Synthesis and Biological Investigation of Bile Acid-Paclitaxel Hybrids.

Chenodeoxycholic acid and ursodeoxycholic acid (CDCA and UDCA, respectively) have been conjugated with paclitaxel (PTX) anticancer drugs through a high-yield condensation reaction. Bile acid-PTX hybrids (BA-PTX) have been investigated for their pro-apoptotic activity towards a selection of cancer cell lines as well as healthy fibroblast cells. Chenodeoxycholic-PTX hybrid (CDC-PTX) displayed cytotoxicity and cytoselectivity similar to PTX, whereas ursodeoxycholic-PTX hybrid (UDC-PTX) displayed some anticancer activity only towards HCT116 colon carcinoma cells. Pacific Blue (PB) conjugated derivatives of CDC-PTX and UDC-PTX (CDC-PTX-PB and UDC-PTX-PB, respectively) were also prepared via a multistep synthesis for evaluating their ability to enter tumor cells. CDC-PTX-PB and UDC-PTX-PB flow cytometry clearly showed that both CDCA and UDCA conjugation to PTX improved its incoming into HCT116 cells, allowing the derivatives to enter the cells up to 99.9%, respect to 35% in the case of PTX. Mean fluorescence intensity analysis of cell populations treated with CDC-PTX-PB and UDC-PTX-PB also suggested that CDC-PTX-PB could have a greater ability to pass the plasmatic membrane than UDC-PTX-PB. Both hybrids showed significant lower toxicity with respect to PTX on the NIH-3T3 cell line.

Balancing the efficacy vs. the toxicity of promiscuous natural products: Paclitaxel-based acid-labile lipophilic prodrugs as promising chemotherapeutics.

TumorSelect® is an anticancer technology that combines cytotoxics, nanotechnology, and knowledge of human physiology to develop innovative therapeutic interventions with minimal undesirable side effects commonly observed in conventional chemotherapy. Tumors have a voracious appetite for cholesterol which facilitates tumor growth and fuels their proliferation. We have transformed this need into a stealth delivery system to disguise and deliver anticancer drugs with the assistance of both the human body and the tumor cell. Several designer prodrugs are incorporated within pseudo-LDL nanoparticles, which carry them to tumor tissues, are taken up, internalized, transformed into active drugs, and inhibit cancer cell proliferation. Highly lipophilic prodrug conjugates of paclitaxel suitable for incorporation into the pseudo-LDL nanoparticles of the TumorSelect® delivery vehicle formulation were designed, synthesized, and evaluated in the panel of 24-h NCI-60 human tumor cell line screening to demonstrate the power of such an innovative approach. Taxane prodrugs, viz., ART-207 was synthesized by tethering paclitaxel to lipid moiety with the aid of a racemic solketal as a linker in cost-effective, simple, and straightforward synthetic transformations. In addition to the typical 24-h NCI screening protocol, these compounds were assessed for growth inhibition or killing of ovarian cell lines for 48 and 72h-time intervals and identified the long-lasting effectiveness of these lipophilic prodrugs. All possible, enantiomerically pure isomers of ART-207 were also synthesized, and cytotoxicities were biosimilar to racemic ART-207, suggesting that enantiopurity of linker has a negligible effect on cell proliferation. To substantiate further, ART-207 was evaluated for its in vivo tumor reduction efficacy by studying the xenograft model of ovarian cancer grown in SCID mice. Reduced weight loss (a measure of toxicity) in the ART-207 group was observed, even though it was dosed at 2.5x the paclitaxel equivalent of Abraxane®. As a result, our delineated approach is anticipated to improve patient quality of life, patient retention in treatment regimes, post-treatment rapid recovery, and overall patient compliance without compromising the efficacy of the cytotoxic promiscuous natural products.

Fluorinated paclitaxel prodrugs for potentiated stability and chemotherapy.

