Subcutaneous Delivery of Albumin: Impact of Thermosensitive Hydrogels

Abstract

Albumin demonstrates remarkable promises as a versatile carrier for therapeutic and diagnostic agents. However, noninvasive delivery of albumin-based therapeutics has been largely unexplored. In this study, injectable thermosensitive hydrogels were evaluated as sustained delivery systems for Cy5.5-labeled bovine serum albumin (BSA-Cy5.5). These hydrogels were prepared using aqueous solutions of Poloxamer 407 (P407) or poly(lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PLGA-PEG-PLGA), which could undergo temperature-triggered phase transition and spontaneously solidify into hydrogels near body temperature, serving as in situ depot for tunable cargo release. In vitro, these hydrogels were found to release BSA-Cy5.5 in a sustained manner with the release half-life of BSA-Cy5.5 from P407 and PLGA-PEG-PLGA hydrogels at 16 h and 105 h, respectively. Without affecting the bioavailability, subcutaneous administration of BSA-Cy5.5-laden P407 hydrogel resulted in delayed BSA-Cy5.5 absorption, which reached the maximum plasma level (Tmax) at 24 h, whereas the Tmax for subcutaneously administered free BSA-Cy5.5 solution was 8 h. Unexpectedly, subcutaneously injected BSA-Cy5.5-laden PLGA-PEG-PLGA hydrogel did not yield sustained BSA-Cy5.5 plasma level, the bioavailability of which was significantly lower than that of P407 hydrogel (p < 0.05). The near-infrared imaging of BSA-Cy5.5-treated mice revealed that a notable portion of BSA-Cy5.5 remained trapped within the subcutaneous tissues after 6 days following the subcutaneous administration of free solution or hydrogels, suggesting the discontinuation of BSA-Cy5.5 absorption irrespective of the formulations. These results suggest the opportunities of developing injectable thermoresponsive hydrogel formulations for subcutaneous delivery of albumin-based therapeutics.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Peters T Jr. Serum albumin. Adv Protein Chem. 1985;37:161–245.

    CAS  Article  Google Scholar 

  2. 2.

    Kratz F. Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. J Control Release. 2008;132(3):171–83.

    CAS  Article  Google Scholar 

  3. 3.

    Sleep D. Albumin and its application in drug delivery. Expert Opin Drug Deliv. 2015;12:793–812.

    CAS  Article  Google Scholar 

  4. 4.

    Hoogenboezem EN, Duvall CL. Harnessing albumin as a carrier for cancer therapies. Adv Drug Deliv Rev. 2018;130:73–89.

    CAS  Article  Google Scholar 

  5. 5.

    Li J, Mooney DJ. Designing hydrogels for controlled drug delivery. Nat Rev Mater. 2016;1:1–17.

    Google Scholar 

  6. 6.

    Dimatteo R, Darling NJ, Segura T. In situ forming injectable hydrogels for drug delivery and wound repair. Adv Drug Deliv Rev. 2018;127:167–84.

    CAS  Article  Google Scholar 

  7. 7.

    Li Z, Guan J. Thermosensitive hydrogels for drug delivery. Expert Opin Drug Deliv. 2011;8:991–1007.

    CAS  Article  Google Scholar 

  8. 8.

    Jeong B, Kim SW, Bae YH. Thermosensitive sol–gel reversible hydrogels. Adv Drug Deliv Rev. 2012;64:154–62.

    Article  Google Scholar 

  9. 9.

    Mathew AP, Uthaman S, Cho K-H, Cho C-S, Park I-K. Injectable hydrogels for delivering biotherapeutic molecules. Int J Biol Macromol. 2018;110:17–29.

    CAS  Article  Google Scholar 

  10. 10.

    Kim Y-J, Matsunaga YT. Thermo-responsive polymers and their application as smart biomaterials. J Mater Chem B. 2017;5:4307–21.

    CAS  Article  Google Scholar 

  11. 11.

    Dumortier G, Grossiord JL, Agnely F, Chaumeil JC. A review of poloxamer 407 pharmaceutical and pharmacological characteristics. Pharm Res. 2006;23:2709–28.

    CAS  Article  Google Scholar 

  12. 12.

    Akash MSH, Rehman K. Recent progress in biomedical applications of Pluronic (PF127): pharmaceutical perspectives. J Control Release. 2015;209:120–38.

    CAS  Article  Google Scholar 

  13. 13.

    Jeong B, Lee DS, Shon JI, Bae YH, Kim SW. Thermoreversible gelation of poly (ethylene oxide) biodegradable polyester block copolymers. J Polym Sci, Part A: Polym Chem. 1999;37:751–60.

    CAS  Article  Google Scholar 

  14. 14.

    Morikawa K, Okada F, Hosokawa M, Kobayashi H. Enhancement of therapeutic effects of recombinant interleukin 2 on a transplantable rat fibrosarcoma by the use of a sustained release vehicle, pluronic gel. Cancer Res. 1987;47:37–41.

