Penetration Of Paclitaxel Research Articles

Evaluation of polyelectrolyte nanoparticles of chitosan and hyaluronic acid as topical delivery systems for cytotoxic agents

In this study, we developed polyelectrolyte complexes (PECs), composed of hyaluronic acid and chitosan, aiming at obtaining a bioadhesive topical formulation for potential application for skin cancer treatment. Selected nanocarriers were obtained at a 1:1 (w/w) ratio of polyelectrolytes (0.25 mg/mL each) and probe sonication, displayed nanometric size (209.4 nm, PDI = 0.19), and cationic zeta potential (+28.0 mV). PECs presented bioadhesive potential, demonstrated by shifts in size and zeta potential upon incubation with mucin, and reduced transepidermal water loss. Paclitaxel (PTX) and 5-fluorouracil (5-FU), cytotoxic drugs with distinct physical-chemical characteristics, were incorporated at 0.25 and 0.75 %, respectively; propylene glycol addition was necessary for PTX incorporation. Compared to the control, 2.3- (9.4±3.6 μg/cm2) and 4.5-fold (2.8±0.8 μg/cm2) increases in PTX penetration into the stratum corneum and viable skin layers, respectively, were observed after 12 hours. No increase in 5-FU penetration was demonstrated. Incorporation in PECs resulted in slight increases in the cytotoxicity of PTX and 5-FU against melanoma cells, reducing IC50 values by 1.5- and 1.2-fold (1.55 and 35.10 μM for PTX and 5-FU, respectively) compared to the control solutions. IC50 values found for keratinocytes were higher (5.74 and 162.6 μM for paclitaxel and 5-FU, respectively). At non-cytotoxic concentrations, drug-loaded PECs promoted 24–31 % reductions on cell migration, suggesting that drug incorporation in PECs did not hinder their biological effects.

Loading and release of\xa0cancer chemotherapy drugs utilizing simultaneous temperature and pH-responsive nanohybrid

BackgroundRecently, the development of nanocarriers and the improvement of their biochemical properties have became of great importance. Single-walled carbon nanotubes (SWCNT) have many applications in drug delivery systems (DDS) as a common carbon-based structure. In the current work, the penetration, co-loading, and co-release of Doxorubicin (DOX) and Paclitaxel (PAX), as two cancer chemotherapy agents, were investigated using a novel modified copolymer with functionalized SWCNT.ResultsThis study proposes a dual-responsive smart carrier that is sensitive to pH and temperature. The carrier consists of functionalized SWNT and Dimethyl acrylamide-trimethyl chitosan (DMAA-TMC) grafting on SWCNT. This suggested carrier was investigated by utilizing molecular simulations. Interaction energies between DOX, PAX, and carrier as well as the affinity of drugs to the nanocarrier were studied. The energy analysis of drug release and adsorption presented that DOX and PAX delivery using this carrier is selective and sensitive at healthy and cancerous conditions. The attraction of DMAA-TMC, as a biodegradable and biocompatible copolymer, with SWCNT showed that degradation mechanism in acidic environment deformed the copolymer. This leads to a smart release mechanism in an acidic cancerous tissue. Additionally, it improves hydrophilicity, optimum nano-particle size, and cell cytotoxicity concerns.ConclusionsThe simulation results manifested a significant contribution of DMAA-TMC in the adsorption and release of cancer chemotherapy drugs in normal and neoplastic tissues. The interaction of copolymer also improves the biocompatibility and biodegradability of the SWCNT. Smart drug delivery carrier can be a valuable nanohybrid for loading, transporting, and releasing of cancer chemotherapy drugs.Graphical abstract

Abstract PS14-05: Phase 1/2 clinical trial of a topical submicron particle paclitaxel (SOR007) for the treatment of cutaneous metastases