Robust colloidal stability is an essential prerequisite for effective drug delivery. Herein, a series of fluorinated paclitaxel prodrugs bridged with redox-responsive linkages were synthesized, and the effect of fluorination on the assembly behavior and physiological stability was investigated. The 17-fluorinated ethanol-modified paclitaxel prodrug could self-assemble into stable nanoparticles without the addition of any surfactants. Fluorinated paclitaxel prodrug nanoparticles possessed potent cytotoxicity toward cancer cells and superior antitumor activity. This study offers a universal fluorination approach to improve drug delivery efficacy by enhancing the self-assembly capability and improving the colloidal stability of prodrugs for potentiating chemotherapy.

Pulmonary Delivery of Reactive Oxygen Species/Glutathione-Responsive Paclitaxel Dimeric Nanoparticles Improved Therapeutic Indices against Metastatic Lung Cancer.

Chemotherapeutics often failed to elicit optimal antitumor responses against lung cancer due to their limited exposure and accumulation in tumors. To achieve an effective therapeutic outcome of paclitaxel (PTX) against metastatic lung cancer with attenuated systemic and local toxicities, pulmonary delivery of redox-responsive PTX dimeric nanoparticles (NPs) was introduced. PTX dimers conjugated through variable lengths of diacid linkers containing disulfide bonds (-SS-) (i.e., α-PTX-SS-PTX, ß-PTX-SS-PTX, and γ-PTX-SS-PTX) were initially synthesized and were subsequently self-assembled into uniform nanosized particles in the presence of vitamin E TPGS with high drug loading capacity (DE > 97%). Among various redox-sensitive scaffolds, ß-PTX-SS-PTX NPs exhibited an optimal reactive oxygen species/glutathione-responsive drug release behavior, causing a lower local toxicity profile of PTX in the lungs. The scaffolds also demonstrated excellent colloidal stability, cellular uptake efficiency, and discriminating cytotoxicity between cancer and healthy cells. Further, they depicted an improved lung retention as compared to the control nanovesicles (ß-PTX-CC-PTX) devoid of the redox-sensitive disulfide motif. In the B16F10 melanoma metastatic lung cancer mouse model, intratracheally delivered ß-PTX-SS-PTX NPs exhibited a stronger anticancer potential with reduced systemic toxicity as compared to Taxol intravenous injection containing an equivalent PTX dose. The PTX dimeric NPs could also dramatically reduce the local toxicity relative to Taxol following their pulmonary delivery. Thus, this study presents redox-responsive PTX dimeric NPs as a promising nanomedicine for improved therapeutic efficacy against metastatic lung cancer.

Asymmetric Total Synthesis of Taxol.

Taxol is one of the most famous natural diterpenoids and an important anticancer medicine. Taxol represents a formidable synthetic challenge and has prompted significant interest from the synthetic community. However, in all the previous syntheses of Taxol, there have been no reports of closing the desired eight-membered ring through C1-C2 bond formation. Furthermore, the existence of Taxol-resistant tumors and side effects of Taxol make the development of new approaches to synthesize Taxol and its derivatives highly desirable. Here, we report the asymmetric total synthesis of Taxol using a concise approach through 19 isolated intermediates. The synthetically challenging eight-membered ring was constructed efficiently by a diastereoselective intramolecular SmI2-mediated pinacol coupling reaction to form the C1-C2 bond. The unique biomimetic oxygen ene reaction and the newly developed facile tandem C2-benzoate formation and C13 side chain installation improved the efficiency of the synthesis. The mild oxygen ene reaction under light conditions would be an alternative reaction involved in Taxol biosynthesis. This new convergent approach will allow the diverse creation of Taxol derivatives to enable further biological research.

Synthesis of small molecules targeting paclitaxel-induced MyD88 expression in triple-negative breast cancer cell lines.

