Exemestane Delivery Via Polymeric Micellar-Folic Acid Triggered Nanoparticles For Amelioration In Breast Cancer Therapy: Design, Optimization And Evaluation Studies

Year 2026, Volume: 46 Issue: 1, 48 - 60, 01.03.2026

Komal Parmar , Nidhikumari Rathod

https://doi.org/10.52794/hujpharm.1727738

https://izlik.org/JA53NK24AY

Abstract

The objective of the work was to develop folic acid conjugated nano-micelle as targeted and promising drug delivery for exemestane in breast cancer management. Folic acid was conjugated with poloxamer-338, then nano-micelles containing exemestane were prepared employing thin-film hydration method. Optimization was carried out utilizing Box-Behnken design using stirring speed, stirring time and hydration temperature as independent variables. Results of the optimized batch for Particle Size, PDI, Zeta Potential, and % EE was found to be 180.13nm, 0.648, -12.90mV, and 85.65%, respectively. Drug release of Exemestane from nano-micelle was found to be 83.16% and 89.6% after 24h in phosphate buffer pH 7.4 and 0.5%w/v SLS, respectively. In vitro cytotoxicity studies exhibited enhanced efficacy of the nano-micelles. Results of stability studies exhibited no remarkable changes indicating a stable formulation. Overall, the present study demonstrates folic acid conjugated polymeric nano-micelles as a promising nanocarrier to enhance the efficiency of exemestane for the breast-cancer therapy.

Keywords

Exemestane , Polymeric nanomicelles , Poloxamer 338 , Box-Behnken Design , In vitro cytotoxicity studies

