CN103239733A - Integrin targeting drug loaded albumin nanoparticle formulation and its preparation method - Google Patents
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Abstract
The invention belongs to the field of medical technology and relates to an integrin targeting drug loaded albumin nanoparticle formulation and its preparation method. According to the invention, a gemcitabine-carried albumin nanoparticle target administration system is prepared by gemcitabine raw medicine, bovine serum albumin BSA, a RGD polypeptide, injection water, a dehydrating agent, a cross-linking agent and sodium hydroxide. The drug-loaded albumin nanoparticles have good dispersibility with a distribution range of particle size being 94-166nm, average particle size being 130nm, Zeta potential being -30.77mV, an encapsulation efficiency being 92.16%, a drug loading capacity being 12.8%, 30min burst release rate being 53.25+/-2.23% and 8 hours in vitro cumulative release rate reaching 90%. It is verified through experiments that the targeted nanoparticles provided by the invention can significantly increase the drug accumulation in the target sites, have good slow release and tumor targeting effects, can improve therapeutic effects and relieve toxic and side effects of chemotherapeutic drugs and enhance the tolerance of patients to treatment.
Description
Technical field
The invention belongs to doctor's technical field, relate to and integrate plain targeting type medicine carrying albumin nano granular preparation, be specifically related to a kind of gemcitabine albumin nano granular with targeting anti-tumor and preparation method thereof and application of mediated by integrin.
Background technology
Studies show that, cancer of pancreas grade malignancy height, incidence and mortality approaches, and along with the raising of people's living standard, sickness rate is ascendant trend year by year.It is reported that the newly-increased case load of global cancer of pancreas in 2002 is 23.23 ten thousand, death reaches 22.70 ten thousand, occupies the 8th of the tumor cause of the death in western countries, and case fatality rate is high; 2002 to 2006, the whole city, Shanghai newly diagnosed cancer of pancreas 8190 examples altogether, and total incidence is 12.17/10 ten thousand, and the markization sickness rate is 6.22/10 ten thousand; Cancer of pancreas accounts for the 8th of Shanghai City male morbidity, and the 7th of women, men and women fall ill than being 1.18: 1; 1973 to 2006, the mark sickness rate of urban district, Shanghai masculinity and femininity rose 62.20% and 75.54% respectively.
Gemcitabine is that medication is treated in a linearize of cancer of pancreas, since listing in 1996, has obtained certain curative effect.But clinical practice shows that because the gemcitabine molecular weight is little, hydrophilic is strong, and metabolism is fast, and plasma half-life only has about 17min, is difficult to reach effective blood drug level; The yield of single medicine gemcitabine has only 23.8%, median survival interval only 5.65 months, even if drug combination, the clinical response rate is all not high.In the clinical practice, for overcoming above-mentioned shortcoming, tend to increase dosage, and simultaneously corresponding whole body toxic and side effects can increase also, patient tolerability reduces.The curative effect that how further to improve chemotherapy is a great problem that present treatment of pancreatic cancer faces.Research is arranged by changing the dosage form of medicine, as adriablastina albumin nanoparticle, paclitaxel albumin nano granular, gemcitabine albumin nano granular, infiltration and retention effect (the Enhanced Permeability and Retention Effect of the enhancing by nanoparticle, the EPR effect) improves the concentration of tumor tissues Chinese medicine, realization is to the passive target of tumor, thus the therapeutic effect of raising medicine.But, still there is new problem, namely drug level is more or less the same in cancerous tissue and normal pancreatic tissue, and this just may cause medicine in killing tumor cell, also can damage normal pancreatic tissue.Therefore, need to increase the guidance quality of nanoparticle, further improve the concentration of medicine in tumor.
Show according to the study, at present guidance quality mainly is by acquisitions such as antibody-mediated, receptor-mediated, magnetic and pH sensitivity, wherein antibody-mediated mainly by the Ag-Ab effect, cause the human immunity reaction easily, and magnetic and pH sensitivity clinical practice technology are still immature, in receptor-mediated guiding, galactose, transferrins, folic acid etc. studies show that, express not highly in pancreatic cancer cell for preceding two kinds, no specificity can't be as the guidance quality carrier.
Folic acid is the native ligand of folacin receptor, the expression of folacin receptor in malignant cell is apparently higher than normal cell, with folic acid as carrier, guidance quality is higher, but when carrying medicine and entering tumor cell, can increase tumor cell to the picked-up of folic acid, on the contrary for tumor cell provides nutrition, promote the metabolism of tumor cell.So seeking better oriented carrier has become the key that improves cancer of pancreas intervention chemotherapy effect.