Acquired paclitaxel (PTX) chemoresistance in triple-negative breast cancer (TNBC) can be inferred from the overexpression of toll-like receptor 4 (TLR4) and myeloid differentiation primary response 88 (MyD88) proteins and the activation of the TLR4/MyD88 cascading signalling pathway. Finding a new inhibitor that can attenuate the activation of this pathway is a novel strategy for reducing PTX chemoresistance. In this study, a series of small molecule compounds were synthesised and tested in combination with PTX against TNBC cells. The trimethoxy-substituted compound significantly decreased MyD88 overexpression and improved PTX activity in MDA-MB-231TLR4+ cells but not in HCCTLR4- cells. On the contrary, the trifluoromethyl-substituted compound with PTX synergistically improved the growth inhibition in both TNBC subtypes. The fluorescence titrations indicated that both compounds could bind with MD2 with good and comparable binding affinities. This was further supported by docking analysis, in which both compounds fit perfectly well and form some critical binding interactions with MD2, an essential lipid-binding accessory to TLR4 involved in activating the TLR-4/MyD88-dependent pathway.

Exquisite Vesicular Nanomedicine by Paclitaxel Mediated Co-assembly with Camptothecin Prodrug.

We report that the self-assembly of drug amphiphiles, Evans blue conjugated camptothecin prodrug (EB-CPT), can be modulated by another anticancer drug paclitaxel (PTX), resulting in ultrahigh quality of nanovesicles (NVs) with uniform shape and diameters of around 80 nm with the EB-CPT:PTX weight ratio of 1:1, 1:2, and 1:3, denoted as ECX NVs. Significantly, the co-assembly of EB-CPT and PTX without adding other excipients has nearly 100 % drug loading efficiency (DLE) and ultrahigh drug loading content (DLC) of PTX alone of up to 72.3±1.7 wt % which, to our best knowledge, is among the highest level reported in literature. Moreover, the ECX NVs with the EB-CPT:PTX weight ratio of 1:2 showed remarkable combination index of 0.59 at a level of 50 % efficacy against HCT116 cells in vitro and greatly improved tumor inhibition effect in vivo compared with two clinically approved CPT- and PTX-based anticancer nanomedicines (Onivyde and Abraxane) individually and their combinations.

Paclitaxel and naringenin-loaded solid lipid nanoparticles surface modified with cyclic peptides with improved tumor targeting ability in glioblastoma multiforme.

The present work describes the systematic development of paclitaxel and naringenin-loaded solid lipid nanoparticles (SLNs) for the treatment of glioblastoma multiforme (GBM). So far only temozolomide therapy is available for the GBM treatment, which fails by large amount due to poor brain permeability of the drug and recurrent metastasis of the tumor. Thus, we investigated the drug combination containing paclitaxel and naringenin for the treatment of GBM, as these drugs have individually demonstrated significant potential for the management of a wide variety of carcinoma. A systematic product development approach was adopted where risk assessment was performed for evaluating the impact of various formulation and process parameters on the quality attributes of the SLNs. I-optimal response surface design was employed for optimization of the dual drug-loaded SLNs prepared by micro-emulsification method, where Percirol ATO5 and Dynasan 114 were used as the solid lipid and surfactant, while Lutrol F188 was used as the stabilizer. Drug loaded-SLNs were subjected to detailed in vitro and in vivo characterization studies. Cyclic RGD peptide sequence (Arg-Gly-Asp) was added to the formulation to obtain the surface modified SLNs which were also evaluated for the particle size and surface charge. The optimized drug-loaded SLNs exhibited particle size and surface charge of 129 nm and 23 mV, drug entrapment efficiency >80% and drug loading efficiency >7%. In vitro drug release study carried out by micro dialysis bag method indicated more than 70% drug was release observed within 8 h time period. In vivo pharmacokinetic evaluation showed significant improvement (p < 0.05) in drug absorption parameters (Cmax and AUC) from the optimized SLNs over the free drug suspension. Cytotoxicity evaluation on U87MG glioma cells indicated SLNs with higher cytotoxicity as compared to that of the free drug suspension (p < 0.05). Evaluation of uptake by florescence measurement indicated superior uptake of SLNs tagged with dye over the plain dye solution. Overall, the dual drug-loaded SLNs showed better chemoprotective effect over the plain drug solution, thus construed superior anticancer activity of the developed nanoformulation in the management of glioblastoma multiforme.

