Advances in Targeted Glioma Therapy with Transferrin-Conjugated Gemcitabine-Loaded PLGA Nanoparticles

Ladi Alik Kumar; Gurudutta Pattnaik; Bhabani Sankar; *; Himansu Bhusan Samal; *

doi:10.25163/angiotherapy.859634

Angiogenesis, Inflammation & Therapeutics | Online ISSN 2207-872X

RESEARCH ARTICLE (Open Access)

Previous Next Contents Vol 8 (5)

Advances in Targeted Glioma Therapy with Transferrin-Conjugated Gemcitabine-Loaded PLGA Nanoparticles

Ladi Alik Kumar ¹, Gurudutta Pattnaik ¹, Bhabani Sankar Satapathy^2,*, Himansu Bhusan Samal ^{1, *}

+ Author Affiliations

Journal of Angiotherapy 8 (5) 1-12 https://doi.org/10.25163/angiotherapy.859634

Submitted: 27 March 2024 Revised: 12 May 2024 Published: 14 May 2024

Abstract

Primary brain tumor Glioma has one of the highest fatality rates among brain cancers. Conventional chemotherapy for glioma often suffers from off-target drug loss and suboptimal drug availability in brain tissue. This study aimed to develop a targeted strategy for brain cancer cells using transferrin-conjugated, gemcitabine-loaded poly(lactic-co-glycolic acid) nanoparticles (Tf-GB-PLGA-NPs). GB-PLGA-NPs were prepared via solvent evaporation and nanoprecipitation, followed by conjugation with transferrin. The formulation was characterized for physicochemical properties, in-vitro release, cytotoxicity, apoptosis (U87MG cell line), and in-vivo pharmacokinetics. Tf-GB-PLGA-NPs exhibited a particle size of 143±6.23 nm, a PDI of 0.213, a zeta potential of -25 mV, and an entrapment efficiency of 77.53±1.43%. These nanoparticles showed a spherical morphology and sustained release of gemcitabine (76.54±4.08%) over 24 hours. Tf-GB-PLGA-NPs demonstrated significantly higher cell inhibition against the U87MG cell line compared to GB-PLGA-NPs and pure gemcitabine (P<0.05). Apoptosis in U87MG cells was higher with Tf-GB-PLGA-NPs (61.25%) than with GB-PLGA-NPs (31.61%). Additionally, Tf-GB-PLGA-NPs achieved significantly higher concentrations in the brain than pure gemcitabine and GB-PLGA-NPs, with a 11.16-fold increase in AUC0-t (bioavailability) compared to pure gemcitabine solution and a 2.23-fold increase compared to GB-PLGA-NPs. These findings suggest that Tf-GB-PLGA-NPs could be a potent alternative carrier for delivering gemcitabine to the brain for glioma treatment.

Keywords: Glioma, Transferrin, PLGA nanoparticles, Gemcitabine. U87MG. Apoptosis, Pharmacokinetic

References

Chang J, Jallouli Y, Kroubi M, Yuan XB, Feng W, Kang CS, Pu PY, Betbeder D. (2009). Characterization of endocytosis of transferrin-coated PLGA nanoparticles by the blood–brain barrier. Inte jour. of pharma, 379(2), 285-92.

Chang J, Paillard A, Passirani C, Morille M, Benoit JP, Betbeder D, Garcion E. (2012). Transferrin adsorption onto PLGA nanoparticles governs their interaction with biological systems from blood circulation to brain cancer cells. Pharma. Research, 29, 1495-505.

Cui Y, Xu Q, Chow P.K.-H, Wang D, Wang C.-H. (2013). Transferrin-Conjugated Magnetic Silica PLGA Nanoparticles Loaded with Doxorubicin and Paclitaxel for Brain Glioma Treatment. Biomaterials, 34, 8511–8520.

Cui Y, Xu Q, Chow PK, Wang D, Wang CH. (2013). Transferrin-conjugated magnetic silica PLGA nanoparticles loaded with doxorubicin and paclitaxel for brain glioma treatment. Biomater, 34(33), 8511-20.

Derycke ASL, Kamuhabwa A, Gijsens A, Roskams T, De Vos D, Kasran A, Huwyler J, Missiaen L, De Witte P.A.M. (2004). Transferrin-Conjugated Liposome Targeting of Photosensitizer AlPcS 4 to Rat Bladder Carcinoma Cells. JNCI J. Natl. Cancer Inst, 96, 1620–1630.

Derycke ASL, Kamuhabwa A, Gijsens A, Roskams T, De Vos D, Kasran A, Huwyler J, Missiaen, L.; de Witte, P.A.M. (2004). Transferrin-Conjugated Liposome Targeting of Photosensitizer AlPcS 4 to Rat Bladder Carcinoma Cells. JNCI J. Natl. Cancer Inst, 96, 1620–1630.

