4.8 Article

Polymeric and small molecule-conjugates of temozolomide as improved therapeutic agents for glioblastoma multiforme

Journal

JOURNAL OF CONTROLLED RELEASE
Volume 350, Issue -, Pages 494-513

Publisher

ELSEVIER
DOI: 10.1016/j.jconrel.2022.08.024

Keywords

Glioblastoma Multiforme; Temozolomide; Polymer drug conjugates; Prodrugs; Small molecules

Funding

  1. Department of Biotechnology (DBT) , Ministry of Science and Technology [BT/PR22123/NNT/28/1120/2016]
  2. Lady Tata Memorial Trust (LTMT)
  3. Department of Science and Technology (DST) [2018/IF180652]

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Temozolomide (TMZ) is an important first-line treatment drug for glioblastoma multiforme (GBM), but it has limitations. Nanocarriers and conjugation approaches have been used to improve the therapeutic potential of TMZ.
Temozolomide (TMZ), an imidazotetrazine, is a second-generation DNA alkylating agent used as a first-line treatment of glioblastoma multiforme (GBM). It was approved by FDA in 2005 and declared a blockbuster drug in 2008. Although TMZ has shown 100% oral bioavailability and crosses the blood-brain barrier effectively, however it suffers from limitations such as a short half-life (similar to 1.8 h), rapid metabolism, and lesser accumulation in the brain (similar to 10-20%). Additionally, development of chemoresistance has been associated with its use. Since it is a potential chemotherapeutic agent with an unmet medical need, advanced delivery strategies have been explored to overcome the associated limitations of TMZ. Nanocarriers including liposomes, solid lipid nanoparticles (SLNs), nanostructure lipid carriers (NLCs), and polymeric nanoparticles have demonstrated their ability to improve its circulation time, stability, tissue-specific accumulation, sustained release, and cellular uptake. Because of the appreciable water solubility of TMZ (similar to 5 mg/mL), the physical loading of TMZ in these nanocarriers is always challenging. Alternatively, the conjugation approach, wherein TMZ has been conjugated to polymers or small molecules, has been explored with improved outcomes in vitro and in vivo. This review emphasized the practical evidence of the conjugation strategy to improve the therapeutic potential of TMZ in the treatment of glioblastoma multiforme.

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