Reduction of chemotherapy side effects and targeted inhibition of lymph node metastasis with a calcium phosphate nanoparticle delivery vehicle.

Abstract

Abstract Abstract #2135 Background: The toxic side effects associated with chemotherapy drugs are harmful to patients and reduce the maximum tolerable dose that can be given. Nanoparticulate dyes are used to identify draining lymph nodes in cancer patients and are carried to the lymph node via lymphatic transport. Our hypothesis for this study was that conjugation of cisplatin to nanoparticles of calcium phosphate (CDDP/CaP) would (a) increase lymph node accumulation of cisplatin via lymphatic transport after intralesional injection and (b) inhibit mouse mammary cancer lymph node metastasis without the side effects associated with systemic drug administration.
 Material and Methods: Primary tumors were created in the right rear footpad of BALB/c mice through injection of 66cl4 mouse mammary carcinoma cells and allowed to grow for 7 days before treatment. Study groups consisted of intralesional injection of CDDP/CaP nanoconjugates, control intraperitoneal systemic injections of free drug, or sham injections. The nanoconjugates were synthesized via precipitation of the calcium phosphate nanoparticles followed by an absorption step of charged aquated cisplatin. Draining nodes were collected two weeks after treatment and metastasis burden quantitated using a clonogenic assay (66cl4 is 6-thioguanine resistant). Mice were weighed daily to assess weight loss which serves as a broad indicator of drug toxicity. The experiment was repeated three times. Lymph nodes and plasma were collected for pharmacokinetic studies at multiple time points from separate groups of tumor free animals after nanoconjugate injections or control intraperitoneal injections of free drug. Drug concentrations were determined by Pt analysis.
 Results: The use of calcium phosphate nanoparticles led to elevated, sustained CDDP levels in draining lymph nodes for at least seven days after nanoconjugate injections compared to thirty minutes for the maximum systemic CDDP dosing. The mean metastatic burden of the mice was reduced more than 50% by the nanoconjugate and the free drug treatments, however, the mice given nanoconjugates did not lose weight, and even gained weight, while the mice given free drug all lost weight.
 Discussion: In this murine study, CDDP/CaP nanoconjugates were shown to reduce lymph node metastases as well as free drug yet without the toxic side effects of systemic free drug administration. In addition to cisplatin, other chemotherapy drugs such as taxol can be bound to the calcium phosphate nanoparticles without loss of drug activity. Due to the reduction of systemic toxicity and the localized activity of the chemotherapy through nanoparticle conjugation, this approach may have potentially broad use in neoadjuvant or combination therapy approaches.
 Financial support provided by a Basic, Clinical and Translational Breast Cancer Research Grant from Susan G. Komen for the Cure. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2135.