Intralymphatic chemotherapy using a hyaluronan-cisplatin conjugate.
BACKGROUND
Breast cancers typically spread to regional lymph nodes once they disseminate from the primary tumor, thus adequate evaluation and treatment of the axillary lymph nodes is paramount in early stage disease. One significant problem with current therapy is the side effects chemotherapy agents create systemically, either alone or in combination. The purpose of this study is to determine whether lymphatically targeted cisplatin carriers will increase the localized dose in lymphatic metastases without systemic toxicities.


METHODS
Hyaluronan (HA) is a highly biocompatible polymer that follows lymphatic drainage from the interstitial spaces. We formed complexes of HA and cisplatin by non-covalent conjugation. Complexes were injected subcutaneously into the upper mammary fat pad of female rats, and the tissue distribution determined.


RESULTS
Cisplatin-HA contained up to 0.25 w/w of Pt and released drug with a half-life of 10 h in saline. Cisplatin-HA conjugates had high anti-tumor activity in vitro similar to the free drug: cisplatin-HA IC50 7 microg/mL in MCF7 and MDA-MB-231 human breast cancer cells (free cisplatin IC50 7 microg/mL). Cisplatin-HA conjugates were well tolerated in rodents with no signs of injection site morbidity or major organ toxicity after 96 h. The area-under-the-curve of cisplatin in the axially lymph nodes after injection with cisplatin-HA increased 74% compared with normal cisplatin.


CONCLUSIONS
This study demonstrates a novel intralymphatic drug delivery method in breast cancer to preferentially treat at-risk regional lymph nodes and avoid systemic toxicities. Further in vivo testing related to efficacy of this approach with regard to survival, toxicity, and pharmacokinetics is warranted to support its use in human trials.
Cai
Shuang
S
Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas, USA.
Xie
Yumei
Y
Bagby
Taryn R
TR
Cohen
Mark S
MS
Forrest
M Laird
ML
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007272:Injections, Intralymphatic; D008207:Lymphatic Metastasis / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D018675:Toxicity Tests
D000970:Antineoplastic Agents; D006820:Hyaluronic Acid; D002945:Cisplatin