Doijad RC, Manvi FV, Godhwani DM, Joseph R, Deshmukh NV. (2008). Formulation and targeting efficiency of Cisplatin engineered solid lipid nanoparticles. Indian J Pharm Sci, 70(2), 203-7.

Dyawanapelly S, Kumar A, Chourasia, MK. (2017). Lessons learned from gemcitabine: Impact of therapeutic carrier systems and gemcitabine’s drug conjugates on cancer therapy. Critical Reviews™ in Thera. Drug Carr Syst, 34(1), 63-96.

Fathi Kazerooni, A Bakas ,S Saligheh Rad, H Davatzikos C.(2020). Imaging signatures of glioblastoma molecular characteristics: a radiogenomics review. J. Magn.Reson.Imaging, 52 , 54-69.

Fazil M, Baboota S, Sahni JK, Ameeduzzafar, Ali J. (2015). Bisphosphonates: therapeutics potential and recent advances in drug delivery. Drug Deliv, 22(1), 1-9.

Ferraris C, Cavalli R, Panciani PP, Battaglia L. (2020). Overcoming the blood–brain barrier: successes and challenges in developing nanoparticle-mediated drug delivery systems for the treatment of brain tumours. Int. jour. of nanomed, 30, 2999-3022.

Gurumukhi, V.C.; Bari, S.B. (2022). Quality by Design (QbD)-Based Fabrication of Atazanavir-Loaded Nanostructured Lipid Carriers for Lymph Targeting: Bioavailability Enhancement Using Chylomicron Flow Block Model and Toxicity Studies. Drug Deliv. Transl. Res, 12, 1230–1252.

Hersom M, Helms HC, Pretzer N, Goldeman C, Jensen AI, Severin G, Nielsen MS, Holm R, Brodin B.(2016). Transferrin receptor expression and role in transendothelial transport of transferrin in cultured brain endothelial monolayers. Mole. and Cell. Neuro, 76, 59-67.

Hormuth II DA, Farhat M, Christenson C, Curl B, Quarles CC, Chung C, Yankeelov TE. (2022). Opportunities for improving brain cancer treatment outcomes through imaging-based mathematical modeling of the delivery of radiotherapy and immunotherapy. Adv.Drug Deliv.Rev, 187, 1143-1167

Ikram Ullah Khan. (2023). Synthesis, Characterization and Biomedical Potential of Peptide-Gold Nanoparticle Hydrogels, Biosensors and Nanotheranostics, 2(1), 1-6, 9821

Kashfia Haque, Muhit Rana et al. (2023). Biodegradable Nanoparticles for Sustainable Drug Delivery, Biosensors and Nanotheranostics, 2(1), 1-9, 7334

Koneru T, Mc Cord E, Pawar S, Tatiparti K, Sau S, Iyer AK. (2021). Transferrin: biology and use in receptor-targeted nanotherapy ofgliomas. ACS omega, 6(13), 8727-33.

Kumar LA, Pattnaik G, Satapathy Bhabani S, Mohanty D, Prashanth PA, Dey S, Debata, J. (2024). Preparation and Optimization of Gemcitabine Loaded PLGA Nanoparticle Using Box-Behnken Design for Targeting to Brain: In Vitro Characterization, Cytotoxicity and Apoptosis Study. Curr Nanomat, 9(4), 324-338.

Kumar LA, Pattnaik G, Satapathy BS, Swapna S, Mohanty D.(2021). Targeting to brain tumor: Nanocarrier-based drug delivery platforms, opportunities, and challenges. J. Pharm. Bioallied Sci, 13, 172-177

Li L, Zhang X, Zhou J, Zhang L, Xue J, Tao W.(2022). Non-invasive thermal therapy for tissue engineering and regenerative medicine. Small, 18(36), 2107705-22.

Luo H, Zhang H, Mao J, Cao H, Tao Y, Zhao G, Zhang Z, Zhang N, Liu Z, Zhang, J Luo P. (2023). Exosome-based nanoimmunotherapy targeting TAMs, a promising strategy for glioma. Cell Dea & Dis, 14(4), 235-249.

Maghsoudi S, Taghavi Shahraki B, Rabiee N, Fatahi Y, Dinarvand R, Tavakolizadeh M, Ahmadi S, Rabiee M, Bagherzadeh M, Pourjavadi A, Farhadnejad H, Tahriri M, Webster TJ, Tayebi L. (2020) Burgeoning Polymer Nano Blends for Improved Controlled Drug Release: A Review. Int J Nanomedicine, 15, 4363-4392.

