CN115025064A - Application of nano drug delivery system in inhibiting lymphoma recurrence - Google Patents

Application of nano drug delivery system in inhibiting lymphoma recurrence Download PDF

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CN115025064A
CN115025064A CN202210535544.2A CN202210535544A CN115025064A CN 115025064 A CN115025064 A CN 115025064A CN 202210535544 A CN202210535544 A CN 202210535544A CN 115025064 A CN115025064 A CN 115025064A
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胡豫
梅恒
唐宇翔
陈钊钊
姚惟琪
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Tongji Medical College of Huazhong University of Science and Technology
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Abstract

The invention provides an amphiphilic hydroxyethyl starch coupled polycaprolactone polymer and application of a nano drug-carrying system thereof in inhibiting recurrence of lymphoma. The TGF-beta pathway for inhibiting CAR-T at a tumor part accelerates LY release through the photothermal effect of ICG, effectively down-regulates the expression of an immune check point CTLA-4 of T cells, promotes the differentiation of memory T cells, and effectively inhibits the recurrence of lymphoma.

Description

Application of nano drug delivery system in inhibiting lymphoma recurrence
The technical field is as follows:
the invention relates to the technical field of high-molecular drug carriers, in particular to application of a nano drug delivery system in inhibiting lymphoma recurrence.
Background art:
the nano carrier is an important part formed by a nano medicine carrying system, the nano carrier carries the medicine to obtain a medicinal preparation between 0 and 1000 nanometers, and the accumulation of the medicine at a tumor part can be increased by enhancing the retention and permeation effects, so that the medicine is synergized and attenuated; meanwhile, the blood stability of the medicine is improved, the medicine is prevented from being excreted by the kidney too fast, the half-life period of the loaded medicine is prolonged, and the bioavailability of the medicine is improved. CAR-T has obvious advantages in the aspect of treating blood tumors, and various CAR-T medicaments are currently on the market and are used for treating lymphoma and multiple myeloma. However, for lymphoma treatment, 20-40% of patients with 70% -90% complete remission rates still have relapsed behavior after healing. For such patients, there is a need for effective means to increase the in vivo duration of CAR-T to increase the CAR-T lymphoma recurrence-inhibiting effect. According to research, the CAR-T has the effect of improving the differentiation capacity of effector memory T cells, and the CAR-T can effectively improve the in-vivo sustained tumor inhibition effect. While inhibiting the T cell immune checkpoint CTLA-4 helps to improve the differentiation capacity of CAR-T memory T cells, thereby helping to improve the sustained therapeutic effect of CAR-T. Researches show that the TGF-beta is closely related to the expression of CTLA-4 on the surface of a T cell, and the expression of the CTLA-4 of CAR-T can be down regulated by inhibiting a TGF-beta pathway of the T cell, so that the continuous tumor inhibition effect of the CAR-T can be effectively improved. Therefore, there is a need for effective means to effectively inhibit the TGF- β pathway of CAR-T at the tumor site.
The invention content is as follows:
technical problem to be solved
Aiming at the defects of CAR-T for treating lymphoma, the invention provides the application of the hydroxyethyl starch-polycaprolactone polymer nano drug delivery system LY/ICG @ HES-PCL which is co-entrapped with photosensitizer indocyanine green ICG and TGF-beta inhibitor LY in inhibiting lymphoma recurrence, and the application is used for improving the tumor recurrence inhibiting capacity of CAR-T so as to improve the treatment effect of CAR-T for treating lymphoma.
(II) technical scheme
In order to solve the technical problems, the invention adopts the following technical scheme:
the nano drug-loaded system is hydroxyethyl starch-polycaprolactone polymer which is co-encapsulated with photosensitizer indocyanine green (ICG) and TGF-beta inhibitor LY, and through releasing TGF-beta inhibitor LY at a tumor site, CTLA-4 expression of CAR-T is down-regulated, so that memory T cell differentiation rate of CAR-T is improved, TGF-beta channel of CAR-T is inhibited at the tumor site, and lymphoma recurrence is inhibited by cooperation with CAR-T.