Abstract Background: Cutaneous Metastases (CM) are an infrequent presentation of advanced solid tumors and are usually associated with symptoms of pain, pruritus, and secondary infections, all of which negatively affect quality of life and result in additional morbidity. Systemic chemotherapy, advanced wound care, topical agents, cryo-, electro-, photodynamic-, laser and intralesional therapies have been limited by inconsistent efficacy, inconvenience, or toxicity. In this open-label phase 1/2 clinical trial, submicron particle paclitaxel in an anhydrous base (SOR007) was evaluated for topical treatment of CM from breast cancer (n=21), leiomyosarcoma (n=1) and Paget’s disease (n=1). Previously, in vitro, in vivo, and clinical studies demonstrated penetration of paclitaxel into the dermis with the silicone-based anhydrous producing subtoxic plasma levels in GLP toxicology studies and early clinical trials. Trial Design: The phase 1/2 open label trial evaluated 3 doses of SOR007 (0.15%, 1.0%, 2.0%). Approximately 0.5 grams (1 FTU) of SOR007 per 50 cm2 treatment area was applied BID during a 3+3 dose-rising phase for 28 days (n=10) or a dose-expansion phase at 2% strength BID for 28 days (n=2) or 56 days (n=11) unless discontinuation became necessary due to clinical course of the underlying disease. Results: At least one eligible lesion was treated per subject and classified per RECIST 1.1. In the 28-day application group, 10 subjects were treated and in the 56-day application group, 11 subjects were treated. Lesion response is summarized in the table below for data to date. Lesion response was evaluated within 2 weeks of last treatment day in most subjects. Conclusions: SOR007 was safe when applied to CM lesions. SOR007 resulted in decreased lesion progression or reduced lesion area in the majority of CM subjects. These clinical benefits became more consistent and pronounced at 2% strength with longer treatment suggesting a dose/duration response. Lesion pain reduction is also suggested from the study. Additional clinical research with more subjects and longer treatment periods is in the early planning stage. Lesion ResponseLesion response by SUBJECTLesion response by SUBJECTLesion response by INDIVIDUAL LESIONLesion response by INDIVIDUAL LESIONDose-rising 0.15%, 1%, 2% & Dose expansion 2%Dose-expansion 2%Dose-rising 0.15%, 1%, 2% & Dose expansion 2%Dose-expansion 2%BID x 28 daysBID x 56 daysBID x 28 daysBID x 56 daysN (subjects or lesions)8111823Complete Response0% (0/8)9.1% (1/11)5.5% (1/18)26% (6/23)Objective Response Rate13% (1/8)45% (5/11)17% (3/18)43% (10/23)No lesion progression in evaluable subjects 63% (5/8)82% (9/11)61% (11/18)83% (19/23) Citation Format: Mario E Lacouture, Julie E Lang, Sant Chawla, Shari Goldfarb, Alina Markova, Alexander Pan, Rose Marie Cavanna-Mast, Peter Mast, Christopher Savoie, Gere diZerega. Phase 1/2 clinical trial of a topical submicron particle paclitaxel (SOR007) for the treatment of cutaneous metastases [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-05.

Intracellular Paclitaxel Delivery Facilitated by a Dual-Functional CPP with a Hydrophobic Hairpin Tail.

In our pervious study, a dual-functional peptide R7 was developed to form a complex with paclitaxel (PTX) for enhancement of PTX translocation. However, because of the unstable noncovalent bond between R7 and PTX, PTX redistributed after the introduction of heparin, leading to R7-PTX complex dissociation, further causing less PTX penetration than expected. Thus, a novel positive CPP carrier of P9 was developed to improve CPP-PTX affinity via a double-proline (Pro, P) hairpin tail and enhance PTX translocation through the reduction of translocation energy barrier, confirmed by the MM-PBSA analysis and umbrella sampling simulation. Cellular uptake study reveals that P9 can quickly translocate into the HeLa cells within 1 min and exhibits no noticeable cytotoxicity. Compared to R7, P9 is able to help PTX translocation, leading to a remarkable increase in the intracellular concentration of PTX, eventually resulting in a significant loss in tumor cell viability. In vivo experiments demonstrate that a vein injection of P9-PTX complex dramatically inhibits tumor growth. Our study provides a novel perspective for designing CPP-facilitated drug carrier to enhance antitumor efficiency.

Safety, pharmacokinetics and tissue penetration of PIPAC paclitaxel in a swine model

IntroductionPeritoneal carcinomatosis is difficult to treat. Pressurized Intra-Peritoneal Aerosolised Chemotherapy (PIPAC) is a novel method of delivering chemotherapy to the peritoneal cavity, aiming for homogenous and deeper drug distribution. To date, limited chemotherapeutics have been used with promising results. Here, we evaluate the pharmacokinetics, peritoneal tissue drug concentration, penetration, and short-term safety of PIPAC using solvent-based paclitaxel in swine to guide clinical trials. Materials and methodsPIPAC solvent-based paclitaxel was administered at 60, 30, and 15mg/m2 for 3 cohorts. Each PIPAC procedure was followed by intravenous (IV) administration of the same dose of solvent-based paclitaxel on Day 7, serving as control for pharmacokinetic comparison in the same pig. Safety and toxicity were evaluated by clinical assessment, blood counts and biochemistry. Blood samples were taken for pharmacokinetic analysis. Peritoneal biopsies were taken to measure tissue paclitaxel concentrations and distribution. Results12 Yorkshire x Landrace pigs underwent trial procedures. With PIPAC, there was linear pharmacokinetics and lower systemic exposure to paclitaxel compared to IV administration. MALDI-MSI demonstrated concentration of paclitaxel at the peritoneal surface, with estimated 2 mm penetration. PIPAC paclitaxel had favorable toxicity profile. The most significant adverse event was neutropenia which was dose dependent, with absolute neutrophil count <1.0 × 103/μL seen at the highest dose. One pig developed grade 2 hypersensitivity reaction during IV infusion and one death occurred during the PIPAC procedure, likely from anaphylaxis; these are known potential adverse events mandating standard precautions and monitoring. ConclusionPIPAC paclitaxel at 15mg/m2 may be considered for a Phase I study.

