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Breast intraductal nanoformulations for treating ductal carcinoma in situ II: Dose de-escalation using a slow releasing/slow bioconverting prodrug strategy

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Abstract

Ductal carcinoma in situ (DCIS) represents approximately 20–25% of newly diagnosed breast cancers. DCIS is treated by surgery and possibly radiotherapy. Chemotherapy is only used as adjuvant or neoadjuvant therapy but not as primary therapy. The present study investigated the intraductal administration of Ciclopirox (CPX) formulated in nanosuspensions (NSs) or nanoparticles (NPs) to treat DCIS locally in a Fischer 344 rat model orthotopically implanted with 13762 Mat B III cells. Slow converting esterase responsive CPX prodrugs (CPDs) were successfully synthesized at high purity (> 95%) by directly acetylating the hydroxyl group or by appending a self-immolative linker between CPX and a phenolic ester. Direct esterification CPDs were not sufficiently stable so self-immolative CPDs were formulated in NSs and NPs. Prodrug release was evaluated from poly(lactic-co-glycolic acid) NPs, and CPD4 demonstrated the slowest release rate with the rank order of CPD2 (R = methyl) > CPD3 (R = t-butyl) > CPD4 (R = phenyl). Intraductally administered CPX NS, CPD4 NS, and an innovative mixture of CDP4 NS and NPs (at 1 mg CPX equivalent/duct) demonstrated significant (p < 0.05) in vivo anti-tumor efficacy compared with immediate release (IR) CPX NS and non-treated controls. CPX mammary persistence at 6 h and 48 h after CPD4 NS or NP administration was also greater than after the immediate release CPX NS. A strong correlation between CPX mammary persistence and efficacy is demonstrated. In conclusion, nanoformulations utilizing a slow releasing/slow bioconverting CPX prodrug delivery strategy resulted in significant dose de-escalation (~ five fold) while maintaining anti-tumor efficacy.

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Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

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This work was supported by the Parke-Davis Endowed Chair.

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Authors and Affiliations

  1. Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA

    Firas Al-Zubaydi, Dayuan Gao, Dipti Kakkar, Shike Li, Jennifer Holloway, Zoltan Szekely & Patrick J. Sinko

  2. Department of Pharmaceutics, College of Pharmacy, University of Baghdad, Baghdad, Iraq

    Firas Al-Zubaydi

  3. Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Delhi, 110054, India

    Dipti Kakkar

  4. Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08903, USA

    Zoltan Szekely, Nancy Chan, Shicha Kumar, Hatem E. Sabaawy & Patrick J. Sinko

  5. Dr. Susan Love Research Foundation, 16133 Ventura Suite 1000, Encino, CA, 91436, USA

    Susan Love

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  1. Firas Al-Zubaydi
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All authors whose names appear on the submission made substantial contributions to the article. Firas Al-Zubaydi—writing and original draft preparation; Dayuan Gao, Jenifer Holloway—formal analysis and investigation; Dipti Kakkar—writing, editing, and critical revision of intellectual content; Nancy Chan, Shicha Kumar, Hatem Sabaawy, Susan Love—methodology; Shike Li, Zoltan Szekely—resources; Patrick J Sinko—conceptualization and supervision. All authors read and approved the final manuscript.

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Al-Zubaydi, F., Gao, D., Kakkar, D. et al. Breast intraductal nanoformulations for treating ductal carcinoma in situ II: Dose de-escalation using a slow releasing/slow bioconverting prodrug strategy. Drug Deliv. and Transl. Res. 12, 240–256 (2022). https://doi.org/10.1007/s13346-021-00903-y

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