CN114849039A - Bionic robot system for intestinal drug delivery and preparation method and application thereof - Google Patents
Bionic robot system for intestinal drug delivery and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a worm-like bionic robot system for intestinal drug delivery and a preparation method and application thereof, and relates to the technical field related to biomedical treatment instruments. The bionic insect-like robot system comprises a conical head, a cylindrical body and a spiral tail which are mutually connected to form a swimmer model, wherein a mixed system of near-infrared light thermal-responsive nano particles and medicines is loaded in the conical head and the cylindrical body, a carrying bin is further arranged in the cylindrical body, and a magnetic control device is placed in the carrying bin. The magnetic drive type worm bionic 'swimmer' robot composed of the conical head, the cylindrical body and the spiral tail can resist gastric acid and other obstacles, can reach a fixed point part of an intestinal tract in a targeted mode under the action of a magnetic field, responds to near-infrared irradiation, releases medicines of the head and the body simultaneously, generates active medicines through in-situ reaction, achieves time-space controllability and safe intestinal tract administration, reduces toxic and side effects, and effectively treats intestinal tract diseases.
Description
Technical Field
The invention relates to the technical field related to biomedical therapeutic instruments, in particular to a bionic robot system for intestinal drug delivery and a preparation method and application thereof.
Background
Enteral administration remains the most common method of administration today, in contrast to parenteral administration (intravenous, intramuscular, subcutaneous). Oral drugs can deliver drugs to the gastrointestinal tract noninvasively, more than 80% of drugs are orally taken for various disease treatments, and compared with injection, the oral drugs have low infection risk, low systemic side effect and simple use method. However, due to various factors such as the complex physiological environment of the gastrointestinal tract, the strong acid environment (pH of 1-5) of the stomach, various proteases, microbial flora, food residues and the like in the intestinal tract, and due to the fact that many oral drugs do not have a proper pharmaceutical preparation form, the defects of low bioavailability, high toxic and side effects and the like exist due to different effective action parts and other factors, and the clinical application of an oral administration route is severely limited.
Inflammatory Bowel Diseases (IBD), such as crohn's disease and ulcerative colitis, are chronic, recurring diseases of the gastrointestinal tract that are pathologically characterized by intestinal inflammation and epithelial damage. These diseases begin with inflammation and ultimately can lead to a variety of complications such as diarrhea, rectal bleeding, and colon cancer. The number of people in clinic is on the rapid rise trend for more than 20 years. There are a number of drugs currently used to treat the disease, such as conventional sulfasalazine (SASP) and various other types of 5-aminosalicylic acid (5-ASA) preparations, as well as hormonal drugs such as prednisone. According to guidance and consensus of IBD, SASP orally taken still is the main treatment drug at present, but has more adverse reactions, such as headache, gastrointestinal symptoms of nausea, vomiting, diarrhea and the like, and lacks the effect of targeted intestinal therapy.
The optical window of the biological tissue is positioned in the wavelength range of near infrared light, the scattering, absorption and autofluorescence of the tissue are lower in the near infrared region (700-900 nm), and the maximum penetration depth of the biological tissue can be realized while the phototoxicity to normal cell tissue is reduced. Medical micro/nano robots have received great interest over the past decades because they have great promise for biomedical applications because they can be controlled to navigate directionally into hard-to-reach tissues, with the main driving mechanisms of these swimmers being via external magnetic fields, ultrasound, chemical, etc. forces. The magnetic permeability of a human body is approximately the same as that of air vacuum, the magnetic field is transparent, and the low-frequency magnetic field has good biological safety, so that the time and space of the swimmer in the body can be accurately regulated and controlled by utilizing the magnetic field.
Based on the reasons, the invention prepares the magnetic drive type insect bionic 'swimmer' robot which is composed of a head part, a body part and a tail part. The magnetic control robot can resist gastric acid and other obstacles, reaches a fixed-point part of an intestinal tract in a targeted manner under the action of a magnetic field, responds to near-infrared irradiation and releases the medicines of the head part and the body part at the same time, generates active medicines through in-situ reaction, realizes time-space controllability and safe intestinal tract administration, reduces toxic and side effects, and effectively treats intestinal tract diseases.
Disclosure of Invention
The invention provides a bionic robot system for delivering a road drug, and a preparation method and application thereof, and aims to solve the problems in the background technology.