Cell and the adhesion between cell, cell and substrate of integrin receptor mediation are the bases of tumor invasion and transfer, α
vβ
3Be a member important in the integrin receptor family, it has high expressed at endothelial cells in tumor neogenetic blood vessels and kinds of tumor cells surface, and at ripe blood vessel and normal tissue expression seldom.Studies show that containing arginine-glycine-aspartic acid (RGD) polypeptide of sequence fragment is integrin alpha
vβ
3The main recognition site of receptor, the exogenous RGD peptide of synthetic can pass through α
vβ
3Receptor is combined with tumour-specific, can also include the protein competition α of RGD sequence simultaneously with body
vβ
3Receptor suppresses invasion and attack and the transfer of tumor.Therefore, the present invention selects the RGD peptide as the carrier of cancer of pancreas targeted therapy, and preparation can improve the plain targeting type medicine carrying of the integration albumin nano granular preparation of the targeting of medicine.
Summary of the invention
The objective of the invention is for overcoming the defective of prior art, provide a kind of plain targeting type medicine carrying of integration albumin nano granular preparation that can improve drug targeting, especially a kind of gemcitabine albumin nano granular preparation with targeting anti-tumor of mediated by integrin.
Another object of the present invention provides the preparation method of the plain targeting type medicine carrying of described integration albumin nano granular preparation.
Integrin receptor target type medicine carrying albumin nano granular preparation of the present invention, carry the albumin nano granular targeting drug delivery system of gemcitabine for bag, it is characterized in that, made by gemcitabine crude drug, bovine serum albumin BSA and rgd peptide and water for injection, dehydrant, cross-linking agent and sodium hydroxide; Wherein, the concentration of described its aqueous solution of albumin is 2.5-3.0% (g/ml), and rgd peptide concentration is 5mg/ml, and the concentration of albumin nano granular is 15mg/ml; The volume ratio of dehydrant and albumin aqueous solution is 2: 1-3: 1; Cross-linking agent and albuminous amino mol ratio are 50-100%, and rgd peptide and albumin nano granular volume ratio are 10: 1; Gemcitabine crude drug and albuminous mass ratio 10-25%.
In one embodiment of the present of invention, the preferred dehydrated alcohol of dehydrant.
In one embodiment of the present of invention, the preferred glutaraldehyde of cross-linking agent
In the integrin receptor target type medicine carrying albumin nano granular preparation of the present invention, can targeting under the guiding of rgd peptide in the high expressed integrin alpha
vβ
3The pancreatic cancer cell of receptor and tissue.
The present invention adopts the desolventizing cross-linking method of improvement to prepare bovine serum albumin nanoparticle suspension; adopt the MBS method that rgd peptide and albumin nano granular are carried out coupling again; adopt absorption medicine carrying method that RGD coupling albumin nano granular is carried out medicine carrying then; prepare the nanoparticle of favorable dispersibility; particle size distribution range 94-166nm; mean diameter is 130nm; Zeta potential-30.77mV; envelop rate is 92.16%; drug loading is 12.8%; 30min dashes forward and releases rate is 53.25 ± 2.23%, and the cumulative release rate reached 90% in external 8 hours.
