Harnessing Lipid Polymer Hybrid Nanoparticles for Enhanced Oral Bioavailability of Thymoquinone: In Vitro and In Vivo Assessments

The clinical application of phytochemicals such as thymoquinone (THQ) is restricted due to their limited aqueous solubility and oral bioavailability. Developing mucoadhesive nanocarriers to deliver these natural compounds might provide new hope to enhance their oral bioavailability. Herein, this investigation aimed to develop THQ-loaded lipid-polymer hybrid nanoparticles (THQ-LPHNPs) based on natural polymer chitosan. THQ-LPHNPs were fabricated by the nanoprecipitation technique and optimized by the 3-factor 3-level Box–Behnken design. The optimized LPHNPs represented excellent properties for ideal THQ delivery for oral administration. The optimized THQ-LPHNPs revealed the particles size (PS), polydispersity index (PDI), entrapment efficiency (%EE), and zeta potential (ZP) of <200 nm, <0.25, >85%, and >25 mV, respectively. THQ-LPHNPs represented excellent stability in the gastrointestinal milieu and storage stability in different environmental conditions. THQ-LPHNPs represented almost similar release profiles in both gastric as well as intestinal media with the initial fast release for 4 h and after that a sustained release up to 48 h. Further, the optimized THQ-LPHNPs represent excellent mucin binding efficiency (>70%). Cytotoxicity study revealed much better anti-breast cancer activity of THQ-LPHNPs compared with free THQ against MDA-MB-231 and MCF-7 breast cancer cells. Moreover, ex vivo experiments revealed more than three times higher permeation from the intestine after THQ-LPHNPs administration compared to the conventional THQ suspension. Furthermore, the THQ-LPHNPs showed 4.74-fold enhanced bioavailability after oral administration in comparison with the conventional THQ suspension. Therefore, from the above outcomes, mucoadhesive LPHNPs might be suitable nano-scale carriers for enhanced oral bioavailability and therapeutic efficacy of highly lipophilic phytochemicals such as THQ.

[1]  Linjie Wu,et al.  Construction and Evaluation of Chitosan-Based Nanoparticles for Oral Administration of Exenatide in Type 2 Diabetic Rats , 2022, Polymers.

[2]  M. Hashemi,et al.  Bromelain Loaded Lipid-Polymer Hybrid Nanoparticles for Oral Delivery: Formulation and Characterization , 2022, Applied Biochemistry and Biotechnology.

[3]  S. S. Imam,et al.  Formulation and Evaluation of Apigenin-Loaded Hybrid Nanoparticles , 2022, Pharmaceutics.

[4]  S. S. Imam,et al.  Formulation of Piperine Nanoparticles: In Vitro Breast Cancer Cell Line and In Vivo Evaluation , 2022, Polymers.

[5]  P. R. Vuddanda,et al.  Receptor-Targeted Surface-Engineered Nanomaterials for Breast Cancer Imaging and Theranostic Applications. , 2022, Critical reviews in therapeutic drug carrier systems.

[6]  Deepa Geethakumari,et al.  Folate Functionalized Chitosan Nanoparticles as Targeted Delivery Systems for improved anticancer efficiency of Cytarabine in MCF-7 human breast cancer cell lines. , 2021, International journal of biological macromolecules.

[7]  M. Ghoneim,et al.  Receptor-Mediated Targeted Delivery of Surface-ModifiedNanomedicine in Breast Cancer: Recent Update and Challenges , 2021, Pharmaceutics.

[8]  M. Ghoneim,et al.  Recent Advancement in Chitosan-Based Nanoparticles for Improved Oral Bioavailability and Bioactivity of Phytochemicals: Challenges and Perspectives , 2021, Polymers.

[9]  Tianyang Ren,et al.  Bioadhesive poly(methyl vinyl ether-co-maleic anhydride)-TPGS copolymer modified PLGA/lipid hybrid nanoparticles for improving intestinal absorption of cabazitaxel. , 2021, International journal of pharmaceutics.

[10]  Satish K. Sharma,et al.  Thymoquinone loaded chitosan - Solid lipid nanoparticles: Formulation optimization to oral bioavailability study , 2021 .

[11]  H. Smyth,et al.  Improved intestinal absorption and oral bioavailability of astaxanthin via poly (ethylene glycol)-graft-chitosan nanoparticle: preparation, in vitro evaluation and pharmacokinetics in rats. , 2021, Journal of the science of food and agriculture.

[12]  S. Mir,et al.  Exemestane encapsulated polymer-lipid hybrid nanoparticles for improved efficacy against breast cancer: optimization, in vitro characterization and cell culture studies , 2021, Nanotechnology.

[13]  Ruizhi Zhao,et al.  Exploring the potential of functional polymer-lipid hybrid nanoparticles for enhanced oral delivery of paclitaxel , 2021, Asian journal of pharmaceutical sciences.

[14]  P. Opanasopit,et al.  Mucoadhesive chitosan and thiolated chitosan nanoparticles containing alpha mangostin for possible Colon-targeted delivery , 2021, Pharmaceutical development and technology.