Further, the nano drug delivery system comprises an amphiphilic hydroxyethyl starch-polycaprolactone polymer, and the photosensitive agent indocyanine green ICG and the TGF-beta inhibitor LY are co-entrapped to a hydrophobic shell layer of the polymer through an ultrasonic emulsification method, so that the hydroxyethyl starch-polycaprolactone polymer ICG/LY @ HES-PCL which is co-entrapped with the photosensitive agent indocyanine green ICG and the TGF-beta inhibitor LY is obtained
The invention also provides a preparation method of the nano drug delivery system, which is characterized by comprising the following steps:
s1, preparing the polymer HES-PCL of the amphipathic hydroxyethyl starch coupled polycaprolactone, which comprises the following steps:
1) dissolving polycaprolactone and activating its carboxyl group: dissolving polycaprolactone by using anhydrous dimethyl sulfoxide, then adding 1-hydroxybenzotriazole and N-N' -dicyclohexylcarbodiimide to perform carboxyl activation reaction, and stirring at room temperature for 1-4 hours to obtain a carboxyl-terminated activated polycaprolactone solution;
2) dissolving hydroxyethyl starch: under the condition of helium protection, completely dissolving hydroxyethyl starch in anhydrous dimethyl sulfoxide at 50-70 ℃ to obtain a dimethyl sulfoxide solution of the hydroxyethyl starch:
3) esterification reaction: mixing the carboxyl activated polycaprolactone solution obtained in the step 1) with the dimethyl sulfoxide solution of hydroxyethyl starch obtained in the step 2), performing esterification reaction for 24-72 hours under the protection of nitrogen at the temperature of 40-80 ℃, and purifying to obtain a copolymer mixture;
4) and (3) purification: co-dialyzing the copolymer mixture obtained in the step 3) for 1-5 days by using a PBS (phosphate buffer solution), removing unreacted 1-hydroxybenzotriazole, N-N' -dicyclohexylcarbodiimide, polycaprolactone and a DMSO (dimethyl sulfoxide) solvent, freezing liquid in a dialysis bag at the temperature of-20 to-25 ℃ for 3-5 hours after dialysis, then freeze-drying at the temperature of-40 to-60 ℃, and obtaining the hydroxyethyl starch grafted polycaprolactone copolymer freeze-dried powder after freeze-drying; namely hydroxyethyl starch grafted polycaprolactone copolymer HES-PCL;
s2, dissolving the purified hydroxyethyl starch coupled polycaprolactone polymer HES-PCL into water, adding photosensitizer indocyanine green ICG and TGF-beta inhibitor LY under the condition of ice bath by using an ultrasonicator and under the condition of ultrasonic treatment, and mixing the mixture with a mixture of 1: 1, performing ultrasonic treatment on a dichloromethane solution blended in proportion for 5 min;
s3, adding the emulsion into a high-pressure homogenizer, homogenizing for 2 times at 500bar after the ultrasound is finished, finally obtaining a suspension of hydroxyethyl starch-polycaprolactone copolymer ICG/LY @ HES-PCL, indocyanine green ICG and TGF-beta inhibitor LY which are co-encapsulated with photosensitizer indocyanine green ICG and TGF-beta inhibitor LY, centrifuging for 30min at 5000rpm, removing unencapsulated TGF-beta inhibitor LY, placing the suspension of indocyanine green ICG and ICG/LY @ HES-PCL into a dialysis bag of 3500Da, dialyzing for 3 days by using deionized water, freeze-drying the nanoparticle aqueous solution obtained by dialysis to obtain hydroxyethyl starch-polycaprolactone polymer ICG/LY @ HES-PCL freeze-dried powder which is co-encapsulated with photosensitizer indocyanine green ICG and TGF-beta inhibitor LY, and carrying out the step under the whole-light-shielding condition.
Further, the polymer particle size is 100-200nm, preferably 150 nm.
Further, the indocyanine green ICG drug-loading amount of the nano drug-loading system is 3 wt% -10 wt%, and is further preferably 5.5 wt%;
further, the drug loading amount of the TGF-beta inhibitor LY of the nano drug delivery system is 3 wt% -10 wt%, and the preferred drug loading amount is 6 wt%.
The invention also provides another preparation method of the hydroxyethyl starch-polycaprolactone copolymer nano drug delivery system, which comprises the following steps:
1) dissolving the hydroxyethyl starch-polycaprolactone polymer in water, ultrasonically crushing in ice bath, and simultaneously adding a trichloromethane emulsion solution blended by indocyanine green (ICG) and a TGF-beta inhibitor LY to obtain an ultrasonic emulsion;
2) and (3) placing the emulsion obtained in the step into a high-pressure homogenizer, homogenizing for 1-6 times under 400-1000bar, and purifying to obtain the amphiphilic hydroxyethyl starch-polycaprolactone polymer nano drug delivery system co-encapsulating the indocyanine green ICG and the TGF-beta inhibitor LY.