The preparation method of integrin receptor target type medicine carrying albumin nano granular preparation of the present invention is characterized in that it comprises step:
(1) preparation albumin nano granular:
Preparation 3.0%BSA solution, 1M NaOH regulates pH to 8.5, stirs to drip dehydrated alcohol down, to blue Colloidal fluid formation, continue to stir, add cross-linking agent glutaraldehyde (the amino mol ratio of albumin is 100%), continue at the uniform velocity to stir, low temperature (40 ℃) rotary evaporation is removed ethanol, cross 1 μ m filter membrane, 12000rpm is centrifugal for the residue Colloidal fluid, removes supernatant, precipitation part adding distil water redissolves, and gets the albumin nano granular suspension;
(2) preparation RGD coupling albumin nano granular:
The rgd peptide that takes a morsel is put in the sterilization centrifuge tube, and distilled water tries molten polypeptide, and the polypeptide after the dissolving is sucked back in the former pipe, mixing, get distilled water and continue the dissolving polypeptide, mixing makes abundant dissolving, getting concentration is the 10mg/ml polypeptide, with MBS molten with DMF be 10mg/ml, in MBS: the ratio of albumin nano granular=1: 10 adds MBS in albumin nano granular solution, stirring and evenly mixing, after the room temperature activation 30 minutes, again in albumin nano granular: the ratio of polypeptide=1: 10 adds the polypeptide that dissolves, mixing, room temperature reaction, PBS dialysis, PH7.2,4 ℃ are spent the night, and get the suspension of RGD coupling albumin nano granular; Get polypeptide respectively, the adding distil water dilution is 5mg/ml, and RGD coupling albumin nano granular suspension; Every test tube adds phosphate EDTA solution respectively, establishes control tube, and control tube adds phosphate EDTA solution; In every test tube, add Ellman ' s reagent again, mixing, the light absorption value at the 412nm place is surveyed in reaction, calculates the concentration of peptide free sulfhydryl group to be measured, calculates the coupling rate;
(3) preparation RGD coupling gemcitabine albumin nano granular:
Adopt absorption medicine carrying method that RGD coupling albumin nano granular is carried out medicine carrying, feed intake by the calculating of 10% drug loading, take by weighing an amount of gemcitabine, being mixed with concentration with pure water is 10mg/mL, adds 1M NaOH and regulates pH to 8.5, add an amount of pure water after, with the RGD coupling albumin nano granular suspendible of Jixitabin solution with precipitation, stirring reaches adsorption equilibrium, and the centrifugal drug-carrying nanometer particle that makes of 12000rpm is then used with proalbumin solution with the pure water of volume drug-carrying nanometer particle suspendible postlyophilization; Detect particle diameter, Zeta potential, envelop rate and drug loading.
Among the present invention, described rgd peptide is formed by 5 aminoacid head and the tail ring formation, and its sequence is-Arg
1-Gly
2-Asp
3-D-Tyr
4-Lys
5-, connect a cysteine again on the RGD cyclic peptide simultaneously, be connected with the sulfydryl of BSA.
Among the present invention, RGD coupling albumin nano granular coupling rate is 32%.
Among the present invention, described RGD coupling gemcitabine albumin nano granular particle size distribution range 94-166nm, mean diameter is 130nm, Zeta potential-30.77mV, envelop rate is 92.16%, drug loading be 12.8%, 30min prominent to release rate be 53.25 ± 2.23%, the cumulative release rate reached 90% in external 8 hours.
Among the present invention, medicine carrying albumin nano granular preparation RGD coupling gemcitabine albumin nano granular suspension is rendered as the milky colloidal solution.
The medicine carrying albumin nano granular preparation that the present invention makes can be used for the treatment of cancer of pancreas.
Because rgd peptide can improve the active targeting of pharmaceutical carrier, the targeted nano granule that the present invention makes can significantly improve medicine in the gathering of target site, thereby improve the effect for the treatment of of pancreatic cancer, confirm through test, the present invention integrates plain drug-carrying nanometer particle by the targeting that has that the coupling rgd peptide makes, and has slow-releasing and tumor-targeting preferably, can improve the therapeutic effect of chemotherapeutics, and alleviate the toxic and side effects of chemotherapeutics, improve the patient to the toleration for the treatment of.
For the ease of understanding, below will describe in detail the plain targeting type medicine carrying of a kind of integration of the present invention albumin nano granular preparation and preparation method thereof by concrete drawings and Examples.It needs to be noted, instantiation and accompanying drawing only are in order to illustrate, obviously those of ordinary skill in the art can illustrate according to this paper, within the scope of the invention the present invention is made various corrections and change, and these corrections and change are also included in the scope of the present invention.
Description of drawings
Fig. 1 is that RGD coupling gemcitabine albumin nano granular is to the inhibited proliferation of different pancreas cancer cell strains.
Fig. 2 is the remedy,tissue concentration profile of RGD coupling gemcitabine albumin nano granular in nude mice plantation tumor model.