In order to achieve the technical purpose, the invention mainly adopts the following technical scheme:
a worm-like bionic robot system for intestinal drug delivery comprises a conical head, a cylindrical body and a spiral tail which are mutually connected to form a swimmer model, wherein a mixed system of near-infrared light thermal-responsive nano particles and drugs is loaded in the conical head and the cylindrical body, a loading bin is further arranged in the cylindrical body, and a magnetic control device is placed in the loading bin.
In the invention, the conical head of the swimmer model is 4-8 mm high, and the diameter of the bottom of the swimmer model is 10-14 mm; the height of the cylindrical body of the swimmer model is 4-8 mm, and the diameter of the bottom of the cylindrical body is 10-14 mm; the length of the spiral tail of the swimmer model is 3-18 mm, and the number of spiral turns is 1-6.
Furthermore, the carrying bin is a cuboid empty bin, the length of the carrying bin is 5-10 mm, the width of the carrying bin is 2.5-5 mm, the depth of the carrying bin is 2-5.5 mm, and the length of the magnetic control device is 5-10 mm and the diameter of the magnetic control device is 2.5-5 mm.
As one embodiment of the invention, the near infrared light thermal response nanoparticles in the mixed system are gold-nanodot-modified hollow carbon nanospheres, the particle size is 120-200 nm, the weight of the near infrared light thermal response nanoparticles loaded on a single swimer model is 100-200 micrograms, and the near infrared light thermal response nanoparticles pass through the swimer and then are 2W/cm 2 After power irradiation for 3-5 min, the temperature can be raised to over 60 deg.C.
Preferably, the mixed system is also added with Eudragit L-100, and has gastric acid resistant property.
Preferably, polycaprolactone is also added into the mixed system, and the phase transition temperature of the polycaprolactone is about 50 to 60 ℃.
Preferably, dichloromethane and absolute ethyl alcohol are sequentially added into the mixed system, and the volume ratio of the dichloromethane to the absolute ethyl alcohol is 1: 1-3: 1.
the invention also provides a preparation method of the insect-like bionic robot system for intestinal drug delivery, which comprises the following steps:
the method comprises the following steps: designing an original swimmer model structure by utilizing solidworks software, and respectively printing a conical head, a cylindrical body and a spiral tail of the swimmer model by using a 3D printer and taking polylactic acid as a material;
step two: according to the structures of the conical head part and the cylindrical body part which are printed by 3D, polydimethylsiloxane is used for respectively constructing PDMS molds for carrying a mixed system in the conical head part and the cylindrical body part;
step three: adding the prepared mixed system of the near-infrared light thermal response nano particles and the medicine into PDMS molds of the conical head part and the cylindrical body part, then respectively inserting the head part and the body part structures of 3D printing into the PDMS molds, putting the PDMS molds into an oven for drying, and then stripping the PDMS molds;
step four: the magnetic control device is arranged in the cylindrical body part carrying bin, and the head body and the tail body are bonded by using glue or an adhesive tape.
Further, the conical head part PDMS mold is 4-8 mm high and 12-16 mm in bottom diameter, and the cylindrical body part PDMS mold is 4-8 mm high and 13-17 mm in bottom diameter; the oven temperature is 37 ℃, and the drying time is 180 minutes.
Another object of the present invention is to provide an application of the above insect-like bionic robot system for intestinal drug delivery in intestinal drug delivery.
Compared with the prior art, the invention has the following beneficial effects:
the magnetic drive type worm bionic 'swimmer' robot comprises a conical head part, a cylindrical body part and a spiral tail part, has the characteristics of a worm and a helicobacter, can resist gastric acid and other obstacles, can reach a fixed-point part of an intestinal tract in a targeted mode under the action of a magnetic field, responds to near-infrared irradiation, releases medicines of the head part and the body part at the same time, generates active medicines through in-situ reaction, achieves time-space controllability and safe intestinal tract administration, reduces toxic and side effects, and effectively treats intestinal tract diseases.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention without limiting the invention in which:
FIG. 1 is a diagram of a conical head, a cylindrical body and a spiral tail of a swimmer model printed by using polylactic acid (PLA) as a material and an integral bonding object;
in the figure: 1. a head portion; 2. a body portion; 3. a tail portion;
FIG. 2 is a diagram of a robot moving under the magnetic control driving of an external magnetic field;
FIG. 3 is a diagram of the head and body and the various components carried thereon;
FIG. 4 is a graph of near-infrared responsive temperature rise and thermal responsive drug release from a robot head;
FIG. 5 is a graph of in vitro antioxidant and anti-inflammatory experiments with the head and body of a robot loaded with a prodrug and an activator, respectively;
FIG. 6 is a diagram of a real object moving in the rabbit's blind intestine by the bionic robot;
fig. 7 is a graph showing the in vivo therapeutic effect of the insect-like biomimetic robot system in an inflammatory bowel disease model.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Referring to fig. 1, the present invention provides a worm-like bionic robot system for intestinal drug delivery, comprising a conical head 1, a cylindrical body 2 and a spiral tail 3, which are connected to each other to form a swimmer model, wherein the conical head 1 of the swimmer model is 4-8 mm high and the bottom diameter is 10-14 mm; the height of the cylindrical body 2 of the swimmer model is 4-8 mm, and the diameter of the bottom of the cylindrical body is 10-14 mm; the length of the spiral tail 3 of the swimmer model is 3-18 mm, the number of spiral turns is 1-6, and the spiral tail 3 can be regulated and controlled.
