Skip to main content

Advertisement

SpringerLink
Log in

Doxorubicin-Loaded Mixed Micelles for the Effective Management of Skin Carcinoma: In Vivo Anti-Tumor Activity and Biodistribution Studies

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Skin cancer is an alarming concern due to increased radiation and chemical exposure. Doxorubicin is a drug prescribed for various cancers by parenteral route. Apart from the pharmaceutical challenge of being a biopharmaceutical classification system (BCS) Class III drug, the side effects of doxorubicin are also a great concern. With an aim to enhance its safety and bioavailability, a phospholipid-based micellar system was developed. The developed nanometric and symmetric carriers not only offered substantial drug loading, but also offered a temporal drug release for longer durations. The pH-dependent drug release assured the spatial delivery at the target site, without loss of drug in the systemic circulation. The cancer cell toxicity studies along with the in vivo anti-tumor studies established the superior efficacy of the developed system. The blood profile studies and the biochemical estimations confirmed the safety of the developed nanocarriers. Lesser amount of drug was available for the microsomal degradation, as inferred by the biodistribution studies. The findings provide a proof of concept for the safer and effective doxorubicin delivery employing simple excipients like phospholipids for the management of skin cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Muggia FM, Green MD. New anthracycline antitumor antibiotics. 1991; 11: 43–64.

  2. Borišev I, Mrđanovic J, Petrovic D, Seke M, Jović D, Srđenović B, et al. Nanoformulations of doxorubicin: how far have we come and where do we go from here? 2018; 29: 332002.

  3. Mohan P, Rapoport N. Doxorubicin as a molecular nanotheranostic agent: effect of doxorubicin encapsulation in micelles or nanoemulsions on the ultrasound-mediated intracellular delivery and nuclear trafficking. 2010; 7: 1959–1973.

  4. McGowan JV, Chung R, Maulik A, Piotrowska I, Walker JM. Yellon DM. Anthracycline chemotherapy and cardiotoxicity. 2017;31:63–75.

    CAS  Google Scholar 

  5. Han X. Zhou Y. Liu W. Precision cardio-oncology: understanding the cardiotoxicity of cancer therapy. 2017;1:31.

    Google Scholar 

  6. Pillai G. Ceballos-Coronel ML. Science and technology of the emerging nanomedicines in cancer therapy: a primer for physicians and pharmacists. 2013;1:2050312113513759.

    Google Scholar 

  7. Yu C, Zhou M, Zhang X, Wei W, Chen X. Zhang X. Smart doxorubicin nanoparticles with high drug payload for enhanced chemotherapy against drug resistance and cancer diagnosis. 2015;7:5683–90.

    CAS  Google Scholar 

  8. Fan D, Yu J, Yan R, Xu X, Wang Y. Xie X, et al. Preparation and evaluation of doxorubicin-loaded micelles based on glycyrrhetinic acid modified gelatin conjugates for targeting hepatocellular carcinoma. 2018;2018:1–13.

    Google Scholar 

  9. Niu G, Cogburn B. Hughes J. Preparation and characterization of doxorubicin liposomes. 2010;624:211–9.

    CAS  Google Scholar 

  10. Kang KW, Chun M-K, Kim O, Subedi RK, Ahn S-G. Yoon J-H, et al. Doxorubicin-loaded solid lipid nanoparticles to overcome multidrug resistance in cancer therapy. 2010;6:210–3.

    CAS  Google Scholar 

  11. Fernandes RS, Silva JO. Mussi SV, Lopes SCA, Leite EA, Cassali GD, et al. Nanostructured lipid carrier co-loaded with doxorubicin and docosahexaenoic acid as a theranostic agent: evaluation of biodistribution and antitumor activity in Experimental model. 2018;20:437–47.

    CAS  Google Scholar 

  12. Yang F, Wang H, Li X, Ma Z, Wang D. Wang L, et al. Hydrophilic mesoporous carbon nanospheres with high drug-loading efficiency for doxorubicin delivery and cancer therapy. 2016;11:1793–806.

    Google Scholar 

  13. Prylutska S V., Skivka LM, Didenko G V., Prylutskyy YI, Evstigneev MP, Potebnya GP, et al. Complex of C60 fullerene with doxorubicin as a promising agent in antitumor therapy 2015; 10:499: 1–7.

  14. Liu Z, Fan AC, Rakhra K, Sherlock S, Goodwin A. Chen X, et al. Supramolecular stacking of doxorubicin on carbon nanotubes for in vivo cancer therapy. 2009;48:7668–72.

  15. Liu Z, Francis PS, Barrow CJ, Yang W, Liu J. Wang T, et al. Switching off the interactions between graphene oxide and doxorubicin using vitamin C: combining simplicity and efficiency in drug delivery. 2018;6:1251–9.

