Citronellol-cabazitaxel (CIT-ss-CTX) conjugate self-assembled nanoparticles (CSNPs) were designed and prepared by conjugating cabazitaxel with citronellol via the disulfide bond that is redox-sensitive to the high concentration of glutathione within tumor cells. Notably, the CSNPs maintained in the cell cytotoxicity. Moreover, the AUC0-t of CSNPs was 6.5-fold higher than that of cabazitaxel solutions and the t1/2 was prolonged 2.3 times. Furthermore, we found that CSNPs could be employed as an efficient carrier for other hydrophobic drugs or imaging agents. Thus, the in vivo targeting study was implemented via using 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide (DiR)-loaded CSNPs as imaging agent, which showed CSNPs could effectively accumulate at the tumor site. Curcumin, a hydrophobic anticancer drug, was successfully loaded in CSNPs which exhibits good stability and synergistic antitumor effects. The citronellol–cabazitaxel conjugate therefore has a promising perspective as a multifunctional nanomedicine for combination therapy and theranostics attributed to its long-circulation property, redox-sensitive mechanism, and high drug coloading capability.

Recently, nanomedicine without drug carriers has attracted many pharmacists’ attention. A novel paclitaxel–s–s–paclitaxel (PTX–s–s–PTX) conjugate with high drug loading (∼78%, w/w) was synthesized by conjugating paclitaxel to paclitaxel by using disulfide linkage. The conjugate could self-assemble into uniform nanoparticles (NPs) with 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide (DiR) encapsulated within the core of PTX–s–s–PTX NPs for photothermal therapy (PTT). The DiR-loaded self-assembled nanoparticles (DSNs) had a mean diameter of about 150 nm and high stability in biological condition. A disulfide bond is utilized as a redox-responsive linkage to facilitate a rapid release of paclitaxel in tumor cells. DSNs indicated significant cytotoxicity as a result of the synergetic chemo-thermal therapy. DSNs were featured with excellent advantages, including high drug loading, redox-responsive releasing behavior of paclitaxel, capability of loading with photothermal agents, and combinational therapy with PTT. In such a potent nanosystem, prodrug and photothermal strategy are integrated into one system to facilitate the therapy efficiency.Keywords: anticancer; disulfide; high drug loading; photothermal therapy; redox responsive;

In contrast with common thought, we generated highly hydrophobic anticancer prodrug self-assembled nanoparticles without the aid of surface active substances, based on the conjugation of docetaxel to d-α-tocopherol succinate. The reduction-sensitive prodrug was synthesized with a disulfide bond inserted into the linker and was compared with a control reduction-insensitive prodrug. The morphology and stability of self-assembled nanoparticles were investigated. Cytotoxicity and apoptosis assays showed that the reduction-sensitive nanoparticles had higher anticancer activity than the reduction-insensitive nanoparticles. The reduction-sensitive nanoparticles exhibited favorable in vivo antitumor activity and tolerance compared with docetaxel Tween80-containing formulation and the reduction-insensitive nanoparticles. Taken together, the unique nanomedicine demonstrated a number of advantages: (i) ease and reproducibility of preparation, (ii) high drug payload, (iii) superior stability, (iv) prolonged circulation, and (v) improved therapeutic effect. This highly reproducible molecular assembly strategy should motivate the development of new nanomedicines.Different from traditional idea, we designed and synthesized a highly hydrophobic reduction-sensitive docetxel prodrug with a disulfide bond inserted into the linker between docetaxel and vitamin E, which could self-assemble in water to form self-assembled nanoparticles without the help of surface active substances. Compared with a docetaxel Tween80-containing formulation, the unique nanomedicine had many advantages, including high drug payload, advanced stability, superior reproducibility, low toxicty, prolonged circulation and increased therapeutic efficacy. The highly reproducible self-assembled nanoparticles prepared by simple nanoprecipitation technology are more attractive and effective nanomedicines, and might be a promising nano-drug delivery system for other anticancer drug.Download high-res image (210KB)Download full-size image

•The burst of CO2 bubbles was resulted from the acid-base reaction.•The approach was applied to prepare twelve drugs nanosuspensions.•The approach is low energy-consumption process and do not need specialized equipment.•The final products have good reproducibility and are easy for scale-up.The exploration of a simple and robust approach to produce nanosuspensions is a meaningful attempt for clinical translation. CO2-assisted effervescence was firstly developed to prepare nanosuspensions and was found to be easy for scale-up. Drug nanosuspensions were easily obtained by adding aqueous carbonate to the pre-treated mixture of drug, stabilizer and organic acid. The burst of CO2 bubbles resulted from the acid-base reaction insert a micro gas bubble smashing and mixing effect to the formation of nanosuspensions, leading to smaller sizes and a refined size distribution. We successfully prepared nanosuspensions with twelve structurally diverse drugs. Alternatively, solid carbonate blended with the mixture, allowing for later addition of water, also facilitates the formation of amorphous nanosuspensions. We defined this approach as in situ nanoamorphization (ISN). Intensive in vitro and in vivo investigations for itraconazole and cabazitaxel nanosuspensions validate the availability for administration.A new approach to produce drug nanosuspensions using CO2-assisted in situ Nanoamorphization. (Abbreviation: API, Active pharmaceutical ingredient.).