References

• 1. Williams HD, Trevaskis NL, Charman SA, Shanker RM, Charman WN, Pouton CW, et al. Strategies to address low drug solubility in discovery and development. Pharmacol Rev. 2013;65(1):315-499. https://doi.org/10.1124/pr.112.005660.
• 2. Cristofoletti R, Chiann C, Dressman JB, Storpirtis S. A comparative analysis of biopharmaceutics classification system and biopharmaceutics drug disposition classification system: a cross-sectional survey with 500 bioequivalence studies. J Pharm Sci. 2013;102(9):3136-44. https://doi.org/10.1002/jps.23515.
• 3. Chavda HV, Patel CN, Anand IS. Biopharmaceutics classification system. Sys Rev Pharm. 2010;1:62–69. https://doi.org/10.4103/0975-8453.59514.
• 4. Goo YT, Sa CK, Choi JY, Kim MS, Kim CH, Kim HK, et al. Development of a solid supersaturable micelle of revaprazan for ımproved dissolution and oral bioavailability using box-behnken design. Int J Nanomedicine. 2021;16:1245-1259. https://doi.org/10.2147/ijn.s298450.
• 5. Jagdale SK, Dehghan MH, Paul NS. Enhancement of dissolution of fenofibrate using complexation with hydroxy propyl β-cyclodextrin. Turk J Pharm Sci. 2019;16(1):48-53. https://doi.org/10.4274/tjps.60490.
• 6. Alghaith AF, Mahrous GM, Alenazi AS, ALMufarrij SM, Alhazzaa MS, Radwan AA, et al. Dissolution enhancement of gefitinib by solid dispersion and complexation with β-cyclodextrins: ın vitro testing, cytotoxic activity, and tablet formulation. Saudi Pharm J. 2024;32(6):102070. https://doi.org/10.1016/j.jsps.2024.102070.
• 7. Choi I, Park SY, Lee SW, Kang Z, Jin YS, Kim IW. Dissolution enhancement of sorafenib tosylate by co-milling with tetradecanol post-extracted using supercritical carbon dioxide. Pharmazie. 2020;75(1):13-17. https://doi.org/10.1691/ph.2020.9120.
• 8. Khan KU, Minhas MU, Badshah SF, Suhail M, Ahmad A, Ijaz S. Overview of nanoparticulate strategies for solubility enhancement of poorly soluble drugs. Life Sci. 2022;291:120301. https://doi.org/10.1016/j.lfs.2022.120301.
• 9. Ghezzi M, Pescina S, Padula C, Santi P, Del Favero E, Cantù L, et al. Polymeric micelles in drug delivery: an insight of the techniques for their characterization and assessment in biorelevant conditions. J Control Release. 2021;332:312-336. https://doi.org/10.1016/j.jconrel.2021.02.031.
• 10. Li L, Zeng Y, Chen M, Liu G. Application of nano-micelles in enhancing bioavailability and biological efficacy of bioactive nutrients. Polymers (Basel). 2022;14(16):3278. https://doi.org/10.3390/polym14163278.
• 11. Fares AR, ElMeshad AN, Kassem MAA. Enhancement of dissolution and oral bioavailability of lacidipine via pluronic P123/F127 mixed polymeric micelles: formulation, optimization using central composite design and in vivo bioavailability study. Drug Deliv. 2018;25(1):132-142. https://doi.org/10.1080/10717544.2017.1419512.
• 12. Quartier J, Lapteva M, Boulaguiem Y, Guerrier S, Kalia YN. Polymeric micelle formulations for the cutaneous delivery of sirolimus: a new approach for the treatment of facial angiofibromas in tuberous sclerosis complex. Int J Pharm. 2021;604:120736. https://doi.org/10.1016/j.ijpharm.2021.120736.
• 13. Nezir AE, Bolat ZB, Ozturk N, Kocak P, Zemheri E, Gulyuz S, et al. Targeting prostate cancer with docetaxel-loaded peptide 563-conjugated petox-co-peı30%-b-pcl polymeric micelle nanocarriers. Amino Acids. 2023;55(8):1023-1037. https://doi.org/10.1007/s00726-023-03292-3.
• 14. Jabbari A, Yaghoobi E, Azizollahi H, Shojaee S, Ramezani M, Alibolandi M, et al. Design and synthesis of a star-like polymeric micelle modified with as1411 aptamer for targeted delivery of camptothecin for cancer therapy. Int J Pharm. 2022;611:121346. https://doi.org/10.1016/j.ijpharm.2021.121346.
• 15. Hari SK, Gauba A, Shrivastava N, Tripathi RM, Jain SK, Pandey AK. Polymeric micelles and cancer therapy: An ingenious multimodal tumor-targeted drug delivery system. Drug Deliv Transl Res. 2023;13(1):135-163. https://doi.org/10.1007/s13346-022-01197-4. 16. Torchilin VP. Passive and active drug targeting: Drug delivery to tumors as an example. Schäfer-Korting M: Drug delivery. Springer; Berlin/Heidelberg, Germany; 2010. 3-53 p.
