generated through a wireless heating module, and the phase change material is triggered to be melted in a grading manner, so that programmed sequential release of medicines to brain tissues is realized, cooperative treatment of chemotherapy-aging cell removal in the brain is realized, the limit of blood brain barrier is effectively broken, and the problem of brain tumor recurrence is solved.

Inventors

  • ZOU HAOCHEN
  • WANG TING
  • WANG LIANHUI
  • LI TING

Assignees

  • 南京邮电大学

Dates

Publication Date
20260512
Application Date
20260210

Claims (9)

  1. 1. The phase-change controlled-release multistage implantable brain drug delivery device comprises a biological interface layer, a temperature-sensitive drug carrying layer and a wireless heating and packaging module, wherein the temperature-sensitive drug carrying layer is arranged on the biological interface layer, at least two types of phase-change material nanoparticles are arranged in the temperature-sensitive drug carrying layer and are used for wrapping chemotherapeutic drugs, at least one type of phase-change material nanoparticles are used for wrapping anti-aging drugs, the melting point of each type of phase-change material nanoparticles is different, the wireless heating and packaging module is arranged on the temperature-sensitive drug carrying layer and is used for heating the temperature-sensitive drug carrying layer under the action of an external radio frequency field, the different phase-change material nanoparticles in the temperature-sensitive drug carrying layer are promoted to sequentially melt and release the wrapped drugs, and the biological interface layer is used for forming tight conformal adhesion with the surface of a wetted brain tumor resection cavity and forming a unidirectional channel for permeation of the drugs in the temperature-sensitive drug carrying layer to brain tissues.
  2. 2. The phase-change controlled-release multistage implantable brain drug delivery device according to claim 1, wherein at least one type of inner core of the phase-change material nanoparticle is formed by blending lauric acid and stearic acid according to a mass ratio of 4:1, the melting point of the inner core is set to 39 ℃, and a chemotherapeutic drug temozolomide is wrapped in the inner core.
  3. 3. The phase-change controlled-release multistage implantable brain drug delivery device according to claim 1, wherein at least one type of inner cores of the phase-change material nanoparticles are formed by blending lauric acid and stearic acid according to a mass ratio of 2:1, the melting point is set to be 42 ℃, and the anti-aging drug wrapped inside is ABT-263.
  4. 4. The phase-change controlled-release multistage implantable brain drug delivery device according to claim 1, wherein the wireless heating and packaging module is composed of a patterned induction coil formed by depositing biodegradable metallic zinc, and is double-sided packaged by a hydrophobic polylactic acid layer for isolating cerebrospinal fluid and preventing corrosion of circuits.
  5. 5. The phase-change controlled-release multistage implantable brain drug delivery device according to claim 1, wherein the biological interface layer is a fibroin nanofiber membrane subjected to ethanol annealing treatment.
  6. 6. A method of preparing a phase-change controlled release multi-stage implantable brain drug delivery device according to any one of claims 1-5, comprising the steps of: 1) Mixing lauric acid and stearic acid according to a weight ratio of 4:1, and dissolving the lauric acid and stearic acid and the chemotherapeutic drug temozolomide in methanol together to prepare a first drug-carrying oil phase with a melting point of 39 ℃; 2) Mixing LA and SA according to a weight ratio of 2:1, and dissolving the mixture and an anti-aging drug ABT-263 in methanol to prepare a second drug-carrying oil phase with a melting point of 42 ℃; 3) Respectively dripping the first and second drug-loaded oil phases obtained in the steps 1) and 2) into lecithin/DSPE-PEG 2000 ethanol aqueous solution preheated to 50 ℃, carrying out vortex oscillation and ice water bath cooling solidification treatment, and removing an organic solvent through centrifugal cleaning to finally obtain the core-shell structure nano particles with surface modified hydrophilic layers and specific thermal response temperatures; 4) Spin-coating 7% PLA solution on a silicon wafer and drying to form a hydrophobic packaging layer, depositing a zinc layer with the thickness of 3 mu m by utilizing thermal evaporation to serve as a wireless heating circuit, spin-coating 5% PLA as an intermediate layer, and then drop-casting and fixing the two drug-carrying PCM-NPs prepared in the step 3) on the surface of the intermediate layer; 5) Spinning fibroin nanofiber membrane above the drug-carrying layer by using an electrostatic spinning technology, covering the silk membrane annealed by ethanol as a brain tissue bonding surface, processing the device into a size suitable for brain implantation by using laser cutting, and stripping to obtain a finished product.
  7. 7. The method for preparing the phase-change controlled-release multistage implantable brain drug delivery device according to claim 6, wherein in the step 3), the rotational speed of vortex oscillation is 2500-3000 rpm, the duration time is 2-3 minutes, the temperature of ice water bath cooling is controlled to be 0-4 ℃, the solidification time is 15-20 minutes, the rotational speed of centrifugal cleaning is 10000-12000 rpm, and the single centrifugal time is 10-15 minutes.
  8. 8. The method according to claim 6, wherein in the step 4), parameters of spin coating 7% PLA solution are set to be 300rpm spin coating 30 s, and parameters of spin coating 10 s and spin coating 50 s are set to be 300rpm spin coating 50 rpm spin coating s, and drying conditions are set to be 12 h volatilized at room temperature.
  9. 9. The method for preparing a phase-change controlled-release multi-stage implantable brain drug delivery device according to claim 6, wherein in the step 5), the advancing rate of the electrostatic spinning solution is 0.3-0.5 mL/h, the receiving distance is 12-15 cm, and the ethanol annealing treatment time is 120 s.

