Prevention of metastasis in a 4T1 murine breast cancer model by doxorubicin carried by folate conjugated pH sensitive polymeric micelles

Abstract

This study primarily focused on the anti-metastatic activity of doxorubicin (DOX) loaded in a pHsensitive mixed polymeric micelle formed from two block polymers: poly(L-lactide) (PLLA) (Mn 3000)-b-poly(ethylene glycol) (PEG) (Mn 2000)-folate and poly(L-histidine) (PHis) (Mn 4700)-b-PEG (Mn 2000). Tumor formation and metastasis in mice were examined using a murine mammary carcinoma cell of 4T1 which is one of the most aggressive metastatic cancer cell lines. The efficacy was evaluated by tumor size, body weight change, survival rate, dorsal skin fold window chamber model, and histological observation of the lung, heart, liver and spleen after treatment with various DOX formulations. When the tumor reached 50-100 mm 3 in size, the mice were treated by 4 times at a 3-day interval at a dose of 10 mg DOX/kg. The mixed micelle formulation resulted in retarded tumor growth, no weight loss, and no death for 4-5 weeks. In another set of the in vivo test for histological evaluation of the organs, the mice were similarly treated but the formulations were injected one day after 4T1 cell inoculation. The treatment by DOX loaded mixed micelle showed no apparent metastasis till 28 days. However, significant metastasis to the lung and heart was observed on Day 28 when the mice were treated with DOX carried by PBS, PLLA-b-PEG micelle and PHis-b-PEG micelle.

Liver Cancer Targeting of Doxorubicin with Reduced Distribution to the Heart Using Hematoporphyrin-Modified Albumin Nanoparticles in Rats

“…This was consistent with the result that nanoparticles, compared to solution dosage forms, were likely to accumulate more in the liver, a major reticuloendothelial system (RES) organ, via a passive mechanism (37). Enhanced permeability and retention (EPR) due to the immature and porous vasculature of tumors (38) might have increased the uptake of nanoparticles in the liver of hepatoma rats. Considering the in vitro results (Figs.…”

A Totally Absorbable Multilayer PLGA Implant Device Containing Doxorubicin Inhibited Tumor Growth and Metastasis without Systemic Toxicity in Murine Breast Cancer and an Ideal Pharmacological Paradigm for Regional Chemotherapy

“…Early on, it has been realized that drugs in PLGA tend to have a huge initial burst release (90% release in 1 st 3 days), followed by a slow, often unpredictable core erosion release [5]- [7]. One way to overcome this challenge is through micro or nano particles [8]. The major problem is the elaborate process.…”

Doxorubicin-mediated radiosensitivity in multicellular spheroids from a lung cancer cell line is enhanced by composite micelle encapsulation

“…21 To reduce the acute toxicity of free doxorubicin and to improve its therapeutic efficacy, various polymeric micelle systems have been designed as delivery vehicles. [22][23][24] Studies have shown that cellular uptake of doxorubicin-loaded micelles and free doxorubicin are very different, ie, doxorubicin micelles are transported into cells by endocytosis, whereas free doxorubicin enters cells by simple diffusion. 18 In this study, we prepared composite PEG-PCL and P105 micelles using the solvent evaporation method to serve as carriers for doxorubicin.…”