Abstract
Active targeting of water-insoluble chemotherapeutic drugs, such as paclitaxel, to breast cancer is a highly desirable because of its associated increase in anticancer efficacy coupled with reduced systemic drug toxicity. However, rational design of these drug delivery platforms should take into account both pathobiological attributes of breast cancer, such as enhanced permeability and retention phenomenon and overexpression of vasoactive intestinal peptide (VIP) receptors, as well as biophysical properties of its ingredients, including ease of preparation, water insoluble drug loading capacity, steric hindrance, nanosize, and scale-up production and storage. To this end, we developed and tested a novel biocompatible and biodegradable nanoparticulate formulation of VIP-conjugated sterically stabilized phospholipid mixed micelles (SSMM-VIP; size ~ 14 nm) composed of disteraroyl phosphatidylethanolamnine-poly(ethylenglycol-2000) and egg yolk phosphatidylcholine. This construct solubilized 1 mg/ml paclitaxel (P-SSMM-VIP) and retained its biophysical properties upon lyophylization and reconstitution in saline. Moreover, it exhibited a twofold increase in cytotoxicity to MCF-7 breast cancer cells in comparison with P-SSMM and paclitaxel in DMSO (P < 0.05). In addition, the construct targeted VIP receptors overexpressed in methyl nitrosurea (MNU)-induced in situ rat breast cancer tissues. There was a twofold increase in accumulation of intravenously administered P-SSMM-VIP (1 mg/kg) in MNU-induced rat breast cancer, coupled with a significantly greater regression of breast cancer in comparison with P-SSMM and Taxol (P < 0.05). At the same time there was a significant reduction in P-SSMM-VIP accumulation in bone marrow, spleen and other organs in comparison with P-SSMM and Taxol (P < 0.05). There was no significant change in systemic arterial pressure during administration of P-SSMM-VIP. Collectively, these data indicate that actively targeting paclitaxel passively loaded into biocompatible, biodegradable, long-circulating SSMM to breast cancer through VIP receptors improves drug efficacy and reduces its uptake in injury-prone normal tissues. We suggest that P-SSMM-VIP is an efficacious and safe, actively targeted drug delivery platform to treat breast cancer.
Highlights
Prognostic and predictive factors play important roles in profiling predicts clinical outcome of breast cancer
Genetic tests derived from gene expression profiling studies are likely to become useful as prognostic and predictive tests to guide clinical decision making in the treatment of primary breast cancer
The 76-gene profile was strongly predictive of those patients who will develop a distant metastasis within 5 years or will remain recurrence free during that period and in multivariate analysis when corrected for traditional prognostic factors including grade (HR 5.55; P < 0.00003)
Summary
Prognostic and predictive factors play important roles in profiling predicts clinical outcome of breast cancer. Results Between August 1993 and July 1999, 885 patients with primary breast cancer and four or more tumor-positive lymph nodes were randomized in 10 Dutch centers in a study of high-dose chemotherapy. We conducted a phase II trial to define the safety, the efficacy, the pathological response rate and survival associated with four cycles DXR–GMZ administered every 3 weeks followed by surgery, four cycles of FAC50 as a primary therapy in MBC. Method Fifty-four patients with invasive breast cancer treated in 2004 underwent axillary ultrasound and cytological puncture with fine needle of suspicious nodes before surgery Suspicious nodes were those with at least one of the following signs: long-to-short axis ratio less than 1.5, absence of hilius and cortical disruption. BrdU and MTT exhibited inhibition of DNA synthesis and metabolic activity of treated MBC cells compared with untreated controls
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