The specific embodiment
Preparation 3.0%BSA solution 10ml, 1M NaOH regulates pH to 8.5.Speed with 1ml/min under the high-speed stirred drips dehydrated alcohol 40ml, to blue Colloidal fluid formation, continues to stir 60min.Constant speed stirs and adds cross-linking agent glutaraldehyde (the amino mol ratio of albumin is 100%) down, continues at the uniform velocity to stir 16-20h.Low temperature (40 ℃) rotary evaporation is removed ethanol, crosses 1 μ m filter membrane, centrifugal 10 minutes of residue Colloidal fluid 12000rpm.Remove supernatant, precipitation part adding distil water redissolves, and obtains the albumin nano granular suspension.Get the 5mgRGD polypeptide, therefrom take out and place sterilized 1.5ml centrifuge tube on a small quantity, try molten polypeptide with 100 μ l distilled waters, the polypeptide after the dissolving is sucked back in the pipe that the 5mgRGD polypeptide is housed mixing.Get 400 μ l distilled waters and continue the dissolving polypeptide, mixing on eddy mixer fully dissolves it, and getting peptide concentration is 10mg/ml; Using DMF molten MBS is 10mg/ml, in MBS: the ratio of albumin nano granular=1: 10 adds MBS, stirring and evenly mixing in albumin nano granular solution, the room temperature activation is after 30 minutes, again in albumin nano granular: the ratio of polypeptide=1: 10 adds the good polypeptide of dissolving, mixing, room temperature reaction 3 hours. dialyse with PBS, PH7.2,4 ℃ are spent the night, and obtain the suspension of RGD coupling albumin nano granular; Adopt absorption medicine carrying method that RGD coupling albumin nano granular is carried out medicine carrying, feed intake by the calculating of 10% drug loading, take by weighing an amount of gemcitabine, being mixed with concentration with pure water is 10mg/mL, adds 1M NaOH and regulates pH to 8.5, add an amount of pure water after, with the RGD coupling albumin nano granular suspendible of Jixitabin solution with precipitation, stir 12h and reach adsorption equilibrium, the centrifugal drug-carrying nanometer particle that makes of 12000rpm is then used with proalbumin solution with the pure water of volume drug-carrying nanometer particle suspendible postlyophilization; Detect particle diameter, Zeta potential, envelop rate and drug loading.
Described RGD coupling gemcitabine albumin nano granular particle size distribution range 94-166nm, mean diameter is 130nm, Zeta potential-30.77mV, envelop rate is 92.16%, drug loading be 12.8%, 30min prominent to release rate be 53.25 ± 2.23%, the cumulative release rate reached 90% in external 8 hours.
Embodiment 2RGD coupling gemcitabine albumin nano granular is to expressing different integrin alphas
vβ
3The inhibition experiment of the pancreas cancer cell strain of level
Get PANC-1, the BxPC-3, SW1990, the CFPAC-1 cell strain that are in exponential phase respectively, surperficial integrin alpha v beta 3 receptor positive expression rate is respectively 13.58%, 86.94%, 71.50%, 12.51%.The pancreas cancer cell strain of adhere-wall culture, exponential phase is got off with 0.05% trypsinization, make single cell suspension with the RPMI RPMI-1640 that contains 10% calf serum, every group with every hole 5 * 10
3Individual cell is inoculated respectively in the 96 well culture plate holes, every pore volume 200 μ l.Culture plate is moved to CO
2In the incubator, at 37 ℃, 5%CO
2And greater than after cultivating 24h under 95% damp condition, cell attachment, cell is close to and merges, culture fluid is abandoned in suction, with dosing respectively behind the static 24h of RPMI RPMI-1640 that contains 0.2% calf serum, be 0.01,0.1,1,10,100 μ g/ml with concentration (by contained GEM), continue to cultivate 24h, 48h, 72h after the administration, every hole adds the MTT solution 50 μ l of 2mg/mI, supernatant is removed in suction after continuing to cultivate 4h, every hole adds inferior maple (DMSO) the 150 μ l of dimethyl, and light shaking is measured absorbance (OD value) at 490nm wavelength place with microplate reader behind the 10min.Cell inhibitory rate (IR)=(matched group OD value-administration group OD value/matched group OD value) * 100%.The result shows that RGD coupling gemcitabine albumin nano granular has obvious inhibitory action to the BxPC-3 cell strain of high expressed α v β 3, shows that RGD coupling gemcitabine albumin nano granular is by having the effect of targeting anti-tumor under the mediated by integrin effect.