Utilization of novel self-nanoemulsifying formulations (SNEFs) loaded paclitaxel for the treatment prosperity of bladder cancer

BackgroundLimited drug penetration into solid tumors has been one of the potential causes of resistance to chemotherapy for the treatment of bladder cancer. The aim of the studies was to develop non-toxic nanoemulsion carriers of paclitaxel and to evaluate their ability to serve as a tool increasing and/or controlling the penetration of paclitaxel through the bladder tissue. MethodsVarious oil-in-water non-toxic self-nanoemulsifying formulations (SNEFs) were developed using Cremercoor MCT, Kollisolv MCT, Miglyol 812, 810, Capmul MCM, Imwitor 988, Imwitor 742 with TO106V, Tween 85, HCO30, Kolliphor EL and Cremophor RH40 at size ranges from approximately 19 to 110 nm that are capable of enhancing the solubility and stability of paclitaxel. Visual assessment was employed and droplet size measurement was taken into initial consideration for optimized SNEFs. Paclitaxel was added with the oil/surfactant mixture before dispersing the mixture in water to form SNEF. The penetration study of the optimal SNEFs formulation was compared with the raw paclitaxel dispersion using transwell apparatus. ResultsInitial characterisation and solubility studies showed that mixed glycerides of Kollisolv MCT/Imwitor 742 with water-soluble surfactant (high HLB) containing formulations generated highly efficient SNEFs as they are stable and produced lower nanodroplets with higher drug loading. The results have demonstrated that the SNEFs have good ability to retain its characteristics under conditions similar to that found in the urinary bladder up to 48 h. However, the results also showed that chemosensitivity of cancer cells exposed to paclitaxel was attenuated in the presence of SNEFs. Larger size SNEFs have shown to induce more inhibitory effects on paclitaxel activity. The reduction effects of SNEFs on doxorubicin (a relatively water-soluble drug) efficacy were almost absent, indication a poor loading of such compounds. ConclusionThe reduction of the efficacy of SNEF loaded treatments does not give a strong indication of their ability to penetrate as examined their ability to penetrate through the cultivated multicell layers (MCL) of bladder cancer. However, these results may open the horizon to reflect the use of SNEFs in the introduction of intravenous paclitaxel because of its potential role in reducing the injection site toxicity.

Abstract No. 608 Pre-clinical investigation of local liquid paclitaxel delivery via a novel perfusion catheter

Non-stent drug delivery platforms have recently emerged as an alternative treatment of peripheral arterial disease. Perfusion catheters have the potential to directly deliver anti-proliferative agents to the medial arterial layer to prevent restenosis. The purpose of this study was to therefore determine the effectiveness of a perfusion catheter to deliver liquid paclitaxel, a proven anti-proliferative agent. A mathematical model was developed to test the impact of chamber pressure on drug penetration into the medial wall. A bench-top model was utilized to determine the varying parameters of a novel occlusion perfusion catheter to maximize liquid paclitaxel delivery using pharmacokinetic evaluation and fluorescent microscopy. Parameters tested included concentration of paclitaxel, delivery pressure, duration of delivery, and the use of an excipient. In addition, bilateral rabbit iliac arteries and pig femoral arteries were treated with the perfusion catheter and pharmacokinetic evaluation performed at 1 hour up to 7 days. The mathematical model demonstrated penetration of drug into the arterial wall is based on treatment chamber pressure. Bench-top testing demonstrated uniform and circumferential penetration of paclitaxel within the treated arteries. The results of the ex vivo test identified two groups with and without an excipient with similar loading conditions (with excipient: 15.4±8.6 ng/mg vs. without excipient: 8.9±6.9 ng/mg, p = 0.77). The in vivo pharmacokinetic analysis of these two groups demonstrated the use of contrast agent increased arterial paclitaxel levels and maintained initial paclitaxel dosing up to 3 days (with excipient: 1 hr: 107±62 ng vs. 3 days: 40±23 ng, p = 0.824; no excipient: 1 hr: 247±120 ng vs. 3 days: 2.92±2.9 ng, p=0.009). Increased pressure treatment chamber also demonstrated higher paclitaxel levels at 1 hour in the in vivo pig study (0.4 atm: 18.92±20.21 ng/mg vs. 0.1 atm: 2.49±1.81 ng/mg) and 7 days (0.4 atm: 0.47±0.43 ng/mg vs. 0.1 atm: 0.018±0.02 ng/mg). These results demonstrate the feasibility to deliver liquid paclitaxel directly to the medial layer of an artery via a perfusion catheter.