The hydroxyethyl starch-polycaprolactone copolymer nano drug delivery system co-entrapped with LY/ICG prepared by the preparation method is applied to inhibiting lymphoma recurrence.
(III) advantageous effects
Compared with the prior art, the invention has the following beneficial effects:
(1) the hydroxyethyl starch-polycaprolactone copolymer ICG/LY @ HES-PCL which is co-encapsulated with the photosensitizer indocyanine green ICG and the TGF-beta inhibitor LY has the particle size of about 100-200nm, and has good stability and uniformity.
(2) The hydroxyethyl starch-polycaprolactone copolymer ICG/LY @ HES-PCL co-entrapped with the photosensitizer indocyanine green ICG and the TGF-beta inhibitor LY prepared by the invention has good tumor accumulation effect on a raji cell lymphoma model, and through the photo-thermal effect of the indocyanine green ICG, the release of the TGF-beta inhibitor LY is accelerated, the expression of the immune check point CTLA-4 of a T cell is effectively reduced, and the differentiation of an effect memory T cell is promoted.
(3) The hydroxyethyl starch-polycaprolactone copolymer ICG/LY @ HES-PCL which is prepared by the invention and co-entraps photosensitizer indocyanine green ICG and TGF-beta inhibitor LY has an obvious lymphoma recurrence inhibition effect compared with CAR-T which is singly used on a raji cell lymphoma model.
Description of the drawings:
in order to more clearly illustrate the technical solution in the embodiments of the present invention, the drawings required to be used in the embodiments will be briefly described below.
FIG. 1 is a TEM image of HES-PCL and ICG/LY @ HES-PCL according to the present invention;
FIG. 2 is a graph of the change in particle size of ICG/LY @ HES-PCL in PBS and FBS solutions in accordance with the present invention;
wherein A is a graph of the change of the particle size of ICG/LY @ HES-PCL in a PBS solution, and B is a graph of the change of the particle size of ICG/LY @ HES-PCL in an FBS solution;
FIG. 3 is a graph showing the effect of transwell experiment ICG/LY @ HES-PCL on CTLA-4 expression level of CD-19+ CAR-T;
wherein A is a flow-type statistical graph of CTLA-4 expression of ICG/LY @ HES-PCL on CD-19+ CAR-T; b is a PD-1 expression flow chart of ICG/LY @ HES-PCL to CD-19+ CAR-T; c is a TIM-3 expression flow chart of ICG/LY @ HES-PCL to CD-19+ CAR-T; d is a Q-PCR statistical chart of the expression quantity of CTLA-4, PD-1 and TIM-3 of CD-19+ CAR-T by ICG/LY @ HES-PCL; e and F are WB statistical graphs of CTLA-4, PD-1 and TIM-3 expression levels of ICG/LY @ HES-PCL to CD-19+ CAR-T.
FIG. 4 is a graph of flow analysis of the differentiation status of memory T cells;
wherein A is a flow-profile of CTLA-4 expression of ICG/LY @ HES-PCL on CD-19+ CAR-T; b is a CTLA-4 expression flow statistical graph of ICG/LY @ HES-PCL to CD-19+ CAR-T; c is a statistical map of memory T cell differentiation of ICG/LY @ HES-PCL versus CD-19+ CAR-T.
FIG. 5 is a graph showing evaluation of the effect of LY/ICG @ HES-PCL on inhibiting lymphoma recurrence by the raji model of NSG mice;
wherein A is the mode of administration of ICG/LY @ HES-PCL and CAR-T; b is a statistical chart of the volume of the lymphoma relapsed by ICG/LY @ HES-PCL and CAR-T inhibition; c is a statistical chart of the recurrence rate of ICG/LY @ HES-PCL synergistic CAR-T lymphoma inhibition; d is the survival graph of ICG/LY @ HES-PCL in combination with CAR-T treatment.
FIG. 6 is a graph of flow measurements of CTLA-4 expression and memory T cell differentiation of T cells in mouse blood;
wherein A is a graph of the effect of ICG/LY @ HES-PCL on CAR-T memory T cell differentiation; b is CAR-T memory T cell differentiation statistics; c is flow detection of the expression quantity of CTLA-4 affecting CAR-T by ICG/LY @ HES-PCL; d is CTLA-4 expression quantity flow statistics.
The specific implementation mode is as follows:
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.