Description

Phase-change controlled-release multi-order implantable brain drug delivery device and preparation method thereof Technical Field The invention relates to the technical fields of biomedical engineering and brain drug delivery, in particular to a phase-change controlled-release multi-order implantable brain drug delivery device and a preparation method thereof. Background Brain diseases, particularly Glioblastoma (GBM), are central nervous system diseases with extremely high mortality. Current clinical standard treatments typically employ surgical excision supplemented with Temozolomide (TMZ) systemic chemotherapy. However, the presence of a specific Blood Brain Barrier (BBB) in the brain severely impedes the passage of drugs from the blood into brain tissue, resulting in low effective blood levels in the brain. Meanwhile, TMZ can induce tumor cells remained in brain tissues to enter an aging state (treatment-Induced Senescence, TIS) while killing the tumor cells, and factors secreted by the aging cells can accelerate the recurrence of brain tumors. The existing brain implantable drug delivery system (such as GLIADEL WAFER) can directly release drugs in the brain, but can only passively diffuse single drugs, so that accurate control of the release time and sequence of the drugs cannot be realized, and complex combined treatment schemes of chemotherapy and anti-aging cannot be matched. Thus, there is a strong need for a degradable intelligent system that can be implanted into the brain, wireless regulation, achieve multi-stage programmed dosing, and not cause brain tissue damage. Disclosure of Invention The invention aims to solve the technical problem of providing a phase-change controlled-release multi-order implantable brain drug delivery device, and aims to solve the problem that the prior art is difficult to accurately control multi-drug sequential release in the brain. The technical scheme includes that the phase-change controlled-release multistage implantable brain drug delivery device comprises a biological interface layer, a temperature-sensitive drug carrying layer and a wireless heating and packaging module, wherein the temperature-sensitive drug carrying layer is arranged on the biological interface layer, at least two types of phase-change material nanoparticles (PCM-NPs) which are mixed and solidified are arranged in the temperature-sensitive drug carrying layer and are used for wrapping chemotherapeutic drugs, at least one type of phase-change material nanoparticles are used for wrapping anti-aging drugs, the melting point of each type of phase-change material nanoparticles is different, the wireless heating and packaging module is arranged on the temperature-sensitive drug carrying layer and is used for heating the temperature-sensitive drug carrying layer under the action of an external radio frequency field, the different phase-change material nanoparticles in the temperature-sensitive drug carrying layer are promoted to sequentially melt and release wrapped drugs, and the biological interface layer is used for forming tight conformal fit with the surface of a wetted brain tumor resection cavity and forming a unidirectional channel for permeation of the drugs in the temperature-sensitive drug carrying layer to brain tissues. Preferably, at least one type of inner core of the phase change material nano-particles is formed by blending lauric acid and stearic acid according to a mass ratio of 4:1, the melting point of the inner core is set to be 39 ℃, and the chemotherapeutic drug temozolomide is wrapped in the inner core. Preferably, at least one type of inner core of the phase change material nano-particles is formed by blending lauric acid and stearic acid according to a mass ratio of 2:1, the melting point is set to be 42 ℃, and the anti-aging medicine wrapped inside is ABT-263. Preferably, the wireless heating and packaging module is composed of a patterned induction coil formed by depositing biodegradable metallic zinc, and is packaged by a hydrophobic polylactic acid (PLA) layer on both sides, so as to isolate cerebrospinal fluid and prevent circuit corrosion. Preferably, the biological interface layer adopts a fibroin nanofiber membrane subjected to ethanol annealing treatment. Preferably, the method comprises the steps of: 1) Lauric acid (Lauric Acid, LA) and stearic acid (STEARIC ACID, SA) are mixed according to a weight ratio of 4:1, and are dissolved in methanol together with a chemotherapeutic drug Temozolomide (TMZ) to prepare a first drug-loaded oil phase with a melting point of 39 ℃; 2) Mixing LA and SA according to a weight ratio of 2:1, and dissolving the mixture and an anti-aging drug ABT-263 in methanol to prepare a second drug-carrying oil phase with a melting point of 42 ℃; 3) Respectively dripping the first and second drug-loaded oil phases obtained in the steps 1) and 2) into lecithin/DSPE-PEG 2000 ethanol aqueous solution preheated to 50 ℃, cooling and solidifying the