Tổng hợp và đánh giá hiệu quả mang thuốc và tiêu diệt tế bào ung thư của một số hệ nanogel trên cơ sở polysaccharide sulfate (heparin, fucoidan) ghép các copolymer tương hợp sinh học TT TA

MINISTRY OF EDUCATION VIETNAM ACADEMY OF AND TRAINING SCIENCE AND TECHNOLOGY GRADUATE UNIVERSITY OF SCIENCE AND TECHNOLOGY - NGUYEN NGOC THE SYNTHESIS AND EVALUATION OF DRUG LOADING EFFICIENCY FOR NANOGELS BASED ON BIOCOMPATIBLE GRAFTED POLYSACCHARIDE SULFATE (HEPARIN, FUCOIDAN) COPOLYMER AGAINST CANCER CELLS GROWTH Subject: Organic Chemistry Subject code: 44 01 14 CHEMISTRY PHD THESIS SUMMARY HO CHI MINH CITY – 2021 The PhD’s thesis was completed at the Graduate University of Science and Technology - Vietnam Academy of Science and Technology 1st Science instructor: Assoc Prof PhD Tran Ngoc Quyen 2nd Science instructor: PhD Nguyen Thi Thanh Thuy 1st Reviewer: … 2nd Reviewer: … 3rd Reviewer: … The thesis will be defended before the Academy-level doctoral thesis evaluation council, meeting at the Academy of Science and Technology - Vietnam Academy of Science and Technology at… o'clock ', date… month … years 20… The thesis can be found at: - Library of Science and Technology Academy - National Library of Vietnam PREAMBLE The urgency of the thesis: Cisplatin (cis-diamminedichloroplatinum (II)) is one of the main anticancer drugs widely used and effective for the treatment of many types of solid tumors However, the study of the clinical effect of cisplatin, later on, was limited by the poor selectivity of the drug between normal and tumor tissues At the same time, the toxicity of the drug has also caused many side effects on the kidneys, myelosuppression, chronic neurotoxicity, thereby leading to drug resistance and dosage restriction during treatment [2- 4] Therefore, to overcome the above limitations, nanoparticle drug carriers have been strongly developed by domestic and foreign scientists, based on increasing drug accumulation in cancer cells and thereby reduce the adverse drug side effects Nanogels are nanopolymer carriers that are attracting the attention of many scientists around the world Nanogel has many outstanding features compared to other nano-carrier systems such as flexible nano-size and size, capable of simultaneously responding to many stimuli from the external environment such as temperature, pH, and intensity ionic strength, which contributes to the effectiveness of controlled drug release [5-7] Therefore, the direction of research and preparation of nanogel carriers to create high biocompatibility of the carrier, reduce the toxicity of the drug, contribute to improving the effectiveness of the drug and treatment will have many scientific implications and application The use of cisplatin complexed hydrate with a carrier can also increase the ability to carry drugs and effectively destroy cancer cells Because of the above reasons, we have carried out the project "Synthesis and evaluation of drug loading efficiency for nanogels based on biocompatible grafted polysaccharide sulfate (heparin, fucoidan) copolymer against cancer cells growth” The research objectives of the thesis: Synthesize and evaluate properties of nanogel carrier based on polysaccharide sulfate (heparin, fucoidan) grafted with different pluronic to investigate anticancer drug cisplatin and cisplatin hydrate effect Since then, the application of nanogel modulation in the transmission of two drugs combining cisplatin hydrate and nanocurcumin aims to reduce the volume of breast cancer tumors in mouse models (Mus musculus var Albino) carrying heterologous tumors from humans The main research contents of the thesis: Synthesize and evaluate the structure and morphology of the nanogels based on heparin grafted with pluronic P123, F127, F68, and F87 with different grafting ratios To synthesize and investigate the effect of carrying the hydrate from cisplatin and cisplatin of the synthesized nanogels Investigate the ability to release the drug as well as the effect of killing the breast cancer cell line MCF-7 of the nanogel Hep-P123 system carrying