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

Firas Al-Zubaydi, Dayuan Gao, Dipti Kakkar, Shike Li, Jennifer Holloway, Zoltan Szekely, Nancy Chan, Shicha Kumar, Hatem E. Sabaawy, Susan Love, Patrick J. Sinko

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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. Graphical abstract: [Figure not available: see fulltext.]

Original languageEnglish (US)
Pages (from-to)240-256
Number of pages17
JournalDrug Delivery and Translational Research
Volume12
Issue number1
DOIs
StatePublished - Jan 2022

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Keywords

  • Ciclopirox
  • Ductal carcinoma in situ
  • Intraductal nanoformulations
  • Nanoparticle
  • Nanosuspension
  • Prodrug approach

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