Preparation and in vitro evaluation of amphiphilic paclitaxel small molecule prodrugs and enhancement of oral absorption.

A series of novel amphiphilic paclitaxel (PTX) small molecule prodrugs, PTX-succinic anhydride-cystamine (PTX-Cys), PTX-dithiodipropionic anhydride (PTX-SS-COOH) and PTX-succinic anhydride-cystamine-valine (PTX-SS-Val) were designed, synthesized and evaluated against cancer cell lines. Compared with paclitaxel, these prodrugs contained water-soluble groups such as amino, carboxyl and amino acid, which improved the aqueous solubility of the prodrugs. More importantly, the valine was introduced in PTX-SS-Val molecule and made the molecule conform to the structural characteristics of intestinal oligopeptide transporter PEPT1 substrate. Thus the oral bioavailability of prodrug could be improved because of the mediation of PEPT1 transporter. These small molecule paclitaxel prodrugs could self-assemble into nanoparticles in aqueous solution, which effectively improved the solubility of paclitaxel, and had certain stability in pH 6.5, pH 7.4 buffer solutions and simulated gastrointestinal fluids. Some of these prodrugs, especially for PTX-Cys and PTX-SS-Val, exhibited nearly equal or slightly better anticancer activity when compared to paclitaxel. Further studies on PTX-Cys and PTX-SS-Val showed that both had good intestinal absorption in the rat single-pass intestinal perfusion (SPIP) experiments. Oral pharmacokinetic experiments showed that PTX-SS-Val could effectively improve the oral bioavailability of PTX.

Hyperthermal paclitaxel-bound albumin nanoparticles co-loaded with indocyanine green and hyaluronidase for treating pancreatic cancers.

Albumin nanoparticles have become an attractive cancer nanomedicine platform due to their pharmaceutical advantages. Recently, photothermal therapy has been extensively applied to cancer treatment due to heat-induced tumor ablation. Herein, we fabricated albumin nanoparticles (HSA-NPs) loaded with paclitaxel (PTX), indocyanine green (ICG; a hyperthermal agent) and hyaluronidase (HAase) that breaks down hyaluronan, a major component of the extracellular matrix (ECM) in tumors. Synthesis was based on a slightly modified nanoparticle albumin-bound (Nab™) technique. The prepared nanoparticles (PTX/ICG/HAase-HSA-NPs) had a spherical shape with an average size of ~ 110 nm and a zeta potential of ~ -30.4 mV. They displayed good colloidal stability and typical patterns of ICG, HSA and HAase in UV-VIS-NIR and circular dichroism spectroscopic analysis. PTX/ICG/HAase-HSA-NPs were found to have excellent hyperthermal effects in response to near-infrared laser irradiation (808 nm) (up to > 50 °C over 4 min). The hyperthermia conducted by PTX/ICG/HAase-HSA-NPs resulted in significant cytotoxicity to pancreatic AsPC-1 cells at both severe (> 50 °C) and mild (41-42 °C) hyperthermal states in conjunction with the inherent cytotoxic activity of paclitaxel. Furthermore, the confocal images of AsPC-1 cell spheroids proved PTX/ICG/HAase-HSA-NPs were able to permeate deeply into the three-dimensional tumor tissue mimicry structure. Most of all, PTX/ICG/HAase-HSA-NPs maintained all these physicochemical and anti-cancer properties irrespective of the amount of embedded HAase (1-5 mg). Our results demonstrated that PTX/ICG/HAase-HSA-NPs are a promising hyperthermal/chemotherapeutic anticancer agent.

Encapsulating paclitaxel in polymeric nanomicelles increases antitumor activity and prevents peripheral neuropathy.