Example one
Preparing a nano drug delivery system of amphiphilic hydroxyethyl starch coupled polycaprolactone:
s1, preparing the polymer HES-PCL of the amphipathic hydroxyethyl starch coupled polycaprolactone, which comprises the following steps:
1) dissolving polycaprolactone and activating its carboxyl group: dissolving polycaprolactone by using anhydrous dimethyl sulfoxide, then adding 1-hydroxybenzotriazole and N-N' -dicyclohexylcarbodiimide to perform carboxyl activation reaction, and stirring at room temperature for 1-4 hours to obtain a carboxyl-terminated activated polycaprolactone solution;
2) dissolving hydroxyethyl starch: under the condition of helium protection, completely dissolving hydroxyethyl starch in anhydrous dimethyl sulfoxide at 50-70 ℃ to obtain a dimethyl sulfoxide solution of the hydroxyethyl starch:
3) esterification reaction: mixing the carboxyl activated polycaprolactone solution obtained in the step 1) with the dimethyl sulfoxide solution of hydroxyethyl starch obtained in the step 2), performing esterification reaction for 24-72 hours under the protection of nitrogen at the temperature of 40-80 ℃, and purifying to obtain a copolymer mixture;
4) and (3) purification: co-dialyzing the copolymer mixture obtained in the step 3) for 1-5 days by using a PBS (phosphate buffer solution), removing unreacted 1-hydroxybenzotriazole, N-N' -dicyclohexylcarbodiimide, polycaprolactone and a DMSO (dimethyl sulfoxide) solvent, freezing the liquid in a dialysis bag at the temperature of-20 to-25 ℃ for 3-5 h after dialysis is finished, then freeze-drying the liquid at the temperature of-40 to-60 ℃, and obtaining the hydroxyethyl starch grafted polycaprolactone copolymer freeze-dried powder after freeze-drying; namely hydroxyethyl starch grafted polycaprolactone copolymer HES-PCL;
s2, dissolving the purified HES-PCL polymer of hydroxyethyl starch coupled polycaprolactone into water, and adding a photosensitizer indocyanine green ICG and a TGF-beta inhibitor LY into the water under ice bath conditions by using an ultrasonicator while performing ultrasonic treatment, wherein the weight ratio of the photosensitizer indocyanine green ICG to the TGF-beta inhibitor LY is 1: 1, performing ultrasonic treatment on a dichloromethane solution blended in proportion for 5 min;
s3, adding the emulsion into a high-pressure homogenizer, homogenizing for 2 times at 500bar after the ultrasonic treatment is finished, finally obtaining a suspension of hydroxyethyl starch-polycaprolactone copolymer ICG/LY @ HES-PCL, indocyanine green ICG and TGF-beta inhibitor LY which co-entrap photosensitizers indocyanine green ICG and TGF-beta inhibitor LY, centrifuging for 30min at 5000rpm, removing unencapsulated TGF-beta inhibitor LY, placing the suspension of indocyanine green ICG and ICG/LY @ HES-PCL in a dialysis bag of 3500Da, dialyzing for 3 days by using deionized water, freeze-drying the nanoparticle aqueous solution obtained by dialysis to obtain the hydroxyethyl starch-polycaprolactone polymer ICG/LY @ HES-PCL freeze-dried powder which co-entrap photosensitizers indocyanine green ICG and TGF-beta inhibitor LY, and carrying out the step under the whole-light-shielding condition.
Detecting the drug loading amount of LY and ICG in ICG/LY @ HES-PCL by an ultraviolet spectrophotometry, weighing the ICG/LY @ HES-PCL by a weight W1, measuring the LY mass W2 and the ICG mass W3 by the ultraviolet spectrophotometry, calculating the drug loading amount of 6.0 wt% by adopting a LY 2/W1 100%, and calculating the drug loading amount of 5.5 wt% by adopting a formula W3/W1 100%. Preparing 1mg/ml ICG/LY @ HES-PCL, dissolving in ultrapure water, and performing ultrasonic treatment for 10min for later use. The copper mesh was placed in a petri dish covered with filter paper, 10. mu.l of nanoparticle dispersion at 1mg/ml was dropped on the copper mesh, naturally dried at room temperature, and the morphology was observed by a transmission electron microscope (H-7000FA, HITACHI). FIG. 1 is a TEM image of HES-PCL and ICG/LY @ HES-PCL prepared by the present invention, as shown in the figure, the nanoparticle has a particle size of 120-130 nm, is uniform in particle size, and is spherical. The stability of ICG/LY @ HES-PCL was determined by observing its particle size in PBS solution and FBS solution over 7 days. ICG/LY @ HES-PCL showed no significant change in particle size in PBS solution over 7 days. ICG/LY @ HES-PCL in FBS solution showed a slight increase in particle size of 40nm within 7 days, with no apparent agglomeration. The results indicate good stability of ICG/LY @ HES-PCL (FIG. 2).