Directional atherectomy with antirestenotic therapy for the treatment of no-stenting zones.

Endovascular treatment for peripheral artery occlusive disease carries unresolved problem of restenosis. Treatment modalities in areas of high mechanical stress like popliteal artery and common femoral artery remains challenging. New-generation devices improved the results of stent therapy in this anatomical territory, but could impact on future surgical options if they are needed. Vessel preparation prior to drug (paclitaxel)-coated balloons (DCB) angioplasty leads to better paclitaxel penetration into the arterial wall and improved drug uptake. The "leave nothing behind" strategies, DCB angioplasty and combined directional atherectomy (DA) and antirestenotic therapy (DAART), can theoretically overcome the problems caused by the mobility of the knee joint. However, calcified and longer lesions remain a challenging subset that is less responsive to DCBs, resulting in higher provisional stent rates. For the treatment of long and calcified femoropopliteal lesions, vessel preparation with DA before DCB angioplasty seems to be safe in mid-term follow-up and might have benefits in more challenging lesion subsets that are at higher risk for acute and chronic technical treatment failure of percutaneous transluminal angioplasty, including DCB angioplasty, such as severely calcified lesions. Treatment with DA+DCB resulted in both increased technical success and fewer flow-limiting dissections compared with treatment with DCB alone. In concept of "leave nothing behind" therapies for isolated popliteal artery lesions, DAART was associated with a higher primary patency rate than DCB angioplasty alone.

Different Nanoformulations Alter the Tissue Distribution of Paclitaxel, Which Aligns with Reported Distinct Efficacy and Safety Profiles.

Previous studies have shown that different paclitaxel formulations produce distinct anticancer efficacy and safety profiles in animals and humans. This study aimed to investigate the distinct pharmacokinetics and tissue distribution of various nanoformulations of paclitaxel, which may translate into potential differences in safety and efficacy. Four nanoparticle formulations ( nab-paclitaxel, mouse albumin nab-paclitaxel [m -nab-paclitaxel], micellar paclitaxel, and polymeric nanoparticle paclitaxel) as well as solvent-based paclitaxel were intravenously administered to mice. Seventeen blood and tissue samples were collected at different time points. The total paclitaxel concentration in each tissue specimen was measured with liquid chromatography-tandem mass spectrometry. Compared with solvent-based paclitaxel, all four nanoformulations demonstrated decreased paclitaxel exposure in plasma. All nanoformulations were associated with paclitaxel blood-cell accumulation in mice; however, m- nab-paclitaxel was associated with the lowest accumulation. Five minutes after dosing, the total paclitaxel in the tissues and blood was approximately 44% to 57% of the administered dose of all paclitaxel formulations. Paclitaxel was primarily distributed to liver, muscle, intestine, kidney, skin, and bone. Compared with solvent-based paclitaxel, the different nanocarriers altered the distribution of paclitaxel in all tissues with distinct paclitaxel concentration-time profiles. nab-paclitaxel was associated with increased delivery efficiency of paclitaxel in the pancreas compared with the other formulations, consistent with the demonstrated efficacy of nab-paclitaxel in pancreatic cancer. All the nanoformulations led to high penetration in the lungs and fat pad, which potentially points to efficacy in lung and breast cancers. Micellar paclitaxel and polymeric nanoparticle paclitaxel were associated with high paclitaxel accumulation in the heart; thus, the risk of cardiovascular toxicity with these formulations may warrant further investigation. The solvent-based formulation was associated with the poorest paclitaxel penetration in all tissues and the lowest tissue-to-plasma ratio. The different nanocarriers of paclitaxel were associated with distinct pharmacokinetics and tissue distribution, which largely align with the observed efficacy and toxicity profiles in clinical trials.