Paclitaxel (PTX) has a great clinical significance as an antitumor drug, although several side effects are strongly dose-limiting. In this way, we prepared a PTX-loaded 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000] polymeric micelles (PM/PTX) in an attempt to improve safety and effectiveness of conventional PTX formulation (CrEL/EtOH/PTX). In this study, we evaluated from both formulations: stability after dilution, hemocompatibility, cellular uptake, acute toxicity in healthy mice, antitumor activity, and toxicity after multiple-dose treatment. PM/PTX appeared to be more stable than CrEL/EtOH/PTX after dilution. PM/PTX did not exhibit hemolytic activity (values <1%), even at high concentrations. In vitro cellular uptake study indicated that polymeric micelles were able to deliver more PTX (5.8 %) than CrEL/EtOH (2.7 %) to 4T1 cells. In the acute toxicity evaluation in healthy mice, CrEL/EtOH/PTX (single dose of 20 mg/kg) induced peripheral neuropathy, which was not observed in PM/PTX group. Similar results were observed after tumor-bearing mice received a multiple-dose regimen (seven doses of 10 mg/kg). Worth mentioning, we also evaluated vehicles, and CrEL/EtOH alone was not capable of inducing neuropathic pain. Besides, PM/PTX exhibited a higher antitumor activity with an inhibition ratio approximately 1.5-fold higher than CrEL/EtOH/PTX group. This study suggested that PM/PTX is safer than CrEL/EtOH/PTX, and was able to improve the antitumor effectiveness in a 4T1 breast cancer model.

Enhancement of Antitumor Efficacy of Paclitaxel-Loaded PEGylated Liposomes by N,N-Dimethyl Tertiary Amino Moiety in Pancreatic Cancer.

INTRODUCTION: Pancreatic cancer, or pancreatic duct adenocarcinoma (PDAC), remains one of the most lethal cancers and features insidious onset, highly aggressive behavior and early distant metastasis. The dense fibrotic stroma surrounding tumor cells is thought to be a shield to resist the permeation of chemotherapy drugs in the treatment of PDAC. Thus, we synthesized a pancreas-targeting paclitaxel-loaded PEGylated liposome and investigated its antitumor efficacy in the patient-derived orthotopic xenograft (PDOX) nude mouse models of PDAC. METHODS: The PTX-loaded PEGylated liposomes were prepared by film dispersion-ultrasonic method and modified by an N,N-dimethyl tertiary amino residue. Morphology characteristics of the PTX-loaded liposomes were observed by transmission electron microscope (TEM). The PDOX models of PDAC were established by orthotopic implantation and imaged by a micro positron emission tomography/computed tomography (PET/CT) imaging system. The in vivo distribution and antitumor study were then carried out to observe the pancreas-targeting accumulation and the antitumor efficacy of the proposed PTX liposomes. RESULTS: PTX loaded well into both modified (PTX-Lip2N) and unmodified (PTX-Lip) PEGylated liposomes with spherical shapes and suitable parameters for the endocytosis process. The PDOX nude mouse models were successfully created in which high 18F-FDG intaking regions were observed by micro-PET/CT. In addition to higher cellular uptakes of PTX-Lip2N by the BxPC-3 cells, the proposed nanoparticle had a notable penetrating ability towards PDAC tumor tissues, and consequently, the antitumor ability of PTX-Lip2N was significantly superior to the unmodified PTX-Lip in vivo PDOX models and even more effective than nab-PTX in restraining tumor growth. CONCLUSION: The modified pancreas-targeting PTX-loaded PEGylated liposomes provide a promising platform for the treatment of pancreatic cancer.

A Paclitaxel Prodrug Activatable by Irradiation in a Hypoxic Microenvironment.