the drug Synthesis and evaluation of nanogel structure and morphology-based on pluronic P123 conjugated fucoidan sulfate polysaccharide Investigate the ability to release drugs as well as destroy the breast cancer cell line MCF-7 of the nanogel system Fud-P123 that carries the drug Synthesize and investigate the ability to release drugs as well as the effect of destroying breast cancer cell line MCF-7 of nanogel Hep-F127 system with drug combining cisplatin hydrate and nanocurcumin Evaluate the effect on volume reduction of breast cancer tumors on mouse models carrying heterozygous tumors from humans of the nanogel system with drug combined The layout of the thesis: the thesis includes the Introduction, Conclusions, Recommendations, and chapters (Chapter 1: Overview, Chapter 2: Research, Chapter 3: Results and discussion) The thesis has 25 tables, 71 figures, and related works published The appendix includes 32 figures and 21 tables of figures CHAPTER 1: OVERVIEW 1.1 Nanogel The term "nanogel" is defined as nanoscale particles formed by the physical or chemical cross-links of polymer networks The size of the nanogels usually ranges from 20-200 nm, thereby reducing renal clearance and prolonging the plasma half-life [2122] These nanogels can trap hydrophobic molecules (anticancer drugs), proteins (enzymes, insulin, antigen proteins), and nucleic acids (DNA plasmids), so they are used as nano polymers in the field of cancer treatment, protein distribution, and artificial vaccines [23] 1.2 Cancer and anticancer drug cisplatin Cancer occurs due to a mutation in ADN, leading to an infinite proliferation of cells, disorganized, not obeying growth control mechanisms The most important issue in cancer is the distinction between benign and malignant tumors Through recent studies, cancer is genetic, that is, due to alterations in genes that lead to changes in cell function and division Cisplatin has been used clinically to treat cancers To date, cisplatin is proven to be one of the effective anti-cancer chemotherapy drugs but needs to be combined with other drugs during treatment and more research is needed to improve treatments to reduce the Side effects of medications In which, the research direction of nanoscale slow-release carrier is considered as one of the most effective solutions to address limitations due to side effects and drug resistance of cisplatin 1.3 Previous studies In the country: there are several research groups on nanoparticles to transport cisplatin or platinum complexes (II), typically: the research group of Nguyen Cuu Khoa and Tran Ngoc Quyen synthesizes dendrimer nanoparticles that carry anticancer drugs 5-fluorouracil and cisplatin; Tran Ngoc Quyen, Nguyen Dai Hai, and the research team in Korea have successfully synthesized the electronegative - heat-sensitive nanogel carrier based on heparin Overseas: authors Xiang-Hong Peng (2011), Liu (2012), Yoon Ki Joung (2013), Lili Liu (2014), Yi Zhang (2018), Seyed Ebrahim Alavi (2019), Pai-An Hwang (2017), Merve Tutuncu (2018) studied a combination of anti-cancer drugs cisplatin and nano-carriers The study combining curcumin with the anticancer drug cisplatin has authors Mendonỗa (2013), Baharuddin (2016), Parveen Kumar (2017) There are no domestic and foreign scientific works on the preparation and application of nanogel from fucoidan, as well as using the nanogel carrier system based on heparin-pluronic to create complexes directly with hydrate cisplatin in combination with nanocurcumin CHAPTER 2: RESEARCH 2.1 Research content - Synthesis of nanogels based on heparin, fucoidan grafted with pluronic P123, F127, F68, and F87 with different grafting ratios - Determine the structure and morphology of products - Investigate the CMC concentration of the synthesized nanogels - Investigate the effect of carrying drugs cisplatin (Cis) and cisplatin hydrate (CisOH) of the synthesized nanogels - Investigate the ability to destroy the breast cancer cell line MCF-7 of nanogel Hep-P123 (1:3) system carrying Cis and CisOH; Fud-P123 (1:3) system carries Cis and