The conical head part 1 and the cylindrical body part 2 are internally loaded with a mixed system of near infrared light thermal response nano particles and medicaments, the near infrared light thermal response nano particles in the mixed system are hollow carbon nanospheres (AuHCN) modified by gold nano points, the particle size is 120 plus 200 nanometers, the weight of the near infrared light thermal response nano particles loaded on a single SWIMER model is 100 plus 200 micrograms, and the near infrared light thermal response nano particles are loaded into a SWIMER rear model and 2W/cm 2 After power irradiation for 3-5 min, the temperature can be raised to over 60 deg.C. Further adding Eudragit L-100(EUD L-100) to the mixed system, and has gastric acid resistant property; polycaprolactone (PCL) is added, and the phase transition temperature is about 50-60 ℃.
The cylindrical body 2 is also internally provided with a carrying bin which is a cuboid empty bin with the length of 5-10 mm, the width of 2.5-5 mm and the depth of 2-5.5 mm, and a magnetic control device is placed in the carrying bin, the length of the magnetic control device is 5-10 mm, and the diameter of the magnetic control device is 2.5-5 mm.
Example 2
The embodiment provides a preparation method of a worm-like bionic robot system for intestinal drug delivery, which comprises the following steps:
1. 3D printing of swimmer structure
Utilize solidworks software design swimmer model's conical head, cylindrical body and spiral afterbody triplex structure, wherein, conical head is high 6 millimeters, bottom diameter 12 millimeters, cylindrical body is high 6 millimeters, bottom diameter 12 millimeters, the somatic part is carried the storehouse and is cuboid empty storehouse, long 10 millimeters, wide 5 millimeters, dark 5.3 millimeters, the spiral afterbody includes that the pitch is 4 helicoidal of 3 millimeters, utilize polylactic acid (PLA) material to print respectively through the 3D printer.
2. Preparation of PDMS mold for carrying
A structure with a conical height of 6.1 mm and a bottom diameter of 13.8 mm, a structure with a cylindrical height of 6 mm and a bottom diameter of 15.8 mm are designed by utilizing solidworks software, and are respectively fixed on a cell culture dish of 3.5cm, then liquid PDMS is poured into the cell culture dish, the cell culture dish is placed in an oven of 70 ℃ for 3h, and a conical head PDMS mold and a cylindrical body PDMS mold with cavities are constructed after the PDMS is solidified.
3. Swimmer head-carried prodrug molecule
Adding 200 mg of Eudragit L-100 into a 50 ml centrifuge tube, adding 1500 μ L of dichloromethane, stirring for 3 minutes at 400 rpm, adding 500 μ L of absolute ethyl alcohol, stirring for 5 minutes at 400 rpm until the liquid is clear and transparent, adding 200 mg of Polycaprolactone (PCL), stirring for 400 rpm until the solid component is completely dissolved, adding 800 μ g of gold carbon sphere nanoparticles and 6 mg of trans-cyclooctene-5-aminosalicylic acid prodrug molecule, and stirring for 10 minutes in the dark. And taking 250 microliters of the mixed system to a conical cavity PDMS mold, inserting the mold into a swimmer head, and putting the mold into an oven at the temperature of 37 ℃ for more than 180 min. The swimmer head carrying the prodrug molecule can be stripped off.
