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Evaluation of complete pathologic response and histologic toxicity using a subcutaneous delivery system with combination nanoconjugated doxorubicin and cisplatin for locally advanced breast cancer in vivo.

279 Background: Systemic doxorubicin (DOX) and platinum agents in breast cancer can be limited by their toxicity and have low penetration into lymphatics contributing to locoregional (LR) recurrence. Subcutaneous (s.c.) delivery of single agent nanoconjugated (HA-DOX) or cisplatin (HA-CIS) can significantly boost LR drug delivery with lower toxicity in vivo. The purpose of this study is to evaluate histologic response and toxicity of combination s.c. delivery of HA-DOX/HA-CIS as a significant improvement over IV delivery with standard drugs reduces dose levels and expands the therapeutic dosing range for these drugs.


METHODS
1.5x106 MDA-MB-468LN human breast cancer cells (metastatic line) were injected into the mammary fat pad of female Nu/Nu mice. When tumors reached 6mm, mice (n=8 per group) were then treated with standard DOX/CIS IV combination therapy or s.c. injections of HA-DOX/HA-CIS at 25%,50%,75%,100%,125%, and 150% MTD for these drugs. Drugs were dosed weekly x 3 wks and tissues were collected for histology at 4 and 12wk timepoints.


RESULTS
Only the nanoconjugate groups demonstrated a complete clinical response (CR) to therapy and a complete pathologic response (CPR) histologically [CR =62.5% of mice and CPR=12.5% at 50% MTD;CR=87.5% and CPR=25% at 75%MTD; p<0.0001 vs. IV groups which had no CRs and some partial responses (12.5% at 50%MTD and 25% at 75%MTD)]. HA groups had no lymphatic or bony metastases while 1 animal (12.5%) in the IV 50% MTD group had spinal metastases (p<0.01). Mild cardiac and renal toxicity was noted in the 25% and 50% MTD IV groups respectively while no cardiac or renal toxicity was observed in the HA groups (p<0.01). Finally HA conjugation increased the therapeutic dose range of DOX and CIS up to 150% of standard formulation MTD.


CONCLUSIONS
Subcutaneous nanocarrier-delivery of combination DOX/CIS demonstrated significantly improved tumor response with CPR and lower toxicity on histology compared to standard drugs. This delivery platform successfully treats LR and distant metastatic disease at lower doses and improves the dosing range of these drugs compared to standard agents.