CisOH - Investigate the release ability of nanogel Hep-P123-CisOH (1:3) and Fud-P123-CisOH (1:3) - Synthesize and investigate the ability to release drugs as well as the effect of killing breast cancer cell line MCF-7 of nanogel Hep-F127 system with drug combining cisplatin hydrate and nanocurcumin (Hep-F127-CisOH-Cur) - Create a mouse model with a tumor - Evaluate treatment effects of Hep-F127-CisOH-Cur nanogel system in mice carrying heterozygous tumors from humans 2.2 Research Methods The process of synthesizing the grafted copolymer Hep-P123, Hep-F127, Hep-F68, Hep-F87, Fud-P123 is done through stages, the method is referenced as previously published by the research team [50] - Product structure is determined by 1H-NMR spectroscopy and FT-IR spectroscopy - Using the TGA method to determine the percentage of pluronic content grafted to polysaccharide sulfate - The morphology and size of products are determined by electron microscopy transmitted through TEM - Using iodine and UV-Vis spectroscopy method to determine CMC value of nanogels - Investigate the ability to destroy the breast cancer cell line MCF-7 of the drug nanogel system by SRB staining - Investigate the ability of nanogels to carry and release drugs through plasma emission spectroscopy (ICP-OES) - Model of a mouse carrying tumor by Xenograft method - Evaluate tumor size in mice by measuring the tumor size and volume Evaluation of treatment efficacy using SOD2 immunohistochemical and H&E staining CHAPTER 3: RESULTS AND DISCUSSION 3.1 Results of synthesis and survey of nanogel Hep-P123 Hep-P123 products with different grafting ratios (1:3; 1:7; 1:10; 1:14 mmol/mmol) are synthesized from intermediate products NPC-P123-NPC, NPC-P123-Ami and Hep-DAB, white, colloidal The products were structured by FT-IR spectrum, 1H-NMR spectrum, TGA, TEM, and CMC 3.1.1 Results of determining the composition and structure of copolymer Hep-P123 3.1.1.1 Analysis results of FT-IR spectrum Figure 3.1 FT-IR spectrum of P123, Figure 3.6 FT-IR spectrum of Hep- NPC-P123-NPC, NPC-P123-Ami DAB,NPC-P123-Ami, Hep-P123 The FT-IR spectral data in figure 3.1 are listed in table 3.1 Table 3.1 FT-IR results of P123, NPC-P123-NPC, NPC-P123-Ami Location Wavelength (cm-1) Functional P123 NPC-P123- NPC-P123- NPC Ami 2972-2887 2972-2887 2972-2887 1108 1108 1108 groups -CH (-CH2 and a -CH3) b C-O-C c -NO2 1593 1593 d -COO-NPC 1769 1769 e -NHCOO- 1642 Through the summary of spectral data of substances in Table 3.1, it shows that characteristic oscillating signals at positions a, b always appear in molecules P123, NPC-P123-NPC, and NPCP123-Ami The oscillation signal in the e position appears only in the NPC-P123-Ami product due to the formation of urethane bonds from the replacement of an NPC end of the NPC-P123NPC molecule to Ami Spectral data in figure 3.6 are listed in table 3.3 Table 3.3 FT-IR results of NPC-P123-Ami, Hep-DAB, Hep-P123 Location Functional groups Wavelength (cm-1) NPC- Hep-DAB Hep-P123 P123-Ami a -OH (Hep) 3453 3453 b O=S=O (Hep) 1238 1238 c -C-H (-CH2 and -CH3) 2972-2887 2972-2887 1107 d C-O-C (P123) 1107 e -NO2 (NPC) 1593 19 Results of types of nano-carriers Hep-F127, Hep-F87, and Hep-F68 at ratios 1:3 and 1:14 showed higher hydrate cisplatin carrier results When compared with the Hep-P123 nanosystem, Hep-P123-CisOH (1:3) had the highest percentage of CisOH carrying 30.30% 3.3 Fud-P123 nanogel synthesis results and survey 3.3.1 The results determine the composition and structure of Fud-P123 3.3.1.1 Analysis results of FT-IR spectrum Figure 3.25 FT-IR spectra of Fud-DAB, NPC-P123-Ami, and FudP123 The FT-IR spectral data in figure 3.25 are listed in table 3.12 Table 3.12 FT-IR results of NPC-P123-Ami, Fud-DAB, Fud-DAB Location Functional groups Wavelength (cm-1) NPC-P123- Fud- Fud- Ami DAB P123 a -OH (Fud) 3425 3425 b O=S=O (Fud) 1255 1255 20 c -CH (-CH2 and - 2972-2887 2972- CH3) 2887 d C-O-C (P123) 1108 e -NO2 (NPC) 1593 f -COO-NPC 1769 g -NHCOO- 1108 1644 Through table 3.12, summarizing spectral data of substances having repetition of characteristic oscillating