    CAS  Google Scholar 

  16. Rana S, Bhattacharjee J, Barick KC, Verma G, Hassan PA, Yakhmi JV. Interfacial engineering of nanoparticles for cancer therapeutics. Nanostructures Cancer Ther: Elsevier Inc.; 2017. p. 177–209.

  17. Kumar P, Kumar R, Singh B, Malik R, Sharma G. Chitkara D, et al. Biocompatible phospholipid-based mixed micelles for tamoxifen delivery: promising evidences from in - vitro anticancer activity and dermatokinetic studies. 2017;18:2037–44.

    CAS  Google Scholar 

  18. India. Ministry of Health and Family Welfare., Indian Pharmacopoeia Commission. Indian pharmacopoeia, 2007. Indian Pharmacopoeia Commission 2007.

  19. de Andrade DF, Zuglianello C, Pohlmann AR, Guterres SS. Beck RCR. Assessing the In vitro drug release from lipid-core nanocapsules: a new strategy combining dialysis sac and a continuous-flow system. 2015;16:1409–17.

  20. Dash S, Murthy PN, Nath L. Chowdhury P. Kinetic modeling on drug release from controlled drug delivery systems. n.d.;67:217–23.

  21. Eriksson MAL, Gabrielsson J. Nilsson LB. Studies of drug binding to plasma proteins using a variant of equilibrium dialysis. 2005;38:381–9.

    CAS  Google Scholar 

  22. Wu Y, Zhang P, Yang H. Ge Y, Xin Y. Effects of demethoxycurcumin on the viability and apoptosis of skin cancer cells. 2017;16:539–46.

    CAS  Google Scholar 

  23. Yang S, Zhu F, Wang Q, Liang F, Qu X, Gan Z, et al. Nano-rods of doxorubicin with poly(l-glutamic acid) as a carrier-free formulation for intratumoral cancer treatment 2016; 4: 7283–92.

  24. Ernsting MJ, Tang W-L, MacCallum NW, Li S-D. Preclinical pharmacokinetic, biodistribution, and anti-cancer efficacy studies of a docetaxel-carboxymethylcellulose nanoparticle in mouse models 2012; 33: 1445–54.

  25. Preet S, Bharati S, Panjeta A, Tewari R. Rishi P. Effect of nisin and doxorubicin on DMBA-induced skin carcinogenesis- a possible adjunct therapy. 2015;36:8301–8.

    CAS  Google Scholar 

  26. Bain BJ, Bates I, Laffan MA, Lewis SM, Shirley M. Dacie and Lewis practical haematology. 12th Edition. Elsevier; 2016.

  27. Feldman AT. Wolfe D. Tissue processing and hematoxylin and eosin staining. 2014;1180:31–43.

    CAS  Google Scholar 

  28. Preet S, Pandey SK, Kaur K, Chauhan S. Saini A. Gold nanoparticles assisted co-delivery of nisin and doxorubicin against murine skin cancer. 2019;53:101147.

    CAS  Google Scholar 

  29. Mayer LD, Tai LCL, Bally MB, Mitilenes GN, Ginsberg RS. Cullis PR. Characterization of liposomal systems containing doxorubicin entrapped in response to pH gradients. 1990;1025:143–51.

    CAS  Google Scholar 

  30. Thotakura N, Sharma G, Singh B, Kumar V. Raza K. Aspartic acid derivatized hydroxylated fullerenes as drug delivery vehicles for docetaxel: an explorative study. 2018;46:1763–72.

    CAS  Google Scholar 

  31. Cagel M, Bernabeu E, Gonzalez L, Lagomarsino E, Zubillaga M, Moretton MA, et al. Mixed micelles for encapsulation of doxorubicin with enhanced in vitro cytotoxicity on breast and ovarian cancer cell lines versus Doxil® 2017; 95: 894–903.

  32. Wang C, Qi P, Lu Y, Liu L, Zhang Y. Sheng Q, et al. Bicomponent polymeric micelles for pH-controlled delivery of doxorubicin. 2020;27:344–57.

    CAS  Google Scholar 

  33. Lee KY. Chiu YT, Lo CL. Preparation and characterization of potential doxorubicin-loaded mixed micelles formed from Vitamin E containing graft copolymers and PEG-b-PLA diblock copolymers. 2015;5:83825–36.

    CAS  Google Scholar 

  34. Yang C, Xiao J, Xiao W, Lin W, Chen J. Chen Q, et al. Fabrication of PDEAEMA-based pH-responsive mixed micelles for application in controlled doxorubicin release. 2017;7:27564–73.

    CAS  Google Scholar 

  35. López O, De La Maza A, Coderch L, López-Iglesias C, Wehrli E, Parra JL. Direct formation of mixed micelles in the solubilization of phospholipid liposomes by Triton X-100 1998; 426: 314–18.

