Synthesis and Characterization of a Novel Dual-Responsive Nanogel for Anticancer Drug Delivery

In this study, to reduce the side effects of anticancer drugs and also to increase the efficiency of current drug delivery systems, a pH and temperature-responsive polymeric nanogel was synthesized by copolymerization of N-vinylcaprolactam (VCL) and acrylic acid (AA) monomers (P(VCL-co-AA)) with a novel cross-linker, triethylene glycol dimethacrylate (TEGDMA), as a biocompatible and nontoxic component. The structural and physicochemical features of the P(VCL-co-AA) nanogel were characterized by FT-IR, DLS/Zeta potential, FE-SEM, and 1HNMR techniques. The results indicated that spherical polymeric nanogel was successfully synthesized with a 182 nm diameter. The results showed that the polymerization process continues with the opening of the carbon-carbon double bond of monomers, which was approved by C-C band removing located at 1600 cm−1. Doxorubicin (Dox) as a chemotherapeutic agent was loaded into the P(VCL-co-AA), whit a significant loading of Dox (83%), and the drug release profile was investigated in the physiological and cancerous site simulated conditions. P(VCL-co-AA) exhibited a pH and temperature-responsive behavior, with an enhanced release rate in the cancerous site condition. The biocompatibility and nontoxicity of P(VCL-co-AA) were approved by MTT assay on the normal human foreskin fibroblasts-2 (HFF-2) cell line. Also, Dox-loaded P(VCL-co-AA) had excellent toxic behavior on the Michigan Cancer Foundation-7 (MCF-7) cell line as model cancerous cells. Moreover, Dox-loaded P(VCL-co-AA) had higher toxicity in comparison with free Dox, which would be a vast advantage in reducing Dox side effects in the clinical cancer treatment applications.

[1]  Y. Hiruta.  Poly(N-isopropylacrylamide)-based temperature- and pH-responsive polymer materials for application in biomedical fields , 2022, Polymer Journal.

[2]  Wei Hong,et al.  Preparation of pH-responsive poly(methyl methacrylate) nanoparticles with CO2-triggered aggregation , 2022, Journal of Polymer Research.

[3]  D. Janas,et al.  Application of carbon nanotubes in sensing/monitoring of pancreas and liver cancer. , 2022, Chemosphere.

[4]  S. Han,et al.  Dual Responsive poly(vinyl caprolactam)-Based Nanogels for Tunable Intracellular Doxorubicin Delivery in Cancer Cells , 2022, Pharmaceutics.

[5]  Yuzhuo Wang,et al.  Doxorubicin-loaded graphene oxide nanocomposites in cancer medicine: stimuli-responsive carriers, co-delivery and suppressing resistance , 2022, Expert opinion on drug delivery.

[6]  V. Uskoković,et al.  Doxorubicin-Loaded, pH-Sensitive Albumin Nanoparticles for Lung Cancer Cell Targeting. , 2021, Journal of pharmaceutical sciences.

[7]  Ruilong Sheng,et al.  Novel Contact Lenses Embedded with Drug-Loaded Zwitterionic Nanogels for Extended Ophthalmic Drug Delivery , 2021, Nanomaterials.

[8]  S. Davaran,et al.  Synthesis of temperature/pH dual-responsive mesoporous silica nanoparticles by surface modification and radical polymerization for anti-cancer drug delivery , 2021 .

[9]  Kuen-Song Lin,et al.  In vitro study of doxorubicin-loaded thermo- and pH-tunable carriers for targeted drug delivery to liver cancer cells , 2021, Journal of Industrial and Engineering Chemistry.

[10]  A. Alam,et al.  Dual Targeting Smart Drug Delivery System for Multimodal Synergistic Combination Cancer Therapy with Reduced Cardiotoxicity. , 2021, Acta biomaterialia.

[11]  S. Davaran,et al.  Direct surface modification of mesoporous silica nanoparticles by DBD plasma as a green approach to prepare dual-responsive drug delivery system , 2021 .

[12]  Solmaz Maleki Dizaj,et al.  Application of Advanced Nanomaterials for Kidney Failure Treatment and Regeneration , 2021, Materials.

[13]  M. Cucchiarini,et al.  The Potential Application of Magnetic Nanoparticles for Liver Fibrosis Theranostics , 2021, Frontiers in Chemistry.

[14]  S. Davaran,et al.  Preparation and in-vitro evaluation of mesoporous biogenic silica nanoparticles obtained from rice and wheat husk as a biocompatible carrier for anti-cancer drug delivery. , 2021, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[15]  W. Dehaen,et al.  Synthesis of pH-sensitive nanocarriers based on polyacrylamide grafted nanocrystalline cellulose for targeted drug delivery to folate receptor in breast cancer cells , 2021 .

[16]  H. Thu,et al.  Recent Advancements in Stimuli Responsive Drug Delivery Platforms for Active and Passive Cancer Targeting , 2021, Cancers.

[17]  A. Akbarzadeh,et al.  An improved method in fabrication of smart dual-responsive nanogels for controlled release of doxorubicin and curcumin in HT-29 colon cancer cells , 2021, Journal of Nanobiotechnology.

[18]  Shuh‐Kuen Chang,et al.  Temperature and pH Dual Responsive Nanogels of Modified Sodium Alginate and NIPAM for Berberine Loading and Release , 2021, ACS omega.

[19]  D. Aebisher,et al.  An analytical study of Trastuzumab-dendrimer-fluorine drug delivery system in breast cancer therapy in vitro. , 2021, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[20]  I. Lambrinoudaki,et al.  Updates on the treatment of invasive breast cancer: Quo Vadimus? , 2020, Maturitas.

[21]  Hua-lin Liao,et al.  Molecular dynamics study of the thermosensitive properties of poly (N-vinyl caprolactam) in water , 2021 .