signals on fucoidan molecule at position a, b and on molecule P123 at position c, d always appears in the spectrum of the Fud-P123 molecule after synthesis The oscillation of the oscillating signal in the f position to the g position indicates the formation of a urethane bond from the reaction between Fud-DAB and NPC-P123-Ami, followed by the disappearance of the e-signal 3.3.1.2 Results of spectrum analysis 1H-NMR Figure 3.24 1H-NMR Spectrum Figure 3.26 1H-NMR spectrum by Fud-DAB of Fud-p123 The 1H-NMR spectral data in figure 3.24 and 3.26 are listed in Table 3.13 21 Table 3.13 Spectrum result 1H-NMR of NPC-P123-Ami, Fud-DAB, and Fud-P123 Location H of the of H group Chemical displacement (δ, ppm) NPC-P123- Fud- Ami DAB Fud-P123 a -CH3 (PPO) 1.12-1.14 1.10 b -OCH2- 3.61-3.63 3.63-3.67 CH2O- (PEO) c, d -CH=CH- 7.38-7.40 (aromatic and 8.27-8.28 ring) e -CH2-O-NPC 4.43 f -CH2-O-Ami 4.22 i –CH2-CH2- 4.22 1.67-1.75 1.74 3,04 3,04 (DAB) h -CH2-NH- Through the summary of spectral data of Fud-P123 products synthesized from NPC-P123-Ami and Fud-DAB in table 3.13, showed that there is a repetition of characteristic proton signals on the P123 molecule in position a, b The successful coupling reaction between Fud-DAB and NPC-P123-Ami leads to complete loss of the proton signal at position c, d, e, leaving only the signal at position f, successfully synthesizing Fud- P123 3.3.1.3 TGA analysis results of Fud-P123 Experimental results from the TGA diagram can calculate the percentage of pluronic P123 mass grafted to fucoidan is 68.36%, as reported by Hongliang Kang [121] 22 3.3.1.4 Results of analysis of CMC value of Fud-P123 CMC value of Fud-P123 grafted copolymer was measured to be 0.025 %wt, greater than the CMC value of pure P123 which was 0.0028 %wt This result indicates that fucoidan when grafted to P123 will increase the hydrophilic part of the polymer leading to an increase in CMC value 3.3.1.5 Analysis results TEM and DLS of Fud-P123 Figure 3.29 Results TEM and DLS of Fud-P123 TEM image of Fud-P123 in figure 3.29 showed that the nanoparticles were spherical with diameter arranged in the range 40-61 nm (TEM) Particle size distribution in the range 62.96 nm by DLS at 25°C This result shows that the Fud-P123 nanogel particle size is larger than that of the pure P123 pluronic micelle (5-10 nm), indicating that when the P123 pins were grafted to fucoidan, at the CMC concentration the copolymer itself assemble to form nanogels 3.3.2 Fud-P123 nanogel synthesis results carry drugs cisplatin and cisplatin hydrate 3.3.2.1 Analysis results of FT-IR spectrum of Fud-P123-Cis and Fud-P123-CisOH 23 Figure 3.30 FT-IR spectra of Fud-P123, Fud-P123-Cis, and FudP123-CisOH The FT-IR spectral data in figure 3.30 are listed in Table 3.14 Table 3.14 Results of FT-IR spectrum of Fud-P123; FudP123-Cis; Fud-P123-CisOH Location Wavelength (cm-1) Functional groups Fud- Fud- Fud-P123- P123 P123-Cis CisOH a -OH 3425 3425 3425 b O=S=O (Fud) 1255 1253 1253 c -CH (-CH2 and 2972- 2972-2887 -CH3) 2887 d C-O-C (P123) 1108 1108 A -NH2 (Cis) 3288 3281 B -C=O 1637 (complex) C -SO2-O (complex) 1295 24 Through the summary of spectral data of substances in Table 3.14, there is the repetition of characteristic oscillating signals on fucoidan molecule at position a, b and on molecule P123 at position c, d always appears in Fud-P123-Cis and Fud-P123CisOH molecules after synthesis In the spectrum of Fud-P123CisOH appeared new absorption oscillations at positions A, B, C, showing the complex formation of CisOH and the carboxylate, sulfate group on fucoidan While spectroscopy of Fud-P123-Cis appears only oscillating signal at position A Through FT-IR spectra, Fud-P123-Cis and Fud-P123-CisOH compounds have been synthesized successfully 3.3.2.2 Analysis results of ICP-OES of Fud-P123-Cis and FudP123-CisOH The experiment shows that Cis encapsulation is lower than that of CisOH, typically: Fud-P123-Cis (8.66%) < Fud-P123CisOH (22%) The results of comparing the drug carrier efficiency of Hep-P123 and Fud-P123 carriers showed that the cisplatin carrier efficiency of