Example two
This example utilizes a transwell experiment to study the effect of ICG/LY @ HES-PCL on CTLA-4 expression of CD-19+ CAR-T as follows: raji cells and LY/ICG @ HES-CH nanoparticles prepared in example 1 were mixed in a 24-well plate in advance, irradiated with near infrared light for 5min, and then transferred to the upper chamber (pore size ≈ 2 μm) of a transwell cell, seeded with CAR-T cells in the lower chamber, and the transwell cell was cultured at 37 ℃ for 3 days with 5% CO2, and then analyzed for CTLA-4 expression of CD-19+ CAR-T by Q-PCR and Western Blot, and the ICG, ICG @ HES-PCL nano-drug + near infrared light irradiated group was set as a control group. After 3 days, CTLA-4 expression of CAR-T is significantly reduced in a LY/ICG @ HES-PCL group and a LY/ICG @ HES-PCL + near infrared light irradiation group compared with CTLA-4 expression of CAR-T used alone, and the expression of immune checkpoints such as TIM-3 and PD-1 is not obviously different, which indicates that LY/ICG @ HES-PCL and a LY/ICG @ HES-PCL + near infrared light irradiation group can release LY and the CTLA-4 expression of CAR-T is reduced by inhibiting a TGF-beta pathway (figure 3). Continuing with flow analysis of the differentiation status of memory T cells (FIG. 4), the experimental results showed that the memory T cells (CD44-CD62L +) of CAR-T were also improved with the down-regulation of CTLA-4, indicating that LY/ICG @ HES-PCL and LY/ICG @ HES-PCL + near infrared light irradiation group can reduce the CTLA-4 expression of CAR-T by releasing LY, thereby improving the differentiation ratio of the memory T cells of CAR-T.
EXAMPLE III
The established NSG mouse raji model is utilized to evaluate the lymphoma recurrence inhibiting effect of LY/ICG @ HES-PCL. After inoculation of raji cells in NSG mice, LY/ICG @ HES-PCL was administered on day-3 and near infrared light was administered on day-1. After tumor resection on day 10, LY/ICG @ HES-PCL was administered continuously on days 11 and 13, and after one generation of tumor resection on day 15, the average recurrence tumor weight, mouse survival, recurrence rate, and tumor recurrence status were recorded.
The experimental results are shown in fig. 4: LY/ICG @ HES-PCL and LY/ICG @ HES-PCL + NIR light groups on day 28, only 1 of 4 mice had relapsed, and no significant lymphoma relapse was observed until day 31. On day 31, LY/ICG @ HES-PCL + near infrared light plus CAR-T group achieved (90.3%) lymphoma inhibition much more than 2.7-fold for CAR-T group alone (34.1%). Half of the life time of LY/ICG @ HES-PCL + near infrared light + CAR-T group for lymphoma treatment was 24 days, and was also higher than 17.5 days for CAR-T group (FIG. 5).
Example four
In this example, rat-made NSG mice were bled on day 25 after administration, and CTLA-4 expression of T cells and differentiation status of memory T cells in the blood of the mice were measured by flow measurement.
The results of the experiment are shown in FIG. 5: in both LY/ICG @ HES-PCL and LY/ICG @ HES-PCL + NIR irradiated groups, CTLA-4 expression of CAR-T was significantly down-regulated and effector memory T cell ratio (CD44-CD62L +) was significantly increased as compared to CTLA-4 expression in CAR-T group (FIG. 6). Shows that in the mice, the LY/ICG @ HES-PCL and the LY/ICG @ HES-PCL + near infrared light irradiation group can improve the differentiation rate of the memory T cells of the CAR-T by releasing LY, thereby improving the relapse effect of the CAR-T in inhibiting the lymphoma.
In conclusion, the amphiphilic hydroxyethyl starch coupled polycaprolactone nano drug delivery system provided by the invention releases TGF-beta inhibitor LY at a tumor site to down-regulate CTLA-4 expression of CAR-T, so that the differentiation rate of memory T cells of CAR-T is improved, a TGF-beta pathway of CAR-T is inhibited at the tumor site, and recurrence of lymphoma is inhibited by cooperation of CAR-T.