The innate hypoxic microenvironment of most solid tumors has a major influence on tumor growth, invasiveness, and distant metastasis. Here, a hypoxia-activated self-immolative prodrug of paclitaxel (PTX2 -Azo) was synthesized and encapsulated by a peptide copolymer decorated with the photosensitizer chlorin e6 (Ce6) to prepare light-boosted PTX nanoparticle (Ce6/PTX2 -Azo NP). In this nanoparticle, PTX2 -Azo prevents premature drug leakage and realizes specific release in hypoxic tumor microenvironment and the photosensitizer Ce6 not only efficiently generates singlet oxygen under light irradiation but also acts as a positive amplifier to promote the release of PTX. The combination of photodynamic therapy (PDT) and chemotherapy results in excellent antitumor efficacy, demonstrating the great potential for synergistic cancer therapy.

Recent Development of Copolymeric Nano-Drug Delivery System for Paclitaxel.

BACKGROUND: Paclitaxel (PTX) has been clinically used for several years due to its good therapeutic effect against cancers. Its poor water-solubility, non-selectivity, high cytotoxicity to normal tissue and worse pharmacokinetic property limit its clinical application. OBJECTIVE: To review the recent progress on the PTX delivery systems. METHODS: In recent years, the copolymeric nano-drug delivery systems for PTX are broadly studied. It mainly includes micelles, nanoparticles, liposomes, complexes, prodrugs and hydrogels, etc. They were developed or further modified with target molecules to investigate the release behavior, targeting to tissues, pharmacokinetic property, anticancer activities and bio-safety of PTX. In the review, we will describe and discuss the recent progress on the nano-drug delivery system for PTX since 2011. RESULTS: The water-solubility, selective delivery to cancers, tissue toxicity, controlled release and pharmacokinetic property of PTX are improved by its encapsulation into the nano-drug delivery systems. In addition, its activities against cancer are also comparable or high when compared with the commercial formulation. CONCLUSION: Encapsulating PTX into nano-drug carriers should be helpful to reduce its toxicity to human, keeping or enhancing its activity and improving its pharmacokinetic property.

A Gastric Cancer Peptide GX1-Modified Nano-Lipid Carriers Encapsulating Paclitaxel: Design and Evaluation of Anti-Tumor Activity.

AIM: The aim of this study was to develop a GX1-modified nanostructured lipid carrier (NLCs) and to evaluate its ability to improve the anti-gastric cancer tumor effects of paclitaxel (PTX). MAIN METHODS: The GX1-modified NLCs were synthesized and loaded with PTX (GX1-PTX-NLCs) by emulsion solvent evaporation technique. The anti-tumor activity and pharmacodynamics were then evaluated by in vitro cell studies and animal experiments. KEY FINDINGS: The GX1-modified NLCs were successfully synthesized and confirmed by 1H NMR and MALDI-TOF-MS. PTX-loaded NLCs produced particles with average size distribution less than or equal to 222 nm and good drug loading and entrapment efficiency. In vitro studies demonstrated that GX1-PTX-NLCs had a more obvious inhibitory effect on Co-HUVEC cells than PTX and unmodified PTX-NLCs. The cellular uptake results also showed that GX1-PTX-NLCs were largely concentrated in Co-HUVEC cells, and the uptake rates of GX1-PTX-NLCs in Co-HUVEC were higher than those of the free drug and the PTX-NLC. In vivo studies demonstrated that GX1-PTX-NLCs possess strong anti-tumor effect and showed higher tumor growth inhibition and lower toxicity in nude mice. SIGNIFICANCE: These results suggest that GX1-modified NLCs enhanced the anti-tumor activity of PTX and reduced its toxicity effectively. GX1-PTX-NLCs may be considered as a potent drug delivery system for therapy of gastric cancer.

An effective method to produce 7-epitaxol from taxol in HCO3.

It is known that 7-epitaxol has much stronger cytotoxicity than taxol does. However, the content of 7-epitaxol in yew is much less than taxol, which makes it more costly to obtain. We describe here a method to effectively convert taxol to 7-epitaxol. The key condition for reaction needs NaHCO3 in solvent acetonitrile (ACN). The conversion rate can be over 82%.

Synthesis of the Taxol Core via Catalytic Asymmetric 1,4-Addition of an Alkylzirconium Nucleophile.