[22]  Jun Huang,et al.  pH-Sensitive nanogels for drug delivery in cancer therapy. , 2020, Biomaterials science.

[23]  Renjith P. Johnson,et al.  Recent developments in stimuli-responsive polymer nanogels for drug delivery and diagnostics: A Review. , 2020, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[24]  S. Sadeghi,et al.  PTBP1 correlates with HER2 positivity, lymph node spread and metastasis in breast cancer , 2020 .

[25]  R. Khalilov,et al.  Effects of quercetin loaded nanostructured lipid carriers on the paraquat-induced toxicity in human lymphocytes. , 2020, Pesticide biochemistry and physiology.

[26]  Man Li,et al.  Facile Strategy by Hyaluronic Acid Functional Carbon Dot-Doxorubicin Nanoparticles for CD44 Targeted Drug Delivery and Enhanced Breast Cancer Therapy. , 2020, International journal of pharmaceutics.

[27]  M. Mutlu,et al.  Controlled release of doxorubicin from polyethylene glycol functionalized melanin nanoparticles for breast cancer therapy: Part I. Production and drug release performance of the melanin nanoparticles. , 2019, International journal of pharmaceutics.

[28]  M. Samiei,et al.  The Potential Applications of Hyaluronic Acid Hydrogels in Biomedicine , 2019, Drug Research.

[29]  Luke M. Geever,et al.  Synthesis and Characterisation of Novel Temperature and pH Sensitive Physically Cross-Linked Poly(N-vinylcaprolactam-co-itaconic Acid) Hydrogels for Drug Delivery , 2019, Gels.

[30]  H. Han,et al.  Advanced drug delivery system with nanomaterials for personalised medicine to treat breast cancer , 2019, Journal of Drug Delivery Science and Technology.

[31]  Michael R Hamblin,et al.  Stimulus-Responsive Polymeric Nanogels as Smart Drug Delivery Systems , 2019, Acta biomaterialia.

[32]  Seamus D. Jones,et al.  Tuning PNIPAm self-assembly and thermoresponse: roles of hydrophobic end-groups and hydrophilic comonomer , 2019, Polymer Chemistry.

[33]  A. Okudan,et al.  Investigation of the Effects of Different Hydrophilic and Hydrophobic Comonomers on the Volume Phase Transition Temperatures and Thermal Properties of N-Isopropylacrylamide-Based Hydrogels , 2019, International Journal of Polymer Science.

[34]  Aftab Ahmad,et al.  Enhanced antitumour activity of doxorubicin and simvastatin combination loaded nanoemulsion treatment against a Swiss albino mouse model of Ehrlich ascites carcinoma , 2019, Clinical and experimental pharmacology & physiology.

[35]  M. Muñoz-Fernández,et al.  Poly(N-vinylcaprolactam) Nanogels with Antiviral Behavior against HIV-1 Infection , 2019, Scientific Reports.

[36]  Joseph A. Hill,et al.  Doxorubicin-induced cardiomyopathy associated with inhibition of autophagic degradation process and defects in mitochondrial respiration , 2019, Scientific Reports.

[37]  T. Etrych,et al.  Polymeric nanogels as drug delivery systems. , 2018, Physiological research.

[38]  Lijuan Feng,et al.  pH‐sensitive polymeric particles as smart carriers for rebar inhibitors delivery in alkaline condition , 2018 .

[39]  M. Eghbal,et al.  The Effects of Cimetidine, N-Acetylcysteine, and Taurine on Thioridazine Metabolic Activation and Induction of Oxidative Stress in Isolated Rat Hepatocytes , 2018, Pharmaceutical Chemistry Journal.

[40]  Y. Kamal,et al.  Poly(N-vinyl caprolactam) thermoresponsive polymer in novel drug delivery systems: A review , 2018 .

[41]  I. Estrela-Lopis,et al.  Nanocapsules for the co-delivery of selol and doxorubicin to breast adenocarcinoma 4T1 cells in vitro , 2017, Artificial cells, nanomedicine, and biotechnology.

[42]  M. Eghbal,et al.  Anti-Cancer Effects of Citalopram on Hepatocellular Carcinoma Cells Occur via Cytochrome C Release and the Activation of NF-kB. , 2017, Anti-cancer agents in medicinal chemistry.

[43]  A. Akbarzadeh,et al.  An update on applications of nanostructured drug delivery systems in cancer therapy: a review , 2017, Artificial cells, nanomedicine, and biotechnology.

[44]  M. Eghbal,et al.  Mechanistic Approach for Toxic Effects of Bupropion in Primary Rat Hepatocytes , 2017, Drug Research.

[45]  Yan Liu,et al.  Highly efficient removal of uranium(VI) from wastewater by polyacrylic acid hydrogels , 2017 .

[46]  C. Ha,et al.  Stimuli Responsive Poly(Vinyl Caprolactam) Gels for Biomedical Applications , 2016, Gels.

[47]  Wei Dong,et al.  Preparation and characterization of a novel pH-sensitive Salecan-g-poly(acrylic acid) hydrogel for controlled release of doxorubicin. , 2015, Journal of materials chemistry. B.

[48]  W. Xia,et al.  Combination delivery of Adjudin and Doxorubicin via integrating drug conjugation and nanocarrier approaches for the treatment of drug-resistant cancer cells. , 2015, Journal of materials chemistry. B.

[49]  N. Yusof,et al.  Doxorubicin-loaded magnetic gold nanoshells for a combination therapy of hyperthermia and drug delivery. , 2014, Journal of colloid and interface science.

[50]  A. Usanmaz,et al.  Polymerization of N-Vinylcaprolactam and Characterization of Poly(N-Vinylcaprolactam) , 2011 .