Skip to main content
2023 BMES Annual Meeting Main banner
Icon Legend
This session is not in your schedule.
This session is in your schedule. Click again to remove it.
Back

    Drug Delivery

    (L-472) Polymersomes as Chemotherapeutic Agents for Non-Invasive Treatment of Glioblastoma

    Saturday, October 14, 2023
    9:30 AM – 10:30 AM PDT
    Location: Exhibit Hall - Row L - Poster # 472
    Introduction:: The World Health Organization estimated an annual incidence of Glioblastoma multiforme (GBM) to be approximately 5 cases per 100,000 people in the United States.1 GBM is a grade IV malignant brain tumor that accounts for 60-70% of all brain tumors. The average 2-year survival rate is 5% without treatment and increases to only 30% with the current gold standard treatment, however, the initial increase is not sustained, as the 5-year survival rate is 7.2%.2 Doxorubicin (DOX) is an effective chemotherapy agent due to its ability to fight a wide range of cancers but has an inability to treat GBM due to the blood-brain barrier (BBB). The BBB protects the brain tissue with a diffusion barrier that has selective permeability.3 Nanoparticles have been shown to be able to cross the BBB with different efficiencies based on their sizes, surface charge, and hydrophilic fraction.4 Specifically, polymersomes are nanoparticles with hollow shells that have the ability to encapsulate and deliver chemotherapeutic drugs.5 Our lab has demonstrated that polymersomes can be delivered across the BBB in a feline model of a neurodegenerative disease through receptor-mediated transcytosis. In this project, we aim to develop HA7-PLA polymersomes as delivery vehicles for DOX in a noninvasive treatment for GBM. Due to the amphiphilic nature of the HA7-PLA polymer, it is thermodynamically driven to form the core-shell polymersome structure via solvent injection, making it a desirable material for encapsulating a hydrophilic drug product. Furthermore, HA is a native ligand for the CD44 receptor, which is upregulated in GBM.

    Materials and Methods::

    Dynamic light scattering (DLS) was used to measure the size and shape of unloaded polymersomes, in addition to confirming desired zeta potential of polymersomes. Transmission Electron Microscopy (TEM) was used to identify if any alteration of shape occurred between the unloaded and loaded polymersomes. A drug loading study was conducted over a 6-hour period to verify the polymersomes fully encapsulated the added DOX and to calculate encapsulation efficiency. A drug release study was conducted over 72 hours to generate a release profile of DOX in a neutral (pH=7.42) versus tumorigenic environment (pH= 6.85).

     


     


    Results, Conclusions, and Discussions::






    The encapsulation efficiency of DOX in HA7-PLA is nearly 100% which indicates the system successfully encapsulated DOX. In Figure 1 TEM images were taken for unloaded and DOX-loaded HA7-PLA polymersome.The images revealed there was no change in the spherical shape of the polymersomes upon encapsulating DOX, which is important because uptake kinetics and intracellular pathways have been shown to be shape-dependent.6 Designing pH-sensitive systems is of interest because they add a variable of control in drug release. Tumor environments are known to have acidic pH levels, so it is important that the polymersomes degrade in acidic environments to release the DOX and target the cancerous cells. In Figure 2, a release profile is shown for a loaded HA7-PLA polymersome in an acidic and neutral environment at pH 6.85 and 7.42, respectively. There is a rapid release of DOX in the acidic study that began to plateau between 15-30 hours. Meanwhile, in the neutral environment, there is little release of DOX suggesting the polymersomes are and will not release DOX near the healthy cells. Measurements for size distribution and zeta potential are shown in Table 1. The average polydispersity index (PDI) of the sample was 0.33 ± 0.02, this indicates the system is highly monodisperse, which is ideal.7 The average particle size was 101.8 ± 16.50 nm, this falls in the desired range of anticancer drug nanocarriers and is expected to have the enhanced permeability retention effect.8,9 The average zeta potential of the sample was -11.3 ± 1.50 mV, which should result in higher cellular uptake by the cancer cells rather than the healthy cells.10 This study aimed to illustrate why polymersomes can be an effective delivery vehicle to treat GBM. The findings revealed HA7-PLA polymersomes have a high affinity for encapsulating DOX while releasing it 3-fold over a 72-hour period in an acidic environment compared to a neutral environment. Dynamic light scattering confirmed the polymersomes were in the desired range, with an average size of 101.8 ± 16.50 nm. These findings confirmed the polymersomes are an adequate size to successfully diffuse through the BBB while not harming the healthy cells.