The Taxol core was prepared in five steps via a key copper-catalyzed asymmetric conjugate addition trapping sequence. The use of a bromodiene-derived alkylzirconium nucleophile followed by trapping with POCl3/DMF gave a highly functionalized intermediate featuring a quaternary center in 69% yield with 92% ee. After 1,2-addition, Suzuki-Miyaura cross-coupling, allylic oxidation, and a type II intramolecular Diels-Alder reaction, the taxol core was obtained in 11% overall yield with 92% ee.

Two-Phase Synthesis of Taxol.

Taxol (a brand name for paclitaxel) is widely regarded as among the most famed natural isolates ever discovered, and has been the subject of innumerable studies in both basic and applied science. Its documented success as an anticancer agent, coupled with early concerns over supply, stimulated a furious worldwide effort from chemists to provide a solution for its preparation through total synthesis. Those pioneering studies proved the feasibility of retrosynthetically guided access to synthetic Taxol, albeit in minute quantities and with enormous effort. In practice, all medicinal chemistry efforts and eventual commercialization have relied upon natural (plant material) or biosynthetically derived (synthetic biology) supplies. Here we show how a complementary divergent synthetic approach that is holistically patterned off of biosynthetic machinery for terpene synthesis can be used to arrive at Taxol.

Glutathione-sensitive and folate-targeted nanoparticles loaded with paclitaxel to enhance oral squamous cell carcinoma therapy.

In this study, a drug delivery system based on glutathione (GSH)-sensitive and folic acid (FA)-targeted nanoparticles loaded with paclitaxel (FA-PEG-S-S-PCL@PTX, FA-NPs) was developed. First, we proved that the FA receptor was significantly expressed in 95 oral squamous cell carcinoma (OSCC) specimens (57.9%). This provided feasibility to release FA-targeted nanoparticles in tumour sites for patients with OSCC. Next, FA-NPs were synthesized and characterized. In vitro, we found enhancement in FA-mediated endocytosis in the HSC3 cells with FA overexpression. Therefore, paclitaxel (PTX) from FA-NPs could be precisely released due to the disulfide bonds that were cleaved by a redox reaction. In vivo, FA-NPs could be accumulated in mice bearing HSC3 cells, where they exhibited effective antitumor effects when compared to the treatments with free PTX and PEG-S-S-PCL@PTX. In summary, this novel drug system has an opportunity to improve OSCC treatment.

Preparation and Characterization of Albumin Nanoparticles of Paclitaxel-Triphenylphosphonium Conjugates: New Approach to Subcellular Targeting.

Mitochondria have been recognized as important targets in cancer therapy due to their role in the respiratory process of cells. One approach employed for mitochondrion targeting is conjugation of a delocalized cation such as triphenylphosphonium (TPP), with antineoplastic agents, for instance paclitaxel (PTX). In cell cytoplasm, TPP-PTX can come close to mitochondria due to its high positive charge, which has a strong tendency toward the enhanced negative charge of mitochondria. The esteric bond of TPP-PTX can break down in the acidic environment of tumor cells and release the PTX, which can act directly on mitochondria to kill tumor cells. TPP-PTX was synthesized in three steps: Succinic anhydride (SUC) reacted with PTX to achieve succinyl paclitaxel (SUC-PTX), which has an acid-labile esteric bond. Then 2-triphenylphosphonium ethylammonium (ATPP) was prepared by attaching 2-bromoethylammunium bromide to TPP. Finally, a TPP-PTX prodrug was synthesized by attaching these materials. The products of all steps were characterized by thin-layer chromatography (TLC), infrared spectroscopy (IR), and nuclear magnetic resonance (1H NMR, 13C NMR). The purity of the products was determined by HPLC methods. TPP-PTX, as a prodrug, was loaded in to human serum albumin (HSA) nanoparticles by a method inspired by nab-technology with 130-160 nm particle size distribution, PdI=0.166 and Zeta potential -12.6 mV.