Evidence That P-glycoprotein Inhibitor (Elacridar)-Loaded Nanocarriers Improve Epidermal Targeting of an Anticancer Drug via Absorptive Cutaneous Transporters Inhibition

Because P-glycoprotein (P-gp) plays an absorptive role in the skin, its pharmacological inhibition represents a strategy to promote cutaneous localization of anticancer agents that serve as its substrates, improving local efficacy while reducing systemic exposure. Here, we evaluated the ability of a nanoemulsion (NE) coencapsulating a P-gp inhibitor (elacridar) with the antitumor drug paclitaxel to promote epidermal targeting. Loaded NE displayed a nanometric size (45.2 ± 4.0 nm) and negative zeta potential (−4.2 ± 0.8 mV). Elacridar improved NE ability to inhibit verapamil-induced ATPase activity of P-gp; unloaded NE-inhibited P-gp when used at a concentration of 1500 μM, while elacridar encapsulation decreased this concentration by 3-fold (p <0.05). Elacridar-loaded NE reduced paclitaxel penetration into the dermis of freshly excised mice skin and its percutaneous permeation by 1.5- and 1.7-fold (p <0.05), respectively at 6 h, whereas larger drug amounts (1.4-fold, p <0.05) were obtained in viable epidermis. Assessment of cutaneous distribution of a fluorescent paclitaxel derivative confirmed the smaller delivery into the dermis at elacridar presence. In conclusion, we have provided novel evidence that NE containing elacridar exhibited a clear potential for P-gp inhibition and enabled epidermal targeting of paclitaxel, which in turn, can potentially reduce adverse effects associated with systemic exposure to anticancer therapy.

The use of an occlusion perfusion catheter to deliver paclitaxel to the arterial wall.

Nonstent drug delivery platforms have recently emerged as an alternative treatment of peripheral arterial disease. Perfusion catheters have the potential to directly deliver antiproliferative agents to the medial arterial layer to prevent restenosis. The purpose of this study was to therefore determine the effectiveness of a perfusion catheter to deliver paclitaxel, a proven antiproliferative agent, to combat restenosis. A benchtop model was utilized to determine the varying parameters of a novel occlusion perfusion catheter to maximize paclitaxel delivery using pharmacokinetic evaluation and fluorescent microscopy. Parameters tested included concentration of paclitaxel, delivery pressure, duration of delivery, and the use of an excipient. In addition, bilateral rabbit iliac arteries were treated with the perfusion catheter and pharmacokinetic evaluation performed at 1hour, 1day and 3days. Benchtop testing demonstrated uniform and circumferential penetration of paclitaxel within the treated arteries. The results of the ex vivo test identified two groups with and without an excipient with similar loading conditions (with excipient: 15.4±8.6ng/mg vs without excipient: 8.9±6.9ng/mg, P=.77). The in vivo pharmacokinetic analysis of these two groups demonstrated the use of contrast agent increased arterial paclitaxel levels and maintained initial paclitaxel dosing up to 3days (With excipient: 1hour: 107±62ng vs 3days: 40±23ng, P=.824; No excipient: 1hour: 247±120ng vs 3days: 2.92±2.9ng, P=.009). These results demonstrate the feasibility to deliver paclitaxel directly to the medial layer of an artery via a perfusion catheter.

Transportan in nanocarriers improves skin localization and antitumor activity of paclitaxel.

In this study, the ability of nanocarriers containing protein transduction domains (PTDs) of various classes to improve cutaneous paclitaxel delivery and efficacy in skin tumor models was evaluated. Microemulsions (MEs) were prepared by mixing a surfactant blend (polyoxyethylene 10 oleoyl ether, ethanol and propylene glycol), monocaprylin, and water. The PTD transportan (ME-T), penetratin (ME-P), or TAT (ME-TAT) was added at a concentration of 1 mM to the plain ME. All MEs displayed nanometric size (32.3–40.7 nm) and slight positive zeta potential (+4.1 mV to +6.8 mV). Skin penetration of paclitaxel from the MEs was assessed for 1–12 hours using porcine skin and Franz diffusion cells. Among the PTD-containing formulations, paclitaxel skin (stratum corneum + epidermis and dermis) penetration at 12 hours was maximized with ME-T, whereas ME-TAT provided the lowest penetration (1.6-fold less). This is consistent with the stronger ability of ME-T to increase transepidermal water loss (2.4-fold compared to water) and tissue permeability. The influence of PTD addition on the ME irritation potential was assessed by measuring interleukin-1α expression and viability of bioengineered skin equivalents. A 1.5- to 1.8-fold increase in interleukin-1α expression was induced by ME-T compared to the other formulations, but this effect was less pronounced (5.8-fold) than that mediated by the moderate irritant Triton. Because ME-T maximized paclitaxel cutaneous localization while being safer than Triton, its efficacy was assessed against basal cell carcinoma cells and a bioengineered three-dimensional melanoma model. Paclitaxel-containing ME-T reduced cells and tissue viability by twofold compared to drug solutions, suggesting the potential clinical usefulness of the formulation for the treatment of cutaneous tumors.

High Tumor Penetration of Paclitaxel Loaded pH Sensitive Cleavable Liposomes by Depletion of Tumor Collagen I in Breast Cancer.