    CAS  PubMed  Google Scholar 

  15. 15.

    Akash MSH, Rehman K, Li N, Gao J-Q, Sun H, Chen S. Sustained delivery of IL-1Ra from pluronic F127-based thermosensitive gel prolongs its therapeutic potentials. Pharm Res. 2012;29:3475–85.

    CAS  Article  Google Scholar 

  16. 16.

    Kim YJ, Choi S, Koh JJ, Lee M. Controlled release of insulin from injectable biodegradable triblock copolymer. Pharm Res. 2001;18:548–50.

    CAS  Article  Google Scholar 

  17. 17.

    Zentner GM, Rathi R, Shih C, McRea JC, Seo M-H, Oh H, et al. Biodegradable block copolymers for delivery of proteins and water-insoluble drugs. J Control Release. 2001;72:203–15.

    CAS  Article  Google Scholar 

  18. 18.

    Hama Y, Koyama Y, Choyke PL, Kobayashi H. Two-color in vivo dynamic contrast-enhanced pharmacokinetic imaging. J Biomed Opt. 2007;12:034016.

    Article  Google Scholar 

  19. 19.

    Chung CK, García-Couce J, Campos Y, Kralisch D, Bierau K, Chan A, et al. Doxorubicin loaded Poloxamer thermosensitive hydrogels: chemical, pharmacological and biological evaluation. Molecules. 2020;25:2219.

    CAS  Article  Google Scholar 

  20. 20.

    Chi SC, Jun H. Release rates of ketoprofen from poloxamer gels in a membraneless diffusion cell. J Pharm Sci. 1991;80:280–3.

    CAS  Article  Google Scholar 

  21. 21.

    Bonacucina G, Cespi M, Mencarelli G, Giorgioni G, Palmieri GF. Thermosensitive self-assembling block copolymers as drug delivery systems. Polymers. 2011;3:779–811.

    CAS  Article  Google Scholar 

  22. 22.

    Vigata M, Meinert C, Hutmacher DW, Bock N. Hydrogels as drug delivery systems: a review of current characterization and evaluation techniques. Pharmaceutics. 2020;12:1188.

    Article  Google Scholar 

  23. 23.

    Chaudhury C, Mehnaz S, Robinson JM, Hayton WL, Pearl DK, Roopenian DC, et al. The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan. J Exp Med. 2003;197:315–22.

    CAS  Article  Google Scholar 

  24. 24.

    Pyzik M, Rath T, Lencer WI, Baker K, Blumberg RS. FcRn: the architect behind the immune and nonimmune functions of IgG and albumin. J Immunol. 2015;194:4595–603.

    CAS  Article  Google Scholar 

  25. 25.

    Sand KMK, Bern M, Nilsen J, Noordzij HT, Sandlie I, Andersen JT. Unraveling the interaction between FcRn and albumin: opportunities for design of albumin-based therapeutics. Front Immunol. 2015;5:682.

    Article  Google Scholar 

  26. 26.

    Shinoda T, Takagi A, Maeda A, Kagatani S, Konno Y, Hashida M. In vivo fate of folate-BSA in non-tumor- and tumor-bearing mice. J Pharm Sci. 1998;87:1521–6.

    CAS  Article  Google Scholar 

  27. 27.

    Dutta K, Das R, Ling J, Monibas RM, Carballo-Jane E, Kekec A, et al. In situ forming injectable thermoresponsive hydrogels for controlled delivery of biomacromolecules. ACS Omega. 2020;5:17531–42.

    CAS  Article  Google Scholar 

  28. 28.

    Qiao M, Chen D, Ma X, Liu Y. Injectable biodegradable temperature-responsive PLGA–PEG–PLGA copolymers: synthesis and effect of copolymer composition on the drug release from the copolymer-based hydrogels. Int J Pharm. 2005;294:103–12.

    CAS  Article  Google Scholar 

  29. 29.

    Andersen JT, Daba MB, Berntzen G, Michaelsen TE, Sandlie I. Cross-species binding analyses of mouse and human neonatal Fc receptor show dramatic differences in immunoglobulin G and albumin binding. J Biol Chem. 2010;285:4826–36.

    Article  Google Scholar 

  30. 30.

    Roopenian DC, Christianson GJ, Sproule TJ, Brown AC, Akilesh S, Jung N, et al. The MHC class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled drugs. J Immunol. 2003;170:3528–33.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Chalet Tan.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Guest Editors: Xiuling Lu and Aliasger K Salem

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Patel, N., Ji, N., Wang, Y. et al. Subcutaneous Delivery of Albumin: Impact of Thermosensitive Hydrogels. AAPS PharmSciTech 22, 120 (2021). https://doi.org/10.1208/s12249-021-01982-3

Download citation

KEY WORDS

  • albumin
  • Poloxamer 407
  • PLGA-PEG-PLGA
  • thermosensitive hydrogels
  • pharmacokinetics