4. swimmer body-loaded prodrug activating molecules
Adding 200 mg of Eudragit L-100 into a 50 ml centrifuge tube, adding 1500 μ L of dichloromethane, stirring for 3 minutes at 400 rpm, adding 500 μ L of absolute ethyl alcohol, stirring for 5 minutes at 400 rpm until the liquid is clear and transparent, adding 200 mg of Polycaprolactone (PCL), stirring for 400 rpm until the solid component is completely dissolved, adding 800 μ g of gold carbon sphere nanoparticles and 6 mg of methyl-tetrazine-phenol, and stirring for 10 minutes in a dark place. And taking 400 microliters of the mixed system to a cylindrical cavity PDMS mold, inserting the swimmer body tail combination part (body part insertion), and putting the system into an oven at the temperature of 37 ℃ for more than 180 min. The swimmer moiety carrying the activating molecule can be detached.
5. Construction of magnetic drive swimmer type worm bionic robot system
A magneton with the length of 9.9 mm and the diameter of 4.3 mm is placed in a cylindrical empty bin of the swimmer cylindrical body, the head and the tail structure are bonded by alpha-cyanoacrylate glue, and the swimmer cylindrical body is placed at room temperature overnight.
Test example 1
Fig. 2 is a real image of the robot moving under the magnetic control driving of the external magnetic field. In particular to a moving image of the swimmer type worm bionic robot in a simulated intestine with a thickness of 2mm and a moving image of the swimmer type worm bionic robot in a bent simulated intestine under the control of a magnetic field.
Test example 2
As shown in FIG. 3, the head and body are shown together with the actual figure carrying different components. In particular to a 3D printed robot head and body and a real object graph respectively wrapping a photo-thermal responsive material Au-C and tumor treatment mode drug molecule DOX.
Test example 3
Fig. 4 shows the near-infrared responsive temperature rise and thermal responsive drug release profiles of the robot head. Wherein, upper left diagram: schematic of drug release experiments in simulated intestinal fluid (SIF, pH 6.8), lower left panel: isolation of pig intestines followed by 10min Near Infrared (NIR) irradiation (2W/cm) 2 ) The latter thermal image. The middle upper graph: the schematic shows the experimental course of a 10min pause after exposure of the S-head to NIR radiation (total of 6 rounds) for 5min, with the following graph: DOX at room temperature (Ctrl), 65 ℃ during NIR irradiation (2W/cm) 2 ) Or by isolating the NIR irradiation period (2W/cm) of the pig intestine 2 ) Release profile in SIF under various conditions. Upper right view: fluorescence image of DOX in SIF after given conditioning treatment. Lower right view: and giving a real object diagram of the S-head after condition processing.
Test example 4
Fig. 5 shows experimental graphs of in vitro antioxidant and anti-inflammatory tests of the robot head and body loaded with prodrug and activator, respectively. Fluorescence images show the ROS production by colonic epithelial cells (IEC) after 24 hours of treatment under the given conditions (upper panel; scale bar, 100 μm) and the morphology of mouse mononuclear Macrophages (MACs) (lower panel; scale bar, 20 μm), non-stimulated cells were used as negative control (Ctrl-), with H 2 O 2 Cells stimulated (for IEC) or lipopolysaccharide (LPS; for MACs) served as positive controls (Ctrl +). Quantitative analysis of ROS positive IEC percentage (green histogram) and red area per MAC (red histogram) in different treatments. Relative mRNA expression levels of IL-1 β and TNF- α inflammatory factors in MACs following different treatments.
Test example 5
This example provides a prepared worm-like biomimetic robotic system for delivering enteric drugs in a rabbit model of IBD, as shown in figure 6.
In IBD rabbit model modeled with 0.2% DSS, after anesthesia, laparotomy dissection was performed to place the swimmer robot system in the cecum, moved to the inflammatory site under the control of an external magnetic field, and applied at 2W/cm 2 Irradiation with near infrared light was stopped for 5min (during which time the intestinal wall was rinsed with PBS) for 10 rounds, and the abdominal closing was waited for 3 hours. The cecal tissues were taken for inflammatory factor ELISA detection, RT-PCR analysis, and histochemical staining analysis, as shown in FIG. 7.