the two carrier systems was nearly equal, while the CisOH carrier efficiency of Hep-P123 carrier system (30.3%) was much higher than the carrier system FudP123 (22%) This result may indicate that the molecular structure of fucoidan contains fewer anionic groups than heparin, resulting in lower complex formation 3.3.3 Results of evaluating the ability to release drugs of FudP123 25 Experimental results show that less than 50% (v/v) CisOH is released after 24 hours in both pH conditions In which, the CisOH release at pH 5.5 is higher than at pH 7.4 When compared with the release ability of the Hep-P123CisOH system, we see that the Fud-P123-CisOH nanosystem releases the drug more slowly and the percentage of CisOH released is less than the Hep-P123-CisOH nanosystem after 24 hours in both pH conditions This can be explained because the structure of fucoidan contains many -CH3 groups, contributing to increasing the hydrophobic interaction that makes the carrier network tighter, so it can hold the drug more tightly and the result is accelerated platinum release slower after 24 hours 3.3.4 Cell toxicity results (on MCF-7 cell lines and fibroblasts) Experimental cytotoxicity after 48 hours showed that nanogel platinum exhibits high proliferative activity against human breast cancer cell line MCF-7 The Fud-P123 nanocarrier system was also evaluated to test the fibroblast toxicity by the SRB staining method Results at a concentration of 100 µg/mL, after 48 hours with the cell survival rate above 80%, showed that the nanocarrier system is biocompatible 3.4 Results for synthesis and evaluation of nanogel Hep-F127 carrying cisplatin hydrate with nanocurcumin (Hep-F127CisOH-Cur) on tumor-carrying mice From the results of carrying drugs of nanogel Hep-P123, HepF127, Hep-F87, and Hep-F68 with different transplant rates, we continue to choose the Hep-F127 nanogel system (1:3) to carry 26 drug a combination of cisplatin hydrate and curcumin for treatment application in mouse models of heterozygous tumors 3.4.1 Results of analysis of FT-IR spectrum of Hep-F127CisOH-Cur On the FT-IR spectrum in figure 3.33 of Hep-F127-Cis and Hep-F127-CisOH-Cur in addition to the characteristic fluctuations of the compound, on the spectrum Hep-F127-CisOH we see absorption bands at -COO connection and SO2-O- have a shift from 1632 cm-1 to 1592 cm-1 and 1241 cm-1 to 1253 cm-1, due to the formation of a bond between CisOH's platinum hydroxide and carboxylate groups/sulfate of Hep-F127 In the spectrum of Hep-F127-CisOH-Cur can see some absorption oscillation peaks of initial curcumin such as C=C (aromatic ring) and C=O and C=C [139], proving that curcumin has been encapsulated and retained its structure in the Hep-F127-CisOH nanocarrier system Figure 3.33 FT-IR spectrum of Hep-F127, Hep-F127-CisOH, Hep-F127-CisOH-Cur 3.4.2 TEM analysis results of Hep-F127-CisOH-Cur 27 TEM results show that the size of micelle Hep-F127 is about 130-170 nm (figure 3.34.a), with a spherical shape When curcumin is encapsulated in a nano-sized Hep-F127-CisOH nanogel complex, it will have a core-shell form (figure 3.34.b) Figure 3.34 TEM measurement results of Hep-F127 (a) and Hep-F127-CisOH-Cur (b) 3.4.3 Analysis results in ICP-OES and UV-Vis of Hep-F127CisOH-Cur The results of CisOH and curcumin content encapsulated in nanocarrier Hep-F127, calculating the following results: Sample %DL %EE name CisOH Curcumin CisOH Curcumin Hep-F127- 26.7 4.6 42.5 70 CisOH-Cur 3.4.4 Survey results of the ability to release drugs of Hep-F127CisOH-Cur CisOH and curcumin were released at pH 5.5 at a faster rate than at pH 7.4 after 96 hours More than half of the survey results on CisOH release from the control CisOH solution sample also showed that about 90% of CisOH was released after hours, this difference indicates the importance of CisOH and curcumin when closed wrapped into the nanogel Hep-F127 complex in 28 reducing the toxicity of the drug thanks to the slow release of the drug from the nanogel carrier 3.4.5 Results of cytotoxicity on cell lines MCF-7 of Hep-F127 and Hep-F127-CisOH-Cur