Md Shamsuddin Sultan Khan, Mohammad Adnan Iqbal, Muhammad Asif, Tabinda Azam, Majed Al-Mansoub, Rosenani S. M. A. Haque, Mohammed Khadeer Ahamed Basheer, Aman Shah Abdul Majid, Amin Malik Shah Abdul Majid1, (2019). Anti-GBM potential of Rosmarinic acid and its synthetic derivatives via targeting IL17A mediated angiogenesis pathway. Journal of Angiotherapy, 2(1), 011-011.

Md Shamsuddin Sultan Khan. (2017). Why Interleukin 17A is the most Potential Next Generation Drug Target in Angiogenesis-mediated diseases. Angiotherapy, 1(1), pages 030-032

Mitra S, Gaur U, Ghosh PC, Maitra AN. (2001). Tumour targeted delivery of encapsulated dextran-doxorubicin conjugate using chitosan nanoparticles as carrier. J Control Release, 74(1-3), 317-23.

Muhit Rana, Kashfia Haque et al. (2023). Nanoparticle-Enhanced Drug Delivery Systems for Targeted Cancer Therapy, Biosensors and Nanotheranostics, 2(1), 1-9, 7332

Nogueira-Librelotto D, Codevilla C, Farooqi A, MB Rolim, C. (2017). Transferrin-Conjugated Nanocarriers as Active-Targeted Drug Delivery Platforms for Cancer Therapy. Curr. Pharm. Des, 23, 454–466.

Nogueira-Librelotto DR, Codevilla CF, Farooqi A, Rolim CM. (2017). Transferrin-Conjugated Nanocarriers as Active-Targeted Drug Delivery Platforms for Cancer Therapy. Curr Pharm Des, 23(3), 454-466.

Pavithra Suppiah, Julia Joseph, Rolla Al-Shalabi, Nik Nur Syazni Nik Mohamed kamal, Nozlena Abdul Samad, (2022). Therapeutic Targeting on Death Pathways In Glioblastoma, Journal of Angiotherapy, 6(2), 637-645, 4312

Qian ZM, Li H, Sun H, Ho K. (2002). Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway. Pharmacol Rev, 54(4), 561-87.

Rai VK, Mishra N, Yadav KS, Yadav NP. (2018). Nanoemulsion as pharmaceutical carrier for dermal and transdermal drug delivery: Formulation development, stability issues, basic considerations and applications. J Control Release, 270, 203-225.

Ramalho MJ, Bravo M, Loureiro JA, Lima J, Pereira MC. (2022). Transferrin-modified nanoparticles for targeted delivery of Asiatic acid to glioblastoma cells. Lif Scie, 296, 120435-47.

Ramalho MJ, Torres ID, Loureiro JA, Lima J, Pereira MC. (2023). Transferrin-conjugated plga nanoparticles for co-delivery of Temozolomide and Bortezomib to glioblastoma cells. ACS Applied Nano Mate, 6(15), 14191-203.

Seker-Polat F, Pinarbasi Degirmenci N, Solaroglu I, Bagci-Onder T.(2022). Tumor cell infiltration into the brain in glioblastoma: from mechanisms to clinical perspectives. Cancers, 14, 443.

Shabani L, Abbasi M, Azarnew Z, Amani AM, Vaez A. (2023). Neuro-nanotechnology: diagnostic and therapeutic nano-based strategies in applied neuroscience. BioMed.Engi. OnLine, 22(1), 1-41.

Shah MA, Schwartz GK. (2006). Cyclin dependent kinases as targets for cancer therapy. Update on cancer therapeutics, 1(3), 311-32.

Su X, Zhang X, Liu W, Yang X, An N, Yang F, Sun J, Xing Y, Shang H. (2022). Advances in the application of nanotechnology in reducing cardiotoxicity induced by cancer chemotherapy. InSem. in Can Bio, 86, 929-942.

Tavano L, Muzzalupo R, Mauro L, Pellegrino M, Andò S, Picci N. (2013). Transferrin-Conjugated Pluronic Niosomes as a New Drug Delivery System for Anticancer Therapy. Langmuir, 29, 12638–12646.

Tiwari P, Yadav K, Shukla RP, Gautam S, Marwaha D, Sharma M, Mishra PR.(2023). Surface modification strategies in translocating nano-vesicles across different barriers and the role of bio-vesicles in improving anticancer therapy. Jour. of Contr. Rele, 363, 290-348.

Wang D, Wang C, Wang L, Chen Y. (2019). A comprehensive review in improving delivery of small-molecule chemotherapeutic agents overcoming the blood-brain/brain tumor barriers for glioblastoma treatment. Drug deliv, 26(1), 551-65.

Zeb A, Gul M, Nguyen TTL, Maeng HJ. (2022) Controlled release and targeted drug delivery with poly(lactic-co-glycolic acid) nanoparticles: reviewing two decades of research. J. Pharm. Invest, 52, 683−724.

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