The remedy,tissue concentration profile of embodiment 3RGD coupling gemcitabine albumin nano granular in nude mice plantation tumor model
Choose 15 of tumor bearing nude mices, be divided into 3 groups at random: the former medicine group of GEM, BSANP-GEM group, RGD-BSANP-GEM group, adopt tail vein injection, dosage is GEM 90mg/kg in GEM.30min after the administration puts to death nude mice, gets tumor tissues, liver, kidney, spleen, pancreas, heart, muscular tissue 0.5cm*0.5cm respectively, each two.Behind the tissue homogenate, adopt the HPLC method that the concentration of gemcitabine in the tissue is detected.Chromatographic condition:: chromatographic column: Phenomenex C18 (250mm * 4.6mm, 4 μ m); Column temperature: 45 ℃; Mobile phase: acetonitrile-0.1% trifluoroacetic acid solution (3: 97, v/v); Flow velocity: 1.0mL/min; Ultraviolet detection wavelength: 268nm; Sample size: 100 μ L.Drug level distributes and shows, the concentration of RGD-BSANP-GEM group in tumor tissues is the highest, reaches 155.734 μ g/g, and compares with former medicine group, and difference has significant difference (P＜0.05).The BSANP-GEM group has higher concentration in tumor tissues and pancreatic tissue, but compares with former medicine group, and difference does not have remarkable significant difference (p＞0.05).The result shows that rgd peptide can increase the distribution of medicine in tumor tissues, improves the targeting to tumor.
Claims (9)
1. integrin receptor target type medicine carrying albumin nano granular preparation, it is characterized in that, be made for the albumin nano granular targeting drug delivery system that bag carries gemcitabine by gemcitabine crude drug, bovine serum albumin BSA and rgd peptide and water for injection, dehydrant, cross-linking agent and sodium hydroxide; Wherein, the concentration of described its aqueous solution of albumin is 2.5-3.0% (g/ml), and rgd peptide concentration is 5mg/ml, and the concentration of albumin nano granular is 15mg/ml; The volume ratio of dehydrant and albumin aqueous solution is 2: 1-3: 1; Cross-linking agent and albuminous amino mol ratio are 50-100%, and rgd peptide and albumin nano granular volume ratio are 10: 1; Gemcitabine crude drug and albuminous mass ratio 10-25%.
2. by the described integrin receptor target type of claim 1 medicine carrying albumin nano granular preparation, it is characterized in that described dehydrant is dehydrated alcohol.
3. by the described integrin receptor target type of claim 1 medicine carrying albumin nano granular preparation, it is characterized in that described cross-linking agent is glutaraldehyde.
4. preparation method for preparing each integrin receptor target type medicine carrying albumin nano granular preparation of claim 1-3 is characterized in that it comprises step:
(1) preparation albumin nano granular:
Preparation 3.0%BSA solution, 1M NaOH regulates pH to 8.5, stirs to drip dehydrated alcohol down, to blue Colloidal fluid formation, continue to stir, add the cross-linking agent glutaraldehyde, continue at the uniform velocity to stir, 40 ℃ of low temperature rotary evaporations are removed ethanol, cross 1 μ m filter membrane, 12000rpm is centrifugal for the residue Colloidal fluid, removes supernatant, precipitation part adding distil water redissolves, and gets the albumin nano granular suspension;
(2) preparation RGD coupling albumin nano granular:
Get rgd peptide and put in the sterilization centrifuge tube, distilled water tries molten polypeptide, and the polypeptide after the dissolving is sucked back in the former pipe, mixing, get distilled water and continue the dissolving polypeptide, mixing makes abundant dissolving, getting concentration is the 10mg/ml polypeptide, with MBS molten with DMF be 10mg/ml, in MBS: the ratio of albumin nano granular=1: 10 adds MBS in albumin nano granular solution, stirring and evenly mixing, after the room temperature activation 30 minutes, again in albumin nano granular: the ratio of polypeptide=1: 10 adds the polypeptide that dissolves, mixing, room temperature reaction, PBS dialysis, PH7.2,4 ℃ are spent the night, and get the suspension of RGD coupling albumin nano granular; Get polypeptide respectively, the adding distil water dilution is 5mg/ml, and RGD coupling albumin nano granular suspension; Every test tube adds phosphate EDTA solution respectively, establishes control tube, and control tube adds phosphate EDTA solution; In every test tube, add Ellman ' s reagent again, mixing, the light absorption value at the 412nm place is surveyed in reaction, calculates the concentration of peptide free sulfhydryl group to be measured, calculates the coupling rate;
(3) preparation RGD coupling gemcitabine albumin nano granular:
Adopt absorption medicine carrying method that RGD coupling albumin nano granular is carried out medicine carrying; feed intake by the calculating of 10% drug loading; take by weighing gemcitabine; being mixed with concentration with pure water is 10mg/mL, adds 1M NaOH and regulates pH to 8.5, behind the adding pure water; with the RGD coupling albumin nano granular suspendible of Jixitabin solution with precipitation; stirring reaches adsorption equilibrium, and the centrifugal drug-carrying nanometer particle that makes of 12000rpm is then used with proalbumin solution with the pure water of volume drug-carrying nanometer particle suspendible postlyophilization.