The network of collagen I in tumors could prevent the penetration of drugs loaded in nanoparticles, and this would lead to impaired antitumor efficacy. In this study, free losartan (an angiotensin inhibitor) was injected before treatment to reduce the level of collagen I, which could facilitate the penetration of nanoparticles. Then the pH-sensitive cleavable liposomes (Cl-Lip) were injected subsequently to exert the antitumor effect. The Cl-Lip was constituted by PEG(5K)-Hydrazone-PE and DSPE-PEG(2K)-R8. When the Cl-Lip reached to the tumor site by the enhanced permeability and retention (EPR) effect, PEG(5K)-Hydrazone-PE was hydrolyzed from the Cl-Lip under the low extra-cellular pH conditions of tumors, then the R8 peptide was exposed, and finally liposomes could be internalized into tumor cells by the mediation of R8 peptide. In vitro experiments showed both the cellular uptake of Cl-Lip by 4T1 cells and cytotoxicity of paclitaxel loaded Cl-Lip (PTX-Cl-Lip) were pH sensitive. In vivo experiments showed the Cl-Lip had a good tumor targeting ability. After depletion of collagen I, Cl-Lip could penetrate into the deep place of tumors, the tumor accumulation of Cl-Lip was further increased by 22.0%, and the oxygen distributed in tumor tissues was also enhanced. The antitumor study indicated free losartan in combination with PTX-Cl-Lip (59.8%) was more effective than injection with PTX-Cl-Lip only (37.8%) in 4T1 tumor bearing mice. All results suggested that depletion of collagen I by losartan dramatically increased the penetration of PTX-Cl-Lip and combination of free losartan and PTX-CL-Lip could lead to better antitumor efficacy of chemical drugs. Thus, the combination strategy might be a promising tactic for better treatment of solid tumors with a high level of collagen I.

Pharmacokinetic synergy from the taxane extract of Taxus chinensis improves the bioavailability of paclitaxel

BackgroundTaxus chinensis (Pilger) Rehd is widely distributed in China and the northern hemisphere, and the most popular medicinal component isolated from Taxus chinensis is paclitaxel (PTX), which has now become the first-line chemotherapeutic drug for breast cancer and ovarian cancer. Oral administration of pure PTX as a potential anti-cancer agent is compromised by low bioavailability. Hypothesis/purposeIn the clinical practice of traditional Chinese medicine, drug co-administration in the form of mixtures or formula could achieve pharmacokinetic/pharmacodynamic synergies. In this study, we aimed to investigate whether there exist any ‘inherent’ phytochemical synergy from Taxus chinensis extract that could improve PTX bioavailability. Study designPharmacokinetic study of PTX after oral administration of Taxus chinensis extracts or single PTX was performed. In addition, comparative cytotoxic studies were carried out on the MCF-7 breast cancer cell lines. MethodsThe plasma concentrations of PTX were determined using a validated high performance chromatography tandem mass spectrometry method. The cytotoxicity was compared using the MTT assay. ResultsOral administration of taxane fractions isolated from Taxus chinensis (containing 17.2% PTX) could achieve remarkably higher blood concentration and systemic exposure of PTX in rats, while the retention of PTX was significantly improved. Further tissue distribution analysis revealed that the penetration of PTX into major tissues was drastically increased compared with that of single PTX. In addition, in MCF-7 cells, the co-existing components in taxane mixtures could strengthen the inhibitory effects of PTX on tumor cell proliferation. ConclusionTogether, these results support that administration of PTX in the form of taxane mixtures may become a novel approach to improve the poor bioavailability of PTX. Moreover, the inherent synergy from Taxus chinensis taxane extracts promises a novel strategy to strengthen PTX efficacy.

Pharmacokinetics of concomitant cisplatin and paclitaxel administered by hyperthermic intraperitoneal chemotherapy to patients with peritoneal carcinomatosis from epithelial ovarian cancer.

Background:Hyperthermic intraperitoneal chemotherapy (HIPEC) is advised as a treatment option for epithelial ovarian cancer (EOC) with peritoneal carcinomatosis. This study was designed to define the pharmacokinetics of cisplatin (CDDP) and paclitaxel (PTX) administered together during HIPEC.Methods:Thirteen women with EOC underwent cytoreductive surgery (CRS) and HIPEC, with CDDP and PTX. Blood, peritoneal perfusate and tissue samples were harvested to determine drug exposure by high-performance liquid chromatography and matrix-assisted laser desorption ionization imaging mass spectrometry (IMS).Results:The mean maximum concentrations of CDDP and PTX in perfusate were, respectively, 24.8±10.4 μg ml−1 and 69.8±14.3 μg ml−1; in plasma were 1.87±0.4 μg ml−1 and 0.055±0.009 μg ml−1. The mean concentrations of CDDP and PTX in peritoneum at the end of HIPEC were 23.3±8.0 μg g−1 and 30.1±18.3 μg−1g−1, respectively. The penetration of PTX into the peritoneal wall, determined by IMS, was about 0.5 mm. Grade 3–4 surgical complications were recorded in four patients, five patients presented grade 3 and two patients presented grade 4 hematological complications.Conclusions:HIPEC with CDDP and PTX after CRS is feasible with acceptable morbidity and has a favorable pharmacokinetic profile: high drug concentrations are achieved in peritoneal tissue with low systemic exposure. Larger studies are needed to demonstrate its efficacy in patients with microscopic postsurgical residual tumours in the peritoneal cavity.