  36. He C, Hu Y, Yin L. Tang C, Yin C. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. 2010;31:3657–66.

    CAS  Google Scholar 

  37. Singh R. Lillard JW. Nanoparticle-based targeted drug delivery. 2009;86:215–23.

    CAS  Google Scholar 

  38. Clogston JD. Patri AK. Zeta potential measurement. 2011;697:63–70.

    CAS  Google Scholar 

  39. Hu Y, Jiang X, Ding Y, Ge H, Yuan Y, Yang C. Synthesis and characterization of chitosan–poly(acrylic acid) nanoparticles 2002; 23: 3193–3201.

  40. Touve MA, Figg CA, Wright DB, Park C, Cantlon J. Sumerlin BS, et al. Polymerization-induced self-assembly of micelles observed by liquid cell transmission electron microscopy. 2018;4:543–7.

    CAS  Google Scholar 

  41. Lin T, Zhu T, Xun Y, Tao Y, Yang Y, Xie J, et al. A novel drug delivery system of mixed micelles based on poly(ethylene glycol)-poly(lactide) and poly(ethylene glycol)-poly(ɛ-caprolactone) for gambogenic acid 2019; 35: 757–64.

  42. Mishra M, Kumar P, Rajawat JS, Malik R, Sharma G. Modgil A. Nanotechnology: revolutionizing the science of drug delivery. 2019;24:5086–107.

    Google Scholar 

  43. Singh A, Thotakura N, Kumar R, Singh B, Sharma G. Katare OP, et al. PLGA-soya lecithin based micelles for enhanced delivery of methotrexate: cellular uptake, cytotoxic and pharmacokinetic evidences. 2017;95:750–6.

    CAS  Google Scholar 

  44. Keller F, Maiga M, Neumayer HH, Lode H. Distler A. Pharmacokinetic effects of altered plasma protein binding of drugs in renal disease. 1984;9:275–82.

    CAS  Google Scholar 

  45. Cevc G. Blume G. Hydrocortisone and dexamethasone in very deformable drug carriers have increased biological potency, prolonged effect, and reduced therapeutic dosage. 2004;1663:61–73.

    CAS  Google Scholar 

  46. Licata S, Saponiero A, Mordente A. Minotti G. Doxorubicin metabolism and toxicity in human myocardium: role of cytoplasmic deglycosidation and carbonyl reduction. 2000;13:414–20.

    CAS  Google Scholar 

  47. Blumenreich MS. The white blood cell and differential count. 1990. In: Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 153.

  48. Singh B, Schoeb TR, Bajpai P, Slominski A. Singh KK. Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function. 2018;9:735.

    Google Scholar 

  49. Qiu L. Hu M, Zhu J. Polymer micelle-based combination therapy of paclitaxel and resveratrol with enhanced and selective antitumor activity. 2014;4:64151–61.

    Google Scholar 

  50. Srivastava S, Natu SM, Gupta A, Pal KA, Singh U. Agarwal GG, et al. Lipid peroxidation and antioxidants in different stages of cervical cancer: prognostic significance. 2009;46:297–302.

    CAS  Google Scholar 

Download references

Acknowledgments

M/s Panacea Biotec Ltd., Mumbai, India, is acknowledged for supplying of ex gratis sample of doxorubicin hydrochloride. M/s Ipca Laboratories, Mumbai and Prof. O. P. Katare, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh are highly acknowledged for providing the phospholipid (Phospholipid 90 G) as a free gift sample.

Funding

Financial support from Department of Biotechnology (DBT), New Delhi, India, in the form of a research grant with the sanction number BT/PR14900/NNT/28/983/2015 is duly acknowledged.

Author information

Authors and Affiliations

  1. Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Dist. Ajmer, Bandarsindri, Rajasthan, 305 817, India

    Nagarani Thotakura & Kaisar Raza

  2. Department of Biophysics, Basic Medical Sciences Block-2, Panjab University, Sector-25, Chandigarh, 160 014, India

    Anshul Panjeta & Simran Preet

  3. School of Pharmaceutical Sciences, Shoolini University of Biotechnology and Management Sciences, Solan, Himachal Pradesh, 173 229, India

    Poonam Negi

Authors
  1. Nagarani Thotakura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anshul Panjeta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Poonam Negi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Simran Preet
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kaisar Raza
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Simran Preet or Kaisar Raza.

Ethics declarations

Conflict of Interest

The authors report no conflict of interest.

Additional information

Publisher’s Note

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

Supplementary Information

ESM 1

(PDF 224 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Thotakura, N., Panjeta, A., Negi, P. et al. Doxorubicin-Loaded Mixed Micelles for the Effective Management of Skin Carcinoma: In Vivo Anti-Tumor Activity and Biodistribution Studies. AAPS PharmSciTech 22, 130 (2021). https://doi.org/10.1208/s12249-021-01993-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-021-01993-0

KEY WORDS

Search

Navigation