5. by the method for claim 4, it is characterized in that described rgd peptide is formed by 5 aminoacid head and the tail ring formation, its sequence is-Arg
1-Gly
2-Asp
3-D-Tyr
4-Lys
5-, connect a cysteine again on the RGD cyclic peptide simultaneously, be connected with the sulfydryl of BSA.
6. by the method for claim 4, it is characterized in that described RGD coupling albumin nano granular coupling rate is 32%.
7. press the method for claim 4, it is characterized in that, described RGD coupling gemcitabine albumin nano granular particle size distribution range 94-166nm, mean diameter is 130nm, Zeta potential-30.77mV, envelop rate are 92.16%, and drug loading is 12.8%, 30min dashes forward and releases rate is 53.25 ± 2.23%, and the cumulative release rate was 90% in external 8 hours.
8. by the method for claim 4, it is characterized in that described RGD coupling gemcitabine albumin nano granular suspension is the milky colloidal solution.
9. the integrin receptor target type medicine carrying albumin nano granular preparation of claim 1 is preparing the purposes for the treatment of in the cancer of pancreas medicine.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104667289A (en) * | 2014-01-28 | 2015-06-03 | 暨南大学 | Antitumor drug carrier and application method thereof |
| WO2020252826A1 (en) * | 2019-06-18 | 2020-12-24 | 江南大学 | Fusion albumin nanoparticle and application thereof |
| CN112225779A (en) * | 2019-07-14 | 2021-01-15 | 北京恒润泰生医药科技有限公司 | Arg(NO2) -Gly-Asp-Val-gemcitabine, its synthesis, antitumor activity and use |
| CN112773777A (en) * | 2020-12-30 | 2021-05-11 | 中国科学院长春应用化学研究所 | cRGD-DFX-BSA-NPS nano particle and preparation method and application thereof |
| EP3758490A4 (en) * | 2018-03-02 | 2021-12-22 | January Therapeutics, Inc. | Nanoparticle compositions |
| US11306111B2 (en) | 2017-07-31 | 2022-04-19 | January Therapeutics, Inc. | Organophosphate derivatives |
| US11306399B2 (en) | 2019-08-13 | 2022-04-19 | January Therapeutics, Inc. | Nanoparticle compositions |
-
2012
- 2012-02-09 CN CN2012100292871A patent/CN103239733A/en active Pending
Non-Patent Citations (1)
| Title |
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| 吉顺荣，等: "RGD偶联吉西他滨白蛋白纳米粒对胰腺癌细胞增殖抑制作用的研究", 《外科理论与实践》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104667289A (en) * | 2014-01-28 | 2015-06-03 | 暨南大学 | Antitumor drug carrier and application method thereof |
| CN104667289B (en) * | 2014-01-28 | 2018-08-14 | 暨南大学 | A kind of antineoplastic drug carrier and its application method |
| US11306111B2 (en) | 2017-07-31 | 2022-04-19 | January Therapeutics, Inc. | Organophosphate derivatives |
| EP3758490A4 (en) * | 2018-03-02 | 2021-12-22 | January Therapeutics, Inc. | Nanoparticle compositions |
| WO2020252826A1 (en) * | 2019-06-18 | 2020-12-24 | 江南大学 | Fusion albumin nanoparticle and application thereof |
| CN112225779A (en) * | 2019-07-14 | 2021-01-15 | 北京恒润泰生医药科技有限公司 | Arg(NO2) -Gly-Asp-Val-gemcitabine, its synthesis, antitumor activity and use |
| CN112225779B (en) * | 2019-07-14 | 2023-06-09 | 北京恒润泰生医药科技有限公司 | Arg(NO 2 ) -Gly-Asp-Val-gemcitabine, synthesis, anti-tumor activity and application thereof |
| US11306399B2 (en) | 2019-08-13 | 2022-04-19 | January Therapeutics, Inc. | Nanoparticle compositions |
| CN112773777A (en) * | 2020-12-30 | 2021-05-11 | 中国科学院长春应用化学研究所 | cRGD-DFX-BSA-NPS nano particle and preparation method and application thereof |
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Application publication date: 20130814 |