Nonvascular drug-eluting stent coated with sodium caprate-incorporated polyurethane for the efficient penetration of paclitaxel into tumor tissue.

To increase the therapeutic potency of nonvascular drug-eluting stents, sodium caprate was employed as a drug-penetration enhancer. A polytetrafluoroethylene-covered drug-eluting stent was coated with a mixture containing sodium caprate, paclitaxel, and polyurethane via the rolling coating technique. The coated stent has a smooth membrane surface with a 40-µm membrane thickness. Paclitaxel was released from the coated stent for two months. In the multilayered cell sheet model, sodium caprate in the polyurethane membrane (PUSC10) showed the possibility of enhancing the paclitaxel tissue penetration. The amount of penetrated paclitaxel for the sodium caprate-containing polyurethane membrane (PUSC10) was two times higher than that of sodium caprate-free polyurethane membrane. Additionally, the potential of sodium caprate was confirmed by a tumor-bearing small animal model. PUSC10 incorporated with Nile red (as a model fluorescence dye for visualization of drug penetration; PUSC10-Nile red) or PUSC10 incorporated with paclitaxel (PUSC10-paclitaxel) membrane was implanted at tumor sites in Balb/c mice. In the case of PUSC10-Nile red, the tissue penetration depth of Nile red was significantly increased from 30 µm (without sodium caprate) to 1060 µm (with sodium caprate). After seven days, an almost four times higher therapeutic area of PUSC10-paclitaxel was observed compared to that of polyurethane-paclitaxel (without sodium caprate) by a terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The results indicate that sodium caprate improves the penetration and therapeutic efficiencies of drugs in drug-eluting stents, and thus, it has potential for local stent therapy.

Enhanced Excitability of Primary Sensory Neurons and Altered Gene Expression of Neuronal Ion Channels in Dorsal Root Ganglion in Paclitaxel-induced Peripheral Neuropathy

The mechanism of chemotherapy-induced peripheral neuropathy after paclitaxel treatment is not well understood. Given the poor penetration of paclitaxel into central nervous system, peripheral nervous system is most at risk. Intrinsic membrane properties of dorsal root ganglion neurons were studied by intracellular recordings. Multiple-gene real-time polymerase chain reaction array was used to investigate gene expression of dorsal root ganglion neuronal ion channels. Paclitaxel increased the incidence of spontaneous activity from 4.8 to 27.1% in large-sized and from 0 to 33.3% in medium-sized neurons. Paclitaxel decreased the rheobase (nA) from 1.6 ± 0.1 to 0.8 ± 0.1 in large-sized, from 1.5 ± 0.2 to 0.6 ± 0.1 in medium-sized, and from 1.6 ± 0.2 to 1.0 ± 0.1 in small-sized neurons. After paclitaxel treatment, other characteristics of membrane properties in each group remained the same except that Aδ neurons showed shorter action potential fall time (ms) (1.0 ± 0.2, n = 10 vs. 1.8 ± 0.3, n = 9, paclitaxel vs. vehicle). Meanwhile, real-time polymerase chain reaction array revealed an alteration in expression of some neuronal ion channel genes including up-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 1 (fold change 1.76 ± 0.06) and Nav1.7 (1.26 ± 0.02) and down-regulation of Kir channels (Kir1.1, 0.73 ± 0.05, Kir3.4, 0.66 ± 0.06) in paclitaxel-treated animals. The increased neuronal excitability and the changes in gene expression of some neuronal ion channels in dorsal root ganglion may provide insight into the molecular and cellular basis of paclitaxel-induced neuropathy, which may lead to novel therapeutic strategies.

A rapid analytical method for the quantification of paclitaxel in rat plasma and brain tissue by high-performance liquid chromatography and tandem mass spectrometry.