[15]  Xiaoyong Song,et al.  Bioadhesive polymer/lipid hybrid nanoparticles as oral delivery system of raloxifene with enhancive intestinal retention and bioavailability , 2021, Drug delivery.

[16]  Rizwanullah,et al.  Effect of Chitosan Coating on PLGA Nanoparticles for Oral Delivery of Thymoquinone: In Vitro, Ex Vivo, and Cancer Cell Line Assessments , 2020, Coatings.

[17]  J. Venugopal,et al.  PEGylated Lipid Polymeric Nanoparticle–Encapsulated Acyclovir for In Vitro Controlled Release and Ex Vivo Gut Sac Permeation , 2020, AAPS PharmSciTech.

[18]  R. Harwansh,et al.  Breast cancer: An insight into its inflammatory, molecular, pathological and targeted facets with update on investigational drugs. , 2020, Critical reviews in oncology/hematology.

[19]  Leonardo M. B. Ferreira,et al.  Modulating chitosan-PLGA nanoparticle properties to design a co-delivery platform for glioblastoma therapy intended for nose-to-brain route , 2020, Drug Delivery and Translational Research.

[20]  V. Jain,et al.  A review of nanotechnology-based approaches for breast cancer and triple-negative breast cancer. , 2020, Journal of controlled release : official journal of the Controlled Release Society.

[21]  S. Mir,et al.  Bilosomes nanocarriers for improved oral bioavailability of acyclovir: A complete characterization through in vitro, ex-vivo and in vivo assessment , 2020 .

[22]  Mahfoozur Rahman,et al.  Polymer-Lipid Hybrid Systems: Scope of Intravenous-To-Oral Switch in Cancer Chemotherapy , 2020 .

[23]  S. Reis,et al.  Mucoadhesive and pH responsive fucoidan-chitosan nanoparticles for the oral delivery of methotrexate. , 2020, International journal of biological macromolecules.

[24]  D. Mooney,et al.  A nanoparticle’s pathway into tumours , 2020, Nature Materials.

[25]  S. Chattopadhyay,et al.  Delivery of thymoquinone through hyaluronic acid-decorated mixed Pluronic® nanoparticles to attenuate angiogenesis and metastasis of triple-negative breast cancer. , 2020, Journal of controlled release : official journal of the Controlled Release Society.

[26]  S. Takka,et al.  Antıtumor actıvıty of gemcitabine hydrochloride loaded lipid polymer hybrid nanoparticles (LPHNS) ın vıtro and ın vıvo. , 2020, International journal of pharmaceutics.

[27]  S. Mitragotri,et al.  Permeation of nanoparticles across the intestinal lipid membrane: dependence on shape and surface chemistry studied through molecular simulations. , 2020, Nanoscale.

[28]  D. Chellappan,et al.  Nanocarriers: more than tour de force for thymoquinone , 2020, Expert opinion on drug delivery.

[29]  E. Davies,et al.  Breast cancer , 2020, Medicine.

[30]  Harshita,et al.  Polymer-Lipid Hybrid Nanoparticles: A Next-Generation Nanocarrier for Targeted Treatment of Solid Tumors. , 2020, Current pharmaceutical design.

[31]  P. Mishra,et al.  Thymoquinone loaded mesoporous silica nanoparticles retard cell invasion and enhance in vitro cytotoxicity due to ROS mediated apoptosis in HeLa and MCF-7 cell lines. , 2019, Materials science & engineering. C, Materials for biological applications.

[32]  M. A. Mirza,et al.  Formulation and evaluation of thymoquinone niosomes: application of developed and validated RP-HPLC method in delivery system , 2019, Drug Development and Industrial Pharmacy.

[33]  M. Moghaddam,et al.  Polymeric nanoparticles as carrier for targeted and controlled delivery of anticancer agents. , 2019, Therapeutic delivery.

[34]  Chandrakala,et al.  Formulation of thymoquinone loaded chitosan nano vesicles: In-vitro evaluation and in-vivo anti-hyperlipidemic assessment , 2019, Journal of Drug Delivery Science and Technology.

[35]  S. Kesari,et al.  Lipid–polymer hybrid nanoparticles as a next-generation drug delivery platform: state of the art, emerging technologies, and perspectives , 2019, International journal of nanomedicine.

[36]  J. Sousa,et al.  Rethinking carbamazepine oral delivery using polymer‐lipid hybrid nanoparticles , 2019, International journal of pharmaceutics.

[37]  S. Mousa,et al.  Protective Roles of Thymoquinone Nanoformulations: Potential Nanonutraceuticals in Human Diseases , 2018, Nutrients.

[38]  Wei Keat Ng,et al.  Thymoquinone loaded in nanostructured lipid carrier showed enhanced anticancer activity in 4T1 tumor-bearing mice. , 2018, Nanomedicine.

[39]  M. R. Mozafari,et al.  Impact of Particle Size and Polydispersity Index on the Clinical Applications of Lipidic Nanocarrier Systems , 2018, Pharmaceutics.

[40]  Bhupinder Singh,et al.  Chitosan-tailored lipidic nanoconstructs of Fusidic acid as promising vehicle for wound infections: An explorative study. , 2018, International journal of biological macromolecules.