Wherein, the upper graph shows the relative mRNA expression levels of IL-1 beta, IL-6 and TNF-alpha inflammatory factors in cecum tissues after treatment of a control group, a 5-ASA-loaded Swimmer group and a prodrug-loaded Swimmer group in a rabbit cecum IBD model, and the mRNA expression level histograms of IL-1 beta, IL-6 and TNF-alpha in the left graph are Ctrl group, 5-ASA group, S-5-ASA group and S-TA + S-TZ group from left to right respectively. The right panel shows the protein level changes of IL-6 and TNF-alpha inflammatory factor in the cecal tissue after treatment of the control group and the different treatment groups (the protein level change of the inflammatory factor is shown from left to right in Ctrl group, 5-ASA group, S-5-ASA group and S-TA + S-TZ group).
The lower panel shows immunofluorescent staining images of IL-6 (upper transverse row) and TNF-alpha (lower transverse row) inflammatory factors in cecal tissue after treatment in the control group and the different treatment groups.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (10)
1. A worm-like biomimetic robot system for intestinal drug delivery, characterized in that: the infrared light-sensitive sensor comprises a conical head, a cylindrical body and a spiral tail which are mutually connected to form a swimmer model, wherein a mixed system of near-infrared light thermal-responsive nanoparticles and medicines is loaded in the conical head and the cylindrical body, a carrying bin is further arranged in the cylindrical body, and a magnetic control device is placed in the carrying bin.
2. The insect-like biomimetic robot system for intestinal drug delivery according to claim 1, characterized in that: the conical head of the swimmer model is 4-8 mm high, and the diameter of the bottom of the swimmer model is 10-14 mm; the cylindrical body of the swimmer model is 4-8 mm high, and the diameter of the bottom of the swimmer model is 10-14 mm; the length of the spiral tail of the swimmer model is 3-18 mm, and the number of spiral turns is 1-6.
3. The insect-like biomimetic robot system for intestinal drug delivery according to claim 2, characterized in that: the loading bin is a cuboid empty bin, the length of the loading bin is 5-10 mm, the width of the loading bin is 2.5-5 mm, the depth of the loading bin is 2-5.5 mm, and the length of the magnetic control device is 5-10 mm and the diameter of the magnetic control device is 2.5-5 mm.
4. The insect-like biomimetic robot system for intestinal drug delivery according to claim 1, characterized in that: the near-infrared light thermal response nano particles in the mixed system are hollow carbon nanospheres modified by gold nano dots, the particle size is 120-200 nanometers, and the weight of the near-infrared light thermal response nano particles loaded on a single swimer model is 100-200 micrograms.
5. The insect-like biomimetic robot system for intestinal drug delivery according to claim 1, characterized in that: further adding the Eudragit L-100 into the mixed system.
6. The insect-like biomimetic robot system for intestinal drug delivery according to claim 1, characterized in that: polycaprolactone is also added into the mixed system, and the phase transition temperature of the polycaprolactone is 50-60 ℃.
7. The insect-like biomimetic robot system for intestinal drug delivery according to claim 1, characterized in that: dichloromethane and absolute ethyl alcohol are sequentially added into the mixed system, and the volume ratio of the dichloromethane to the absolute ethyl alcohol is 1: 1-3: 1.
8. a method of preparing a biomimetic robotic system for intestinal drug delivery as recited in any of claims 1-7, comprising the steps of:
the method comprises the following steps: designing an original swimmer model structure by utilizing solidworks software, and respectively printing a conical head, a cylindrical body and a spiral tail of the swimmer model by using a 3D printer and taking polylactic acid as a material;
step two: according to the structures of the conical head part and the cylindrical body part which are printed by 3D, polydimethylsiloxane is used for respectively constructing PDMS molds for carrying a mixed system in the conical head part and the cylindrical body part;
step three: adding the prepared mixed system of the near-infrared light thermal response nano particles and the medicine into PDMS molds of the conical head part and the cylindrical body part, then respectively inserting the head part and the body part structures of 3D printing into the PDMS molds, putting the PDMS molds into an oven for drying, and then stripping the PDMS molds;
step four: the magnetic control device is arranged in the cylindrical body part carrying bin, and the head body and the tail body are bonded by using glue or an adhesive tape.
9. The method of preparing a biomimetic robotic system for intestinal drug delivery according to claim 8, wherein: the conical head part PDMS mold is 4-8 mm high and 12-16 mm in bottom diameter, and the cylindrical body part PDMS mold is 4-8 mm high and 13-17 mm in bottom diameter; the oven temperature is 37 ℃, and the drying time is 180 minutes.
10. Use of the insect-like biomimetic robot system for intestinal drug delivery according to any of claims 1-7 for intestinal drug delivery.
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