It is commonly observed that hydrophobic molecules alone cannot self-assemble into stable nanoparticles, requiring amphiphilic or ionic materials to support nanoparticle stability and function in vivo. We report herein newly self-assembled nanomedicines through entirely different mechanisms. We present proof-of-concept methodology and results in support of our hypothesis that disulfide-induced nanomedicines (DSINMs) are promoted and stabilized by the insertion of a single disulfide bond into hydrophobic molecules, in order to balance the competition between intermolecular forces involved in the self-assembly of nanomedicines. This hypothesis has been explored through diverse synthetic compounds, which include four first-line chemotherapy drugs (paclitaxel, doxorubicin, fluorouracil, and gemcitabine), two small-molecule natural products and their derivatives, as well as a fluorescent probe. Such an unprecedented and highly reproducible system has the potential to serve as a synthetic platform for a wide array of safe and effective therapeutic and diagnostic nanomedicine strategies.

Although many nanocarriers have been developed to encapsulate paclitaxel (PTX), the drug loading and circulation time in vivo always are not ideal because of its rigid “brickdust” molecular structure. People usually concentrate their attention on the spherical nanocarriers, here paclitaxel nanoparticles with different geometries were established through the chemical modification of PTX, nanoprecipitation, and core-matched cargos. Previously we have developed rod-shape paclitaxel nanocrystals using block copolymer, pluronic F127. Unfortunately, the pharmacokinetic (PK) profile of PTX nanocrystals is very poor. However, when PTX was replaced by its prodrug, the geometry of the nanoparticles changed from rod-shaped to worm-like. The worm-like nanoparticles can be further changed to spherical nanoparticles using the nanoprecipitation method, and changed to fingerprint-like nanoparticles upon the addition of the core-matched PTX. The nanoparticles with nonspherical morphologies, including worm-like nanoparticles and fingerprint-like nanoparticles, offer significant advantages in regards to key PK parameters in vivo. More important, in this report the application of the core-matching technology in creating a core-matched environment capable of controlling the in vivo PK of paclitaxel was demonstrated, and it revealed a novel technique platform to construct nanoparticles and improve the poor PK profiles of the drugs.Keywords: circulation; fingerprint-like; geometry; paclitaxel; pharmacokinetics; worm-like;

Unlike conventional ‘top-down’ and ‘bottom-up’ techniques, a novel low-cost CO2-assisted in situ nanoamorphization (ISN) method has been developed to prepare amorphous drug nanosuspensions. In order to improve the dissolution rate and oral bioavailability of tacrolimus (FK506), herein FK506 nanosuspensions with different particle size were successfully prepared using ISN method through adjusting the amount of acid-base pair and the stabilizer, the mean particle sizes of obtained FK506 nanosuspensions were 167.3 ± 2.8 nm (FK506-NA), 302.8 ± 2.0 nm (FK506-NB) and 513.5 ± 15.1 nm (FK506-NC), respectively. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) confirmed the amorphous state of FK506 in all nanosuspensions that would be beneficial to the improvement of drug bioavailability because the amorphous drug form is more soluble and has a higher dissolution rate than the crystalline state. In vitro dissolution studies showed that the dissolution rate order of different formulation is as follows: FK506-NB > FK506-NA > FK506-NC > FK506-D (without acid-base pair included) > Prograf® (commercial hard capsule). In vivo pharmacokinetic studies showed that all FK506 nanosuspensions clearly increased the oral bioavailability of FK506 in comparison with Prograf®, especially for FK506-NB. The Cmax and AUC0–12 h of FK506-NB were about 2.05-fold (p < 0.01) and 1.5-fold (p < 0.05) higher than that of Prograf®. These findings suggest that this simple and versatile ISN technique has great potential for use in the preparation of nanosuspensions to increase drug oral bioavailability.Download high-res image (148KB)Download full-size image

To achieve optimal therapeutic index of docetaxel, we conjugated docetaxel (DTX) with vitamin E (VE) by ester bond with disulfide bond or thioether bond as spacer to produce DTX-ss-VE or DTX-s-VE. The two prodrugs were successfully loaded into liposomes. The physicochemical characterization and in vitro release profiles of the prodrug loaded liposomes were investigated. MTT assays showed that the cytotoxicity of DTX-ss-VE loaded liposomes on PC3 (IC50 = 27.5 nM) and A549 cells (IC50 = 63.4 nM) was comparable with the cytotoxicity of DTX-s-VE loaded liposomes (IC50 = 99.2 and 159.5 nM, respectively). The pharmacokinetic studies demonstrated that DTX-ss-VE and DTX-s-VE loaded liposomes exhibited an extended DTX half-life (3.6 ± 1.2 and 10.0 ± 3.0 h, respectively) as compared to DTX solutions (2.1 ± 1.5 h) and an increased AUC (30487.3 ± 3791.6 and 20922.1 ± 5633.3 ng/L × h, respectively) compared with DTX solutions (1779.3 ± 226.6 ng/L × h). Finally, the in vivo anti-tumor studies showed that DTX-ss-VE loaded liposomes possessed similar antitumor activity compared with DTX solutions. Unexpectedly, not any tumor inhibition effect was observed in DTX-s-VE loaded liposomes group. In a conclusion, our studies suggested that simplex favorable properties of the anticancer prodrug can not ensure available good therapeutic index and the rational design of prodrug needs a comprehensive understanding of the in vitro and in vivo behavior of the prodrug.Download high-res image (168KB)Download full-size image