Paclitaxel, an antitumor agent for the treatment of several types of cancers, has recently been reported to cause impaired cognitive function and neuropathic pain in humans. To assess the effects of paclitaxel on the central nervous system, a sensitive and accurate method is required to quantify paclitaxel concentrations in plasma and brain tissue obtained from rodents receiving paclitaxel. The biological samples were prepared by liquid-liquid extraction and separated by a 3.5 min reversed-phase liquid chromatography (RPLC) method using a BDS Hypersil C8 column under isocratic conditions. Paclitaxel was quantified using multiple reaction monitoring (MRM) with a triple quadrupole tandem mass spectrometer working in the positive electrospray ionization (ESI+) mode. A stable isotope labeled analogue of paclitaxel was used as the internal standard (IS). The method was validated to be precise and accurate within the dynamic range of 0.5-100 ng/mL based on 100 μL plasma and 1.5-300 ng/g based on 33 mg of brain tissue in homogenate. This method was applied to samples from 2 mg/kg intravenously dosed rats. The plasma concentrations were observed to be 26.62 ± 8.93 ng/mL and brain concentrations 11.08 ± 4.18 ng/g when measured 4 h post-dose. This rapid LC/MS/MS method was validated to be sensitive, specific, precise and accurate for the quantification of paclitaxel in rat plasma and brain tissue homogenate. Application of the method to study samples provided sufficient proof of blood-brain barrier penetration of paclitaxel, allowing further investigation of its influence on the central nervous system.

Enhanced oral bioavailability and anti‐tumour effect of paclitaxel by 20(s)‐ginsenoside Rg3in vivo

The purpose of this study was to investigate the effect of paclitaxel in combination with 20(s)-ginsenoside Rg3 on its anti-tumour effect in nude mice. In the Caco-2 transport assay, the apparent permeability from the apical side to the basal side (P(app)) (A-B) and P(app) (B-A) of paclitaxel were measured when co-incubated with different concentrations of 20(s)-ginsenoside Rg3. The results indicated that the penetration of paclitaxel through the Caco-2 monolayer from the apical side to the basal side was facilitated by 20(s)-ginsenoside Rg3 in a concentration-dependent manner. Meanwhile, 20(s)-ginsenoside Rg3 inhibited P-glycoprotein (P-gp), and the maximum inhibition was achieved at 80 µM (p < 0.05). The pharmacokinetic parameters of paclitaxel after oral co-administration of paclitaxel (40 mg/kg) with various doses of 20(s)-ginsenoside Rg3 in rats were investigated by an in vivo pharmacokinetic experiment. The results showed that the AUC of paclitaxel co-administered with 20(s)-ginsenoside Rg3 was significantly higher (p < 0.001 at 10 mg/kg) compared with the control. The relative bioavailability (RB) % of paclitaxel with 20(s)-ginsenoside Rg3 was 3.4-fold (10 mg/kg) higher than that of the control. The effect of paclitaxel orally co-administered with 20(s)-ginsenoside Rg3 against human tumour MCF-7 xenografts in nude mice was also evaluated. Paclitaxel (20 mg/kg) co-administered with 20(s)-ginsenoside Rg3 (10 mg/kg) exhibited an effective anti-tumour activity with the relative tumor growth rate (T/C) values of 39.36% (p <0.05). The results showed that 20(s)-ginsenoside Rg3 enhanced the oral bioavailability of paclitaxel in rats and improved the anti-tumour activity in nude mice, indicating that oral co-administration of paclitaxel with 20(s)-ginsenoside Rg3 could provide an effective strategy in addition to the established i.v. route.

Paclitaxel Gelatin Nanoparticles for Intravesical Bladder Cancer Therapy

We have noted that inadequate drug delivery to tumor cells is a major cause of failed intravesical therapy for nonmuscle invading bladder cancer, partly due to the dilution of drug concentration by urine production during treatment. To address this problem we developed gelatin nanoparticles of paclitaxel designed to yield constant drug concentrations. The hypothesis that a constant, therapeutic concentration in urine, bladder tissue and tumors can be attained was evaluated in dogs. We studied drug release from paclitaxel gelatin nanoparticles in culture medium in vitro. In vivo studies were performed in tumor-free dogs and in pet dogs with naturally occurring transitional cell carcinoma, in which the pharmacokinetics of paclitaxel gelatin nanoparticles were determined in plasma, urine and tumors. Paclitaxel release from paclitaxel gelatin nanoparticles in vitro and in vivo was rate limited by the drug solubility in aqueous medium. This property yielded constant drug concentrations independent of changes in urine volume during the 2-hour treatment. Intravesical paclitaxel gelatin nanoparticles showed low systemic absorption, and favorable bladder tissue/tumor targeting and retention properties with pharmacologically active concentrations retained in tumors for at least 1 week. Constant drug release from paclitaxel gelatin nanoparticles may overcome the problem of drug dilution by newly produced urine and the sustained drug levels in tumors may decrease treatment frequency.