by SRB staining method The combination of nanocurcumin in nanogel Hep-F127CisOH from experimental results significantly increases the ability to inhibit the growth of breast cancer cells MCF-7 These results demonstrate that the dual drug combination can produce a synergistic effect against breast cancer cell growth in the drug delivery system On the other hand, the cytotoxicity survey results on the MCF-7 cell line of nanogel Hep-F127 by SRB staining method also showed that at a concentration of 100 µg/mL nanogel HepF127 there is no cytotoxicity MCF-7 3.4.6 Test results of nanogel Hep-F127-CisOH-Cur on a mouse model with tumor 3.4.6.1 Results of mouse modeling with tumors The results of the mouse model with the tumor showed that the tumor was solid, hard, rough on the back of the mouse, with a big, round shape with stable spherical shape Figure 3.38 Cell morphology in sliced tumor tissue is antibodystained with immune tissue 29 Compare the histological structure of the tumor obtained from a mouse model of a tumor (Figure 3.38 A-B) with a tumorstained sample of human breast cancer cells (Figure 3.38 C), at The Human Protein Atlas Library showed comparable results 3.4.7 Results of mouse tumor size assessment during treatment Comparison of experimental results shows that Hep-F127CisOH-Cur treatment gives the best tumor reduction effect When the combination of nanocurcumin significantly reduced the side effects of the drug, mice were not inflamed at the injection site and died 10 days after injection compared with cisplatin This result is also consistent with the changes in rat weight evolved during the test 3.4.8 Tumor tissue staining results to evaluate the effectiveness of treatment The experimental results of tumor tissue staining also showed that the combination of nanocurcumin in the nano complex HepF127-CisOH showed a marked effect in reducing tumor volume and killing almost completely cells cancer compared with onedrug treatment This shows that the combined effect of the drug carrier system contributes to reducing the toxicity of the drug and increasing the effectiveness of treatment CONCLUSION Successfully synthesized nanogel carriers based on heparin, fucoidan grafted with pluronic biocompatible polymers with different circuit structures (P123, F127, F87, F68) with different conjugation rates In which, Hep-P123, Hep-F87, Hep-F68, and Fud-P123 are new carrier systems that have not been studied 30 before Nanogel products were evaluated structure by methods H-NMR, FT-IR, TGA, TEM, CMC The heparin-pluronic nanogels (P123, F127, F87, F68) carrying cisplatin drug reached from 2.85% to 13.29% and when complexed with hydrate cisplatin form was from 8.44% to 30.30%, in which the Hep-P123 nanogel complex at 1:3 graft ratio with cisplatin hydrate has the highest percentage of drug carrier Also, the higher the rate of pluronic grafting, the lower the percentage of cisplatin hydrate drug brought into the nanogel This is a new feature of the thesis compared to a recently developed research trend, using a hydrate complex form of cisplatin with a carrier to increase the effectiveness of drug delivery When comparing nanogel Hep-P123 and Fud-P123 with a 1:3 conjugate ratios respectively, Hep-P123 had better cisplatin hydrate This is a new point of the topic, in which the Hep-P123 and Fud-P123 nanogel systems have never been studied at home and abroad Nanogel from the complex between cisplatin hydrate and the carrier Hep-P123 and Fud-P123 (with 1:3 conjugate ratio) had a much slower drug release rate than the control cisplatin hydrate sample Also, in comparison between nanogel Hep-P123 and FudP123, Hep-P123 gave more percent of cisplatin hydrate after 24 hours under both pH 5.5 and 7.4 conditions than Fud-P123 When Hep-P123 and Fud-P123 nanogels were complexed with hydrate cisplatin, there was a higher percentage inhibiting 31 the growth of MCF-7 cell lines compared with cisplatin carried on the respective nanogels Successfully synthesized nanogel carrier based on pluronic F127 conjugated heparin with drug combining