solanesol and Neoplasms

The administration of nanodrugs can lead to metabolism related systemic toxicity due to the use of inert carriers in large quantities. Carrier materials that offer therapeutic effects are therefore a promising means of addressing this limitation. Herein, a hyaluronate-based nanocarrier was prepared from hyaluronic acid (HA) and solanesol. Solanesyl thiosalicylate (STS) derived from solanesol has certain antitumor effects and was used to modify HA. The conjugate (HA-STS) self-assembled into nanoparticles acting as a drug carrier. The synthesis of the conjugates was confirmed by

Topics: Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Humans; Hyaluronic Acid; Nanoparticles; Neoplasms; Terpenes

Metabolites of a large number of inert drug carriers can cause long-term exogenous biological toxicity. Therefore, carriers with simultaneous therapeutic effects may be a good choice for drug delivery. Herein, a series of pharmacologically active solanesol derivatives were synthesized and investigated for use as micellar drug carriers for cancer therapy. Solanesyl thiosalicylic acid (STS) was first synthesized by introducing a thiosalicylic acid group to solanesol, inspired by the characteristic structure of farnesyl thiosalicylic acid (FTS) which is a non-toxic inhibitor of all active forms of the RAS protein. Then, two amphiphilic derivatives of STS were formed with ester- and hydrazone (HZ)-bond linked methyl poly(ethylene glycol)(mPEG), mPEG-STS and mPEG-HZ-STS, respectively. The PEGylated STS could be formed stable nano-sized micelles loaded with Doxorubicin (DOX). In vitro, DOX loaded mPEG-STS and mPEG-HZ-STS micelles exhibited stronger tumor inhibition ability compared with free DOX. In vivo, blank mPEG-STS and mPEG-HZ-STS micelles showed an obvious inhibiting effect on tumor growth while the drug loaded micelles had the greatest tumor inhibition effect. The enhanced therapeutic effects and the synergistic effect observed with this solanesol-based drug delivery system could be attributed to the inherent therapeutic qualities of the drug carriers.

Topics: Antibiotics, Antineoplastic; Cell Line, Tumor; Chemistry, Pharmaceutical; Doxorubicin; Drug Carriers; Drug Delivery Systems; Humans; Micelles; Nanoparticles; Neoplasms; Particle Size; Polyethylene Glycols; Terpenes

The aim of the present study is to take advantage of the unique property of polyisoprenoid chains to adopt a compact molecular conformation and to use these natural and biocompatible lipids as nanocarriers of drugs to deliver siRNA. A new chemical strategy is applied here to conjugate squalene (SQ) and solanesol (SOLA) to siRNA consisting of an activated variant of the azide-alkyne Huisgen cycloaddition also known as copper-free (Cu-free) click chemistry. We conjugated siRNA against TMPRSS2-ERG, a fusion oncogene found in more than 50% of prostate cancers to SQ or SOLA. First, several parameters such as molar ratio, solvents, temperature, incubation time, and the annealing schedule between both siRNA strands were investigated to bioconjugate the SQ or SOLA via Cu-free click chemistry. The best parameters of the new bioconjugation approach allowed us to (i) increase the synthesis yield up to 95%, (ii) avoid the formation of byproducts during the synthesis, and (iii) improve the reproducibility of the bioconjugation. Then, the biological activity of the resulting nanoparticles was assessed. In vitro, all four formulations were able to decrease the corresponding oncogene and oncoprotein expression. In vivo, only two of the four nanoformulations showed anti-neoplastic activity that seems to be tightly related to their dissimilar biodistribution behavior. In conclusion, we performed a new approach easily transposable for pharmaceutical development to synthesize siRNA-SQ and siRNA-SOLA and to obtain efficient siRNA-nanoparticles. The robustness of the process could be extended to several other polyterpenes and likely applied to other siRNA targeting genes whose overexpression results in the development of cancers or other genetic diseases.

Topics: Alkynes; Animals; Azides; Cell Line, Tumor; Click Chemistry; Cycloaddition Reaction; Humans; Mice, SCID; Nanoparticles; Neoplasms; Oligonucleotides; RNA, Small Interfering; RNAi Therapeutics; Squalene; Terpenes

We prepared an amphiphilic redox-responsive conjugate based on mPEGylated solanesol, solanesyl poly(ethylene glycol) dithiodipropionate (SPDP), along with its inert counterpart solanesyl poly(ethylene glycol) succinate (SPGS), which self-assembled in aqueous solution to form redox-responsive micelles. Used as efficient drug carriers for doxorubicin (DOX), the micelles acted as synergistic agents for cancer therapy. Dynamic light scattering (DLS) measurements showed that the SPDP micelles had average diameters of 111nm, which decreased to 88nm after the encapsulation of DOX. The mean diameters and size distribution of the disulfide-containing micelles changed obviously in the presence of the reducing agent glutathione (GSH), whereas no changes occurred in the case of redox-insensitive SPGS micelles. DOX could be loaded into both types of micelles, with drug loading content of about 4.0%. A significantly accelerated release of DOX was triggered by GSH for DOX-loaded SPDP micelles, compared with DOX-loaded SPGS micelles. Blank SPGS and SPDP micelles displayed higher inhibition of HeLa and MCF-7 cell proliferation but less cytotoxicity to normal L-02 cells at similar concentrations. Confocal microscopic observation indicated that a greater amount of DOX was delivered into the nuclei of cells following 9 or 12h incubation with DOX-loaded micelles. In vivo studies on H22-bearing Swiss mice demonstrated the superior anticancer activity of DOX-loaded SPDP micelles over free DOX and DOX-loaded SPGS micelles. All of the data presented here suggested that these SPDP micelles may have a dual function, as they are preferentially toxic for tumor cells alone and are efficient and safe carriers for anticancer drugs.. Various nanoscale drug carriers were used to enhance therapeutic effect of many drugs. While, the metabolites of high quantities of carriers may cause additional short- or long-term toxicities. In this study, a new systems based on solanesol derivatives was developed for anticancer drug delivery. There are two features for this system. One is solanesol originated bioactivity of the carrier, which will synergistically facilitate therapeutic effect of the encapsulated drug. The other is the redox-responsive drug release behavior adaptable to the glutathione-rich atmosphere of tumor cell. All the hypothesis have been elucidated in this work through in vitro and in vivo studies. It was found that this drug delivery system may have a dual function, as they are preferentially toxic for tumor cells alone and are efficient and safe carriers for anticancer drugs.

Topics: Animals; Antibiotics, Antineoplastic; Cell Proliferation; Doxorubicin; Drug Carriers; Female; Hep G2 Cells; Humans; MCF-7 Cells; Mice; Micelles; Nanoparticles; Neoplasms; Polyethylene Glycols; Terpenes; Xenograft Model Antitumor Assays