The present invention has been described above by way of example, but the present invention is not limited to the above-described specific embodiments, and any modification or variation made based on the present invention is within the scope of the present invention as claimed.

Claims (6)

1. The application of the nano drug delivery system in inhibiting lymphoma recurrence is characterized in that the nano drug delivery system is a hydroxyethyl starch-polycaprolactone polymer co-encapsulating photosensitizers of indocyanine green (ICG) and TGF-beta inhibitor LY, and through releasing the TGF-beta inhibitor LY at a tumor site, CTLA-4 expression of CAR-T is down-regulated, so that the memory T cell differentiation rate of CAR-T is improved, the TGF-beta pathway of CAR-T is inhibited at the tumor site, and the CAR-T is cooperated to inhibit lymphoma recurrence.
2. The nano drug delivery system of claim 1, wherein the nano drug delivery system comprises an amphiphilic hydroxyethyl starch-polycaprolactone polymer, and the photosensitive agent indocyanine green ICG and the TGF-beta inhibitor LY are co-entrapped to a hydrophobic shell layer of the amphiphilic hydroxyethyl starch-polycaprolactone polymer through an ultrasonic emulsification method, so that the hydroxyethyl starch-polycaprolactone polymer ICG/LY @ HES-PCL co-entrapped with the photosensitive agent indocyanine green ICG and the TGF-beta inhibitor LY is obtained.
3. The method for preparing the drug delivery nanosystem of claim 1 or 2, comprising the steps of:
s1, preparing a polymer HES-PCL of the amphipathic hydroxyethyl starch coupled polycaprolactone;
s2, dissolving the purified hydroxyethyl starch coupled polycaprolactone polymer HES-PCL into water, adding photosensitizer indocyanine green ICG and TGF-beta inhibitor LY under the condition of ice bath by using an ultrasonicator and under the condition of ultrasonic treatment, and mixing the mixture with a mixture of 1: 1, performing ultrasonic treatment on a dichloromethane solution blended in a ratio for 5 min;
s3, adding the emulsion into a high-pressure homogenizer, homogenizing for 2 times at 500bar after the ultrasound is finished, finally obtaining a suspension of hydroxyethyl starch-polycaprolactone copolymer ICG/LY @ HES-PCL, indocyanine green ICG and TGF-beta inhibitor LY which are co-encapsulated with photosensitizer indocyanine green ICG and TGF-beta inhibitor LY, centrifuging for 30min at 5000rpm, removing unencapsulated TGF-beta inhibitor LY, placing the suspension of indocyanine green ICG and ICG/LY @ HES-PCL into a dialysis bag of 3500Da, dialyzing for 3 days by using deionized water, freeze-drying the nanoparticle aqueous solution obtained by dialysis to obtain hydroxyethyl starch-polycaprolactone polymer ICG/LY @ HES-PCL freeze-dried powder which is co-encapsulated with photosensitizer indocyanine green ICG and TGF-beta inhibitor LY, and carrying out the step under the whole-light-shielding condition.
4. The nanopharmaceutical system of any of claims 1-3, wherein: the particle size of the polymer is 100-200 nm.
5. The nanopharmaceutical system of any of claims 1-3, wherein: the drug loading of the TGF-beta inhibitor LY is 6 wt%.
6. The drug delivery nanosystem of any of claims 1 to 3, wherein: the drug loading rate of the indocyanine green ICG is 5.5 wt%.
CN202210535544.2A 2022-05-17 2022-05-17 Application of nano drug delivery system in inhibiting lymphoma recurrence Pending CN115025064A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180221508A1 (en) * 2015-07-31 2018-08-09 Tarveda Therapeutics, Inc. Compositions and methods for immunomodulation
CN113616806A (en) * 2021-08-26 2021-11-09 华中科技大学 Platinum-icodextrin-polycaprolactone macromolecular compound, nano drug delivery system and application thereof
CN113651965A (en) * 2021-04-08 2021-11-16 华中科技大学同济医学院附属协和医院 High molecular compound, preparation method and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180221508A1 (en) * 2015-07-31 2018-08-09 Tarveda Therapeutics, Inc. Compositions and methods for immunomodulation
CN113651965A (en) * 2021-04-08 2021-11-16 华中科技大学同济医学院附属协和医院 High molecular compound, preparation method and application thereof
CN113616806A (en) * 2021-08-26 2021-11-09 华中科技大学 Platinum-icodextrin-polycaprolactone macromolecular compound, nano drug delivery system and application thereof

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