cisplatin hydrate and nanocurcumin Nanogel products were evaluated structure by methods FT-IR, TEM Complex compounds carrying nanogel Hep-F127 and cisplatin hydrate after combining with nanocurcumin showed high efficiency when tested on a white mouse model with tumor cell line MCF-7 transplant from humans, in which tumor volume decreased by 78.51 ± 13.6% after 14 days of testing This is the highlight of the topic, in which nanogel Hep-F127 carrying drug combining cisplatin hydrate and nanocurcumin has not been studied and tested on animals before Also, when there was a combination of nanocurcumin on the Hep-F127-CisOH drug carrier system, the toxicity of the drug was much lower than the control cisplatin sample, the mice did not show symptoms of inflammation and necrosis in the tail area medicine REQUEST Continue the above topic with other pluronic types Then surveyed the ability to carry and release anti-cancer drugs of the above nanogel systems with different drugs, to achieve the best drug-carrying effect Continuing to study the combination of multi-drug anticancer drugs on nanogel systems after synthesis, to increase the 32 effectiveness of treatment as well as reduce the toxicity of the drug Study on modification of copolymer grafted with targeted agents, to increase tumor treatment efficiency of water-soluble anticancer drugs NEW CONTRIBUTIONS OF THE THESIS Successfully synthesized new nano-carrier systems based on heparin, fucoidan conjugated with different pluronic P123, F127, F87, F68 used to encapsulate anti-cancer drugs cisplatin and cisplatin hydrate In which, Hep-P123, Hep-F87, Hep-F68 and Fud-P123 are new carrier systems that have not been studied before The study of drug-carrying nanogel particles indicated that the higher the pluronic transplant rate, the lower the percentage of cisplatin hydrate drug brought into the nanogel The result is a significant and new feature of the dissertation comparing the modern approach by using a hydrate complex form of cisplatin with carriers to increase the effectiveness of drug delivery Successfully synthesized nanogel system from pluronic F127 conjugated heparin to bring drug combining hydrate cisplatin and nanocurcumin The results of the study are used experimentally on the mouse model of heterozygous tumors that will serve as the foundation for further clinical studies Specifically, Hep-F127cisplatin hydrate carrier complex combined with nanocurcumin is the new approach never being tested on animals 33 LIST OF PUBLISHED WORKS Ngoc The Nguyen, Thi Hiep Nguyen, Minh Thanh Vu, Van Thu Le, Xuan Anh Nguyen, Tram Chau Nguyen, and Thi Bich Tram Nguyen, Novel amphiphilic heparin-pluronic P123 copolymers exhibiting a great potential for Cisplatin delivery, Journal of Materials Science, 2018, 53(18), 12692-12703 IF = 3.394, Q1 Ngoc The Nguyen, Ngoc Nhat Thanh Nguyen, Ngo The Nhan Tran, Phung Ngan Le, Thi Bich Tram Nguyen, Ngoc Hoa Nguyen, Long Giang Bach, Vu Nguyen Doan, Ha Le Bao Tran, Van Thu Le, and Ngoc Quyen Tran, Synergic Activity Against MCF-7 Breast Cancer Cell Growth of NanocurcuminEncapsulated and Cisplatin-Complexed Nanogels, Molecules, 2018, 23(12) (3347), 1-12 IF = 3.060, Q1 Trung Dinh Nguyen, The Ngoc Nguyen, Trang Thuy Thi Nguyen, Igor A Ivanov, Khoa Cuu Nguyen, Quyen Ngoc Tran, Anh Ngoc Hoang and Yuri N Utkin, Nanoencapsulation Enhances Anticoagulant Activity of Adenosine and Dipeptide IleTrp, Nanomaterials, 2019, 9(9), 1191, 1-12 IF = 4.034, Q1 ... "Synthesis and evaluation of drug loading efficiency for nanogels based on biocompatible grafted polysaccharide sulfate (heparin, fucoidan) copolymer against cancer cells growth” The research objectives... reduce the adverse drug side effects Nanogels are nanopolymer carriers that are attracting the attention of many scientists around the world Nanogel has many outstanding features compared to other... research objectives of the thesis: Synthesize and evaluate properties of nanogel carrier based on polysaccharide sulfate (heparin, fucoidan) grafted with different pluronic to investigate anticancer