MINISTRY OF EDUCATION
AND TRAINING
VIETNAM ACADEMY OF
SCIENCE AND TECHNOLOGY
GRADUATE UNIVERSITY OF SCIENCE AND TECHNOLOGY
-----------------------------
HO MINH NHAT
SYNTHESIS OF NANO DENDRIMER
POLY (AMIDOAMINE) WITH ANTI-CANCER DRUGS
(CARBOPLATIN AND OXALIPLATIN)
Major: Polymeric and Composite Materials
Code: 9440125
SUMMARY OF MATERIAL SCIENCE DOCTORAL THESIS
Ho Chi Minh City – 2020
The thesis was completed at:
Institute of Applied Materials Science - Graduate University of Science and Technology
Vietnam Academy of Science and Technology
Supervisors:
1. Prof. Dr. NGUYEN CUU KHOA
2. Assoc. Prof. Dr. NGUYEN NGOC VINH
Reviewer 1:
Reviewer 2:
Reviewer 3:
The thesis shall be defended in front of the Thesis Committee at Academy Level at
Institute of Applied Materials Science - Vietnam Academy of Science and Technology
at….on……
The thesis can be found at:
The National Library of Vietnam
The Library of Graduate University of Science and Technology
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INTRODUCTION
Cancer is currently one of the leading causes of death
worldwide. Chemotherapy is one of the treatments, especially for
metastatic cancer.
Cisplatin is used quite commonly in chemotherapy. However,
this drug has many side effects due to the high toxicity and potential
resistance of cancer cells. Subsequently, carboplatin and oxaliplatin
are widely used due to their significantly reduced toxicity, meanwhile
their toxicity is still high due to poor selectivity and targeting. To
overcome these drawbacks, dendrimer poly(amidoamine) (PAMAM),
with a large number of surface functional groups with high chemical
activity, modification by targeting agents or drug molecules, create the
drug carrier system with increase on effectiveness of treatment.
However, PAMAM has many amine functional groups on
surface that will interact with the cell membrane negatively charged,
causing cell destruction, PAMAM toxicity and applicability limits. To
overcome this, the surface of PAMAM are denatured with poly
(ethyleneglycol) (PEG), a linear polymer with high biological
compatibility, non-toxic, non-immunogenic and well soluble in water.
The binding of PEG to PAMAM also increases the water solubility
and duration in the blood, reduces the accumulation in the liver and
kidneys of PAMAM, increases the endolytic space to help increase the
ability of drug encapsulation. PEG acts as a cap to reduce the drug
release rate of PAMAM, improves the membrane permeability of
PAMAM to help the carrier system penetrate better cells.
According to these, we propose the thesis: "Synthesis of nano
dendrimer poly(amidoamine) with anti-cancer drugs (carboplatin and
oxaliplatin)".
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Objective
Study on synthesis of nano dendrimer PAMAM with
anticancer drugs carboplatin (CAR) and oxaliplatin (OXA) to reduce
the toxicity of the drug to normal cells and improve the effectiveness
on cancer cell destruction by increasing solubility, increasing drug
storage capacity, targeting drugs passively.
Research contents
- Synthesis of PAMAM dendrimer to generation G4.0 from
ethylenediamine.
- Modification of PAMAM (2 even generation G3.0 and G4.0
and 1 odd generation G3.5) by PEG 4,000K with 4 ratios: 1:4; 1:8;
1:16 and 1:32.
- Evaluation of structure and PEGylation of PEG-PAMAM
systems.
- Evaluation of the ability to carry anticancer drugs
carboplatin and oxaliplatin on 3 systems of G3.0-PEG, G3.5-PEG and
G4.0-PEG.
- Analysis of the structure of complexes of PAMAM-PEG
[CAR], PAMAM-PEG [OXA] and evaluation of the carboplatin and
oxaliplatin carrying out performance.
- Investigation of biocompatibility of PAMAM-PEG system.
- Examination of cytotoxicity of the PAMAM-PEG [CAR]
and PAMAM-PEG [OXA] systems on three cancer cell lines: uterine
cancer HeLa, lung cancer A549 and breast cancer MCF-7.
The scientific significance of the thesis
- Modification of PAMAM by PEG (two even generation
G3.0 and G4.0 and one odd generation G3.5) with different ratios to
create drug carrier system targeting cancer cells.
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- The PAMAM-PEG carriers increase the ability to carry
anticancer drugs carboplatin and oxaliplatin (increase encapsulation
efficiency).
- The PAMAM-PEG compounds carrying anticancer drugs
carboplatin and oxaliplatin have the ability to release drugs slowly and
stably (less than 50% after 24 hours) under in vitro conditions.
- The PAMAM-PEG carrier systems and the PAMAM-PEG
[CAR], PAMAM-PEG [OXA] complexes reduce the toxicity of the
anticancer drugs carboplatin and oxaliplatin whilst also exhibiting
effective inhibitory activity on development of cancer cells (on 3 cell
lines: HeLa uterine cancer, A549 lung cancer and MCF-7 breast
cancer).
New contributions of the thesis
Utilizing PAMAM-PEG material carrying two anti-cancer
drugs (carboplatin and oxaliplatin) and investigating carrier
properties, drug release, biocompatibility, cytotoxicity (on three
cancer lines: breast, lung and uterus).
Research methods
- PAMAM dendrimer synthesis method to G4.0 generation:
alkylation reaction (Michael reaction) and amidation reaction.
- PAMAM modification method by PEG (even generation
with mPEG-NPC and odd generation by mPEG-NH
2
)
- Encapsulation method;
- Drug release method;
- Biological compatibility method on L929 cell line;
- Examination method for cytotoxicity on three cancer cell
lines: HeLa uterine cancer, A549 lung cancer and MCF-7 breast
cancer.