[41]  A. C. Jayasuriya,et al.  Drug transport mechanisms and in vitro release kinetics of vancomycin encapsulated chitosan‐alginate polyelectrolyte microparticles as a controlled drug delivery system , 2018, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[42]  H. Gali-Muhtasib,et al.  Thymoquinone-based nanotechnology for cancer therapy: promises and challenges. , 2018, Drug discovery today.

[43]  S. Mir,et al.  Phytochemical based nanomedicines against cancer: current status and future prospects , 2017, Journal of drug targeting.

[44]  P. Rameshthangam,et al.  Anticancer activity of silver and copper embedded chitin nanocomposites against human breast cancer (MCF-7) cells. , 2017, International journal of biological macromolecules.

[45]  H. Santos,et al.  Development and optimization of methotrexate-loaded lipid-polymer hybrid nanoparticles for controlled drug delivery applications. , 2017, International journal of pharmaceutics.

[46]  M. Raish,et al.  Oral bioavailability enhancement and hepatoprotective effects of thymoquinone by self-nanoemulsifying drug delivery system. , 2017, Materials science & engineering. C, Materials for biological applications.

[47]  C. Dora,et al.  Nanostructured lipid carriers of olmesartan medoxomil with enhanced oral bioavailability. , 2017, Colloids and surfaces. B, Biointerfaces.

[48]  Mingtao Ao,et al.  PEG–lipid–PLGA hybrid nanoparticles loaded with berberine–phospholipid complex to facilitate the oral delivery efficiency , 2017, Drug delivery.

[49]  Sumathi Thangarajan,et al.  A novel therapeutic application of solid lipid nanoparticles encapsulated thymoquinone (TQ-SLNs) on 3-nitroproponic acid induced Huntington's disease-like symptoms in wistar rats. , 2016, Chemico-biological interactions.

[50]  C. Prestidge,et al.  Polymer-lipid hybrid systems: merging the benefits of polymeric and lipid-based nanocarriers to improve oral drug delivery , 2016, Expert opinion on drug delivery.

[51]  Gajanand Sharma,et al.  Fabrication, characterization and cytotoxicity studies of ionically cross-linked docetaxel loaded chitosan nanoparticles. , 2016, Carbohydrate polymers.

[52]  P. Fisher,et al.  Overcoming Akt Induced Therapeutic Resistance in Breast Cancer through siRNA and Thymoquinone Encapsulated Multilamellar Gold Niosomes. , 2015, Molecular pharmaceutics.

[53]  Ravi R. Patel,et al.  Rationally developed core–shell polymeric-lipid hybrid nanoparticles as a delivery vehicle for cromolyn sodium: implications of lipid envelop on in vitro and in vivo behaviour of nanoparticles upon oral administration , 2015 .

[54]  R. Tyagi,et al.  Development and characterization of single step self-assembled lipid polymer hybrid nanoparticles for effective delivery of methotrexate , 2015 .

[55]  A. Hosseinzadeh Colagar,et al.  Thymoquinone and its therapeutic potentials. , 2015, Pharmacological research.

[56]  Ravi R. Patel,et al.  Formulation and optimization of itraconazole polymeric lipid hybrid nanoparticles (Lipomer) using box behnken design , 2015, DARU Journal of Pharmaceutical Sciences.

[57]  Neeraj Kumar,et al.  Lipid based nanocarrier system for the potential oral delivery of decitabine: formulation design, characterization, ex vivo, and in vivo assessment. , 2014, International journal of pharmaceutics.

[58]  J. Morgado-Díaz,et al.  Cytotoxic effects of Euterpe oleracea Mart. in malignant cell lines , 2014, BMC Complementary and Alternative Medicine.

[59]  Mushir M. Ali,et al.  Lipid drug conjugate nanoparticle as a novel lipid nanocarrier for the oral delivery of decitabine: ex vivo gut permeation studies , 2013, Nanotechnology.

[60]  Hsing-Wen Sung,et al.  Recent advances in chitosan-based nanoparticles for oral delivery of macromolecules. , 2013, Advanced drug delivery reviews.

[61]  Lingxue Kong,et al.  Chitosan-Modified PLGA Nanoparticles with Versatile Surface for Improved Drug Delivery , 2013, AAPS PharmSciTech.

[62]  G. Mustafa,et al.  Development and evaluation of thymoquinone-encapsulated chitosan nanoparticles for nose-to-brain targeting: a pharmacoscintigraphic study , 2012, International journal of nanomedicine.

[63]  S. Ostad,et al.  Discriminated effects of thiolated chitosan-coated pMMA paclitaxel-loaded nanoparticles on different normal and cancer cell lines. , 2010, Nanomedicine : nanotechnology, biology, and medicine.

[64]  I. Warner,et al.  Delivery of phytochemical thymoquinone using molecular micelle modified poly(D, L lactide-co-glycolide) (PLGA) nanoparticles , 2010, Nanotechnology.

[65]  N. Peppas,et al.  Mechanisms of solute release from porous hydrophilic polymers , 1983 .