• 17. Fernández M, Javaid F, Chudasama V. Advances in targeting the folate receptor in the treatment/imaging of cancers. Chem Sci. 2017;9(4):790-810. https://doi.org/10.1039/c7sc04004k.
• 18. Lombardi P. Exemestane, a new steroidal aromatase ınhibitor of clinical relevance. Biochim. Biophys. Acta Mol Basis Dis. 2002;1587(2–3):326-337. https://doi.org/10.1016/S0925-4439(02)00096-0.
• 19. Shetty YC, Chakkarwar PN, Acharya SS, Rajadhyaksha VD. Exemestane: A milestone against breast cancer. J Postgrad Med. 2007;53(2): 135. https://doi.org/10.4103/0022-3859.32218.
• 20. Singh AK, Chaurasiya A, Singh M, Upadhyay SC, Mukherjee R, Khar RK. Exemestane loaded self-microemulsifying drug delivery system (smedds): development and optimization. AAPS PharmSciTech. 2008;9(2):628–634. https://doi.org/10.1208/s12249-008-9080-6.
• 21. AROMASIN® (exemestane) tablets. USFDA DATA BASE. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/020753s025lbl.pdf. Accessed on 29th September 2025.
• 22. Kamdem LK, Flockhart DA, Desta Z. In vitro cytochrome P450-mediated metabolism of exemestane. Drug Metab Dispos. 2011;39(1):98-105. https://doi.org/10.1124/dmd.110.032276.
• 23. Patil SS, Chougale RD, Manjappa AS, Disouza JI, Hajare AA, Patil KS. Statistically developed docetaxel-laden mixed micelles for improved therapy of breast cancer. OpenNano. 2022;8:100079. doi.org/10.1016/j.onano.2022.100079.
• 24. Vu-Quang H, Vinding MS, Nielsen T, Ullisch MG, Nielsen NC, Nguyen DT, et al. Pluronic F127-folate coated super paramagenic ıron oxide nanoparticles as contrast agent for cancer diagnosis in magnetic resonance ımaging. Polymers (Basel). 2019;11(4):743. https://doi.org/10.3390/polym11040743.
• 25. Throat DB, Pawar K, Paunekar A. Method development and validation of folic acid by UV-visible spectroscopy. Int J Pharm Sci Res. 2015;6(7):3088-3090. http://dx.doi.org/10.13040/IJPSR.0975-8232.6(7).3088-90.
• 26. Kumar A, Singh A, Flora SJS, Shukla R. Box-Behnken design optimized tpgs coated bovine serum albumin nanoparticles loaded with anastrozole. Curr Drug Deliv. 2021;18(8):1136-1147. https://doi.org/10.2174/1567201818666210202104810.
• 27. Wang H, Hong W, Li X, Jin Q, Ye W, Feng Y, et al. Optimization of nanostructured lipid carriers of fenofibrate using a box-behnken design for oral bioavailability enhancement. Curr Drug Deliv. 2022;19(7):773-787. https://doi.org/10.2174/1567201818666210423110745.
• 28. Timur B, Usta DY, Teksin ZS. Investigation of the effect of colloidal structures formed during lipolysis of lipid-based formulation on exemestane permeability using the in vitro lipolysis-permeation model. J Drug Deliv Sci Technol. 2022;77:103797. https://doi.org/10.1016/j.jddst.2022.103797.
• 29. Pourtalebi Jahromi L, Ghazali M, Ashrafi H, Azadi A. A comparison of models for the analysis of the kinetics of drug release from plga-based nanoparticles. Heliyon. 2020;6(2):e03451. https://doi.org/10.1016/j.heliyon.2020.e03451.
• 30. Rizwanullah M, Perwez A, Mir SR, Alam Rizvi MM, Amin S. Exemestane encapsulated polymer-lipid hybrid nanoparticles for improved efficacy against breast cancer: optimization, in vitro characterization and cell culture studies. Nanotechnology. 2021;32(41). https://doi.org/10.1088/1361-6528/ac1098.
• 31. Bose A, Roy Burman D, Sikdar B, Patra P. Nanomicelles: types, properties and applications in drug delivery. IET Nanobiotechnol. 2021;15(1):19-27. https://doi.org/10.1049/nbt2.12018.
• 32. Woodhead JL, Hall CK. Encapsulation efficiency and micellar structure of solute-carrying block copolymer nanoparticles. Macromolecules. 2011;44(13):5443-5451. https://doi.org/10.1021/ma102938g.
• 33. Keerthana M, Komala G, Nagaraju R. Polymeric micelles of oregano - formulation and ın-vitro evaluation. Curr. Trends Biotechnol Pharm. 2023;17:660-670. https://doi.org/10.5530/ctbp.2023.1.7.
• 34. Ramana PV, Krishna YR, Mouli KC. Experimental FT-IR and UV–Vis Spectroscopic studies and molecular docking analysis of anti-cancer drugs exemestane and pazopanib. J Mol Struct. 2022;1263:133051. https://doi.org/10.1016/j.molstruc.2022.133051.