    Acknowledgements (Optional): :

    • NSF grant, DMR #1950557

    • Clemson Chemical and Biomolecular Engineering Department 

    • The Larsen Lab


    DMR #1950557



    References (Optional): :





    1. Mountz, J.; Ahmed, R.; Oborski, M.; Lieberman, F.; Hwang, M. Malignant Gliomas: Current Perspectives in Diagnosis, Treatment, and Early Response Assessment Using Advanced Quantitative Imaging Methods. Cancer Management and Research 2014, 149. https://doi.org/10.2147/CMAR.S54726.




    2. Wu, W.; Klockow, J. L.; Zhang, M.; Lafortune, F.; Chang, E.; Jin, L.; Wu, Y.; Daldrup-Link, H. E. Glioblastoma Multiforme (GBM): An Overview of Current Therapies and Mechanisms of Resistance. Pharmacol Res 2021, 171, 105780. https://doi.org/10.1016/j.phrs.2021.105780.




    3. Zou, D.; Wang, W.; Lei, D.; Yin, Y.; Ren, P.; Chen, J.; Yin, T.; Wang, B.; Wang, G.; Wang, Y. Penetration of Blood–Brain Barrier and Antitumor Activity and Nerve Repair in Glioma by Doxorubicin-Loaded Monosialoganglioside Micelles System. International Journal of Nanomedicine 2017, Volume 12, 4879–4889. https://doi.org/10.2147/IJN.S138257.




    4. Ribovski, L.; Hamelmann, N. M.; Paulusse, J. M. J. Polymeric Nanoparticles Properties and Brain Delivery. Pharmaceutics 2021, 13 (12), 2045. https://doi.org/10.3390/pharmaceutics13122045.




    5. Madkour, L. H. Advanced Drug Delivery Systems: New Nanomedication Technologies. In Nucleic Acids as Gene Anticancer Drug Delivery Therapy; Elsevier, 2019; pp 1–29. https://doi.org/10.1016/B978-0-12-819777-6.00001-9.




    6. Truong, N. P.; Whittaker, M. R.; Mak, C. W.; Davis, T. P. The Importance of Nanoparticle Shape in Cancer Drug Delivery. Expert Opinion on Drug Delivery 2015, 12 (1), 129–142. https://doi.org/10.1517/17425247.2014.950564.












    1. Bhattacharjee, S. DLS and Zeta Potential – What They Are and What They Are Not? Journal of Controlled Release 2016, 235, 337–351. https://doi.org/10.1016/j.jconrel.2016.06.017.




    2. Biswas, A. K.; Islam, M. R.; Choudhury, Z. S.; Mostafa, A.; Kadir, M. F. Nanotechnology Based Approaches in Cancer Therapeutics. Advances in Natural Sciences: Nanoscience and Nanotechnology 2014, 5 (4), 043001. https://doi.org/10.1088/2043- 6262/5/4/043001.




    3. Liu, Y.; Tan, J.; Thomas, A.; Ou-Yang, D.; Muzykantov, V. R. The Shape of Things to Come: Importance of Design in Nanotechnology for Drug Delivery. Therapeutic Delivery 2012, 3 (2), 181–194. https://doi.org/10.4155/tde.11.156.




    4. Saadat, M.; Zahednezhad, F.; Zakeri-Milani, P.; Reza Heidari, H.; Shahbazi-Mojarrad, J.; Valizadeh, H. Drug Targeting Strategies Based on Charge Dependent Uptake of Nanoparticles into Cancer Cells. Journal of Pharmacy & Pharmaceutical Sciences 2019, 22, 191–220. https://doi.org/10.18433/jpps30318.