SN-38:&amp;#x03B2;-cyclodextrin inclusion complex for in situ solidifying injectable polymer implants

Manaspon, Chawan; Nittayacharn, Pinunta; Vejjasilpa, Ketpat; Fongsuk, Chayut; Nasongkla, Norased

doi:10.1109/iembs.2011.6090881

Cited by 6 publications

(4 citation statements)

References 17 publications

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“…Inherent poor water solubility and stability pose a great challenge to develop an optimal formulation of SN38 [8][9][10][11], consequently, several prodrugs, polymer conjugates [3,11,12], micelles [13][14][15][16][17][18], liposomes [19][20][21] and nanoparticles [8][9][10]22], polymeric implants [23] and cells as drug carriers [24] were investigated to improve its biopharmaceutical properties [12][13][14][15][16][17][18][19][20][21][22]25,26]. Broadly, these strategies may be divided into two categories: chemical derivatization of SN38; and encapsulation into a carrier system.…”

Section: Introductionmentioning

confidence: 99%

Challenges in SN38 drug delivery: current success and future directions

Palakurthi

2015

Expert Opinion on Drug Delivery

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The challenges in SN38 drug delivery may be overcome by two ways: ensuring multiple layers of protection against degradation and slow but sustained release of therapeutically effective drug concentrations. It may also be achieved by preparing a polymer-drug conjugate and further encapsulating the conjugate in suitable carrier system; tumor-targeted SN38 delivery by using immunoconjugates, enzyme-activated prodrug therapy and antibody-directed nanoparticle delivery. However, selection of a suitable ligand for tumor targeting and use of safe and biocompatible nanoparticle systems play an important role in realizing this goal.

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Section: Introductionmentioning

confidence: 99%

Challenges in SN38 drug delivery: current success and future directions

Palakurthi

2015

Expert Opinion on Drug Delivery

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“…Cyclodextrins have been shown to increase the cytotoxicity of several antineoplastic drugs like camptothecin (16,17), curcumin (18), doxorubicin, docetaxel (19), paclitaxel (20), etc. SN-38-βCD complex has been used to prepare in situ polymeric implants (21), but there was no detailed study reported on the effect of CDs on improving solubility, stability, and cytotoxicity of SN-38. In this study, we investigated the effects of four different types of modified β-cyclodextrins, namely, sodium sulfobutylether β-cyclodextrin (SBEβCD), hydroxypropyl β-cyclodextrin (HPβCD), randomly methylated β-cyclodextrin (RMβCD), and methylated β-cyclodextrin (MβCD) on the solubility, stability, and cytotoxicity of SN-38.…”

Section: Introductionmentioning

confidence: 99%

SN-38-Cyclodextrin Complexation and Its Influence on the Solubility, Stability, and In Vitro Anticancer Activity Against Ovarian Cancer

Vangara

Ali

et al. 2014

AAPS PharmSciTech

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Abstract. SN-38, an active metabolite of irinotecan, is up to 1,000-fold more potent than irinotecan. But the clinical use of SN-38 is limited by its extreme hydrophobicity and instability at physiological pH. To enhance solubility and stability, SN-38 was complexed with different cyclodextrins (CDs), namely, sodium sulfobutylether β-cyclodextrin (SBEβCD), hydroxypropyl β-cyclodextrin, randomly methylated β-cyclodextrin, and methyl β-cyclodextrin, and their influence on SN-38 solubility, stability, and in vitro cytotoxicity was studied against ovarian cancer cell lines (A2780 and 2008). Phase solubility studies were conducted to understand the pattern of SN-38 solubilization. SN-38-βCD complexes were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction analysis (XRPD), and Fourier transform infrared (FTIR). Stability of SN-38-SBEβCD complex in pH 7.4 phosphate-buffered saline was evaluated and compared against free SN-38. Phase solubility studies revealed that SN-38 solubility increased linearly as a function of CD concentration and the linearity was characteristic of an A P -type system. Aqueous solubility of SN-38 was enhanced by about 30-1,400 times by CD complexation. DSC, XRPD, and FTIR studies confirmed the formation of inclusion complexes, and stability studies revealed that cyclodextrin complexation significantly increased the hydrolytic stability of SN-38 at physiological pH 7.4. Cytotoxicity of SN-38-SBEβCD complex was significantly higher than SN-38 and irinotecan in both A2780 and 2008 cell lines. Results suggest that SBEβCD encapsulated SN-38 deep into the cavity forming stable inclusion complex and as a result increased the solubility, stability, and cytotoxicity of SN-38. It may be concluded that preparation of inclusion complexes with SBEβCD is a suitable approach to overcome the solubility and stability problems of SN-38 for future clinical applications.

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“…To exploit the full therapeutic potential of SN-38, a variety of drug delivery systems have been extensively investigated, including polymeric implants, 11 micelles, [12][13][14] liposomes, 15,16 polymer conjugates, 7,17 and nanoparticles. 9,18 Unfortunately, although these techniques enhanced the solubility of SN-38, there are also many inherent drawbacks, such as low encapsulation efficiency and low drug loading, 10,15 poor stability during conjugation process, and low final yield of polymer conjugates.…”

Section: Introductionmentioning

confidence: 99%

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

Chen¹,

Li²,

Zhang³

et al. 2017

IJN

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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.

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SN-38:β-cyclodextrin inclusion complex for in situ solidifying injectable polymer implants

Cited by 6 publications

References 17 publications

Challenges in SN38 drug delivery: current success and future directions

Challenges in SN38 drug delivery: current success and future directions

SN-38-Cyclodextrin Complexation and Its Influence on the Solubility, Stability, and In Vitro Anticancer Activity Against Ovarian Cancer

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

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