Abstract
Nanomedicine holds great promise for fighting against malignant tumors. However, tumor elevated interstitial fluid pressure (IFP) seriously hinders convective transvascular and interstitial transport of nanomedicines and thus damages its antitumor efficacy. In this study, combretastatin-A4 phosphate (CA4P) was utilized to reduce tumor IFP, and thereby to improve the intratumoral distribution and antitumor efficacy of nanoparticle albumin-bound paclitaxel (nab-paclitaxel). IFP was measured using the wick-in-needle method in tumors growing subcutaneously pretreatment and posttreatment with a single intravenous injection of CA4P. The tracing method of iodine 131 isotope was used for biodistribution analysis of nab-paclitaxel. Liquid chromatography coupled with tandem mass spectrometry was used to detect the intratumoral concentration of paclitaxel. Magnetic resonance imaging was applied to monitor tumor volume and ratios of necrosis. The tumor IFP continued to decline gradually over time following CA4P treatment, reaching approximately 31% of the pretreatment value by 1 h posttreatment. Biodistribution data indicated that both 131I-nab-paclitaxel and paclitaxel exhibited higher tumor uptake in CA4P + 131I-nab-paclitaxel group compared with I131-nab-paclitaxel group. Nab-paclitaxel combined with CA4Pshowed significant tumor growth inhibition and higher tumor necrosis ratio relative to PBS, CA4P and nab-paclitaxel group, respectively. In conclusion, CA4P improved the intratumoral distribution and antitumor efficacy of nab-paclitaxel in W256 tumor-bearing rats.
Highlights
A major challenge in chemotherapy is to change the biodistribution of drugs to reduce free drug toxicity and favor tumor accumulation
The thin layer chromatography (TLC) determination showed that the radiochemical purity (RCP) of 131I- nab-paclitaxel was greater than 95% after purification, and in vitro stabilities of 131I- nab-paclitaxel incubated in rat serum at 37°C were excellent with RCP over 92% up to 24 h
The present work demonstrated that combretastatin-A4 phosphate (CA4P) could improve the uptake and distribution of nab-paclitaxel in W256 breast carcinoma tumor, thereby enhancing the antitumor efficacy of nab-paclitaxel
Summary
A major challenge in chemotherapy is to change the biodistribution of drugs to reduce free drug toxicity and favor tumor accumulation. Nanoparticles flow to different regions of tumors via blood vessels. They must cross the vessel wall, and penetrate through the interstitial space to reach the target cells [5]. Nanomedicines could be preferentially delivered to tumors owing to the enhanced permeability and retention effect, the convective transvascular and interstitial transport for them is severely hampered due to the elevated IFP [3, 7], which leads to a poor penetration into and distribution across the interstitium [7]. Lowering IFP in solid tumors may be a great strategy to improve the uptake and distribution of nanomedicines in tumors
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