In vitro and in vivo evaluation of SN-38 nanocrystals with different particle sizes

Abstract

7-Ethyl-10-hydroxycamptothecin (SN-38) is a potent broad-spectrum antitumor drug derived from irinotecan hydrochloride (CPT-11). Due to its poor solubility and instability of the active lactone ring, its clinical use is significantly limited. As one of the most promising formulations for poorly water-soluble drugs, nanocrystals have attracted increasing attention. In order to solve these problems and evaluate the antitumor effect of SN-38 in vitro and in vivo, two nanocrystals with markedly different particle sizes were prepared. Dynamic light scattering and transmission electron microscopy were used to investigate the two nanocrystals. The particle sizes of SN-38 nanocrystals A (SN-38/NCs-A) and SN-38 nanocrystals B (SN-38/NCs-B) were 229.5±1.99 and 799.2±14.44 nm, respectively. X-ray powder diffraction analysis showed that the crystalline state of SN-38 did not change in the size reduction process. An accelerated dissolution velocity of SN-38 was achieved by nanocrystals, and release rate of SN-38/NCs-A was significantly faster than that of SN-38/NCs-B. Cellular uptake, cellular cytotoxicity, pharmacokinetics, animal antitumor efficacy, and tissue distribution were subsequently examined. As a result, enhanced intracellular accumulation in HT1080 cells and cytotoxicity on different tumor cells were observed for SN-38/NCs-A compared to that for SN-38/NCs-B and solution. Besides, compared to the SN-38 solution, SN-38/NCs-A had a higher bioavailability after intravenous injection; while the bioavailability of SN-38/NCs-B was even lower than that of the SN-38 solution. SN-38/NCs-A exhibited a significant inhibition of tumor growth compared to SN-38 solution and SN-38/NCs-B in vivo. The antitumor effect of SN-38/NCs-B was stronger than SN-38 solution. The tissue distribution study in tumor-bearing mice showed that nanocrystals could markedly improve the drug accumulation in tumor tissue by the enhanced permeability and retention effect compared to SN-38 solution, and the amount of SN-38 in tumors of SN-38/NCs-A group was much more than that of SN-38/NCs-B group. In conclusion, nanocrystals dramatically enhanced the anticancer efficacy of SN-38 in vitro and in vivo, and the particle size had a significant influence on the dissolution behavior, pharmacokinetic properties, and tumor inhibition of nanocrystals.

Amphiphilic Polymeric Nanoparticles Modified with a Protease-Resistant Peptide Shuttle for the Delivery of SN-38 in Diffuse Intrinsic Pontine Glioma

“…44 Camptothecin nanocrystals show very negative ζ-potential values of approximately −40 mV that become less negative upon surface stabilization with different polymers. 45,46 In this work, SN-38 reduced the ζ-potential of the unmodified nanoparticles to +17 ± 1 mV, in good agreement with the literature. 47 This behavior could be explained by the electrostatic interaction of SN-38 molecules with positively charged CS to some extent.…”

Mechanochemical preparation of chrysomycin A self-micelle solid dispersion with improved solubility and enhanced oral bioavailability

“…Moreover, the particle has a negative zeta potential which was − 11.7 mV. It was reported that suitable range of particle sizes for evading filtration in reticuloendothelial system (RES) organs was between 100 and 200 nm [ 32 – 35 ]. In addition, the neutral surface charge of particles (zeta potential ± 10 mV) was proved to prolonged blood circulation and facilitate its accumulation at the tumor tissue [ 33 ].…”

Enhanced Delivery of Imatinib into Vaginal Mucosa via a New Positively Charged Nanocrystal-Loaded in Situ Hydrogel Formulation for Treatment of Cervical Cancer

“…Pluronic F68-stabilized paclitaxel nanocrystals exhibited elevated interaction with cancer cells and intratumor accumulation [15,16]. Pluronic F68 and soybean lecithin-stabilized 7-ethyl-10-hydroxycamptothecin nanocrystals inhibited the growth of MCF-7 model tumors more efficiently [17]. The abovementioned surface modification examples for nanocrystals are mainly based on either physical adsorption of stabilizers or chemical derivatization of the prototype drug.…”