Formulation Of Docetaxel Research Articles

A Novel Dextran-Based Dual Drug Conjugate Targeted Tumors with High Biodistribution Ratio of Tumors to Normal Tissues.

PurposeMost chemotherapeutic agents possess poor water solubility and show more significant accumulations in normal tissues than in tumor tissues, resulting in serious side effects. To this end, a novel dextran-based dual drug delivery system with high biodistribution ratio of tumors to normal tissues was developed.MethodsA bi-functionalized dextran was developed, and several negatively charged dextran-based dual conjugates containing two different types of drugs, docetaxel and docosahexaenoic acid (DTX and DHA, respectively) were synthesized. The structures of these conjugates were characterized using nuclear magnetic resonance and liquid chromatography/mass spectrometry (1H-NMR and LC/MS, respectively) analysis. Cell growth inhibition, apoptosis, cell cycle distribution, and cellular uptake were measured in vitro. Drug biodistribution and pharmacokinetics were investigated in mice bearing 4T1 tumors using LC/MS analysis. Drug biodistribution was also explored by in vivo imaging. The effects of these conjugates on tumor growth were evaluated in three mice models.ResultsThe dextran–docosahexaenoic acid (DHA)– docetaxel (DTX) conjugates caused a significant enhancement of DTX water solubility and improvement in pharmacokinetic characteristics. The optimized dextran–DHA–DTX conjugate A treatment produced a 2.1- to 15.5-fold increase in intra-tumoral DTX amounts for up to 96 h compared to parent DTX treatment. Meanwhile, the concentrations of DTX released from conjugate A in normal tissues were much lower than those of the parent DTX. This study demonstrated that DHA could lead to an improvement in the efficacy of the conjugates and that the conjugate with the shortest linker displayed more activity than conjugates with longer linkers. Moreover, conjugate A completely eradicated all MCF-7 xenograft tumors without causing any obvious side effects and totally outperformed both the conventional DTX formulation and Abraxane in mice.ConclusionThese dextran-based dual drug conjugates may represent an innovative tumor targeting drug delivery system that can selectively deliver anticancer agents to tumors.

Novel methylcellulose based thermosenstive in situ nano liposomes of docetaxel for improved pharmacokinetics and pharmacodynamics with reduced toxicity

The utility of Docetaxel (DTX) in different cancers is highly compromised due to reported side effects from its commercial injectable formulation. In this work, novel methylcellulose (MC) based thermosenstive in situ nano liposomes of anti-cancer drug docetaxel (DTX) was developed for its locoregional delivery in treatment of cancer. An array of biodegradable polymers; Hydroxy propyl methyl cellulose (HPMC), Poloxamer-407 and MC for development of in situ nano liposomes (NL) were utilized alone and in combinations of one another for different sets of formulations. Optimized formulation ISNL-MC-2 exhibited in situ gelation at 36.2 ± 0.5 ºC, ideal syringeability, and sustained drug release (at 37 ± 0.5 ºC) up to 6 days with immediate in vitro gelation (5.5 ± 0.3 min). Further, a significantly higher biological half-life (23 ± 0.2 h) was detected in vivo in comparison to the commercial DTX injectable formulation (1.7 ± 0.1 h). Bio distribution study revealed almost 3 fold higher drug localization from the optimized formulation. When evaluated pharmaco dynamically in Ehrlich Ascites Carcinoma (EAC) induced mice, better tumor inhibition (87.7 ± 2.5%) was seen with the optimized formulation compared to the commercial DTX formulation (76.5 ± 2.1%). The detailed characterization and optimization brought in situ behavior of the optimized formulation close to physiological temperature using suitable concentration of MC and sodium chloride.

Docetaxel in combination with metformin enhances antitumour efficacy in metastatic breast carcinoma models: a promising cancer targeting based on PEGylated liposomes.

Metformin has been shown to kill cancer stem-like cells in genetically various types of breast carcinoma. With the aim to simultaneously eradicate the bulk population of tumour cells and the rare population of cancer stem-like cells in breast cancer tissues, we used the combination chemotherapy of docetaxel (DTX) with metformin (MET). Furthermore, we introduce an active loading method based on ammonium sulphate 250 mM (SA) for encapsulating docetaxel into liposomes. Docetaxel and metformin encapsulated into PEGylated liposomes with two different methods based on remote or passive loading methods, respectively. The size and surface charge of the liposomes were characterized. DTX content in the nanoliposomes was measured by the high-performance liquid chromatography method. The drug release profiles were evaluated in phosphate-buffered dextrose 5% with the pH of 6.5 and 7.4. We examined the antitumour activity of Taxotere (TAX), and liposomal formulation of DTX and MET as a monotherapy or combination therapy. The biodistribution of liposomes was also investigated using 99mTc hexamethyl propylene amine oxime method in BALB/c mice bearing 4T1 breast carcinoma tumours. The final formulations were prepared according to the best physicochemical characteristics which were HSPC/mPEG2000-DSPE/Chol (DTX liposomes) and HSPC/DPPG/mPEG2000-DSPE/Chol (MET liposomes), at molar ratios of 85/5/10 and (55/5/5/35), respectively. In vivo experiments showed that when free or liposomal metformin used in combination with liposomal docetaxel, they prolonged median survival time (MST) from 31 in the control group to 46 days, which demonstrates their promising effects on the survival of the 4T1 breast carcinoma mice models. Moreover, combination therapies could significantly increase life span in comparison with phosphate-buffered saline (PBS) and Taxotere groups at the same dose. Furthermore, in the combination therapy study, treatment with DTX liposomes prepared by ammonium sulphate 250 mM buffer alone resulted in similar therapeutic efficacy to combination therapy. The biodistribution study exhibited significant accumulation of DTX liposomes in the tumours due to the Enhanced Permeability and Retention effect. This study also showed that metformin-based combinatorial chemotherapies have superior efficacy versus their corresponding monotherapy counterparts at same doses. The findings confirm that liposomes based on ammonium sulphate 250 mM could be as a promising formulation for efficient DTX delivering and cancer targeting and therefore merit further investigations.

A phase 2 randomized study of oral docetaxel plus ritonavir (ModraDoc006/r) in patients with metastatic castration-resistant prostate cancer (mCRPC).

5016 Background: Intravenous (IV) docetaxel and oral prednisone is a standard of care regimen in patients (pts) with mCRPC. ModraDoc006 is an oral formulation of docetaxel. To enhance bioavailability of ModraDoc006, it is co-administered with ritonavir (/r). The ModraDoc006 and ritonavir combination is active in multiple docetaxel and cabazitaxel-resistant prostate cancer cell-lines The oral combination (ModraDoc006/r) was compared to IV docetaxel in a randomized phase 2b study in pts with mCRPC evaluating two doses of ModraDoc006/r (30-20/200-100 mg and 20-20/200-100 mg). Data on outcomes in the larger cohort, receiving the lower dose, are being presented. Methods: Eligible pts had mCRPC, performance status of 0-1 and no prior chemotherapy for mCRPC. Sixty-two pts were enrolled in open label 1:1 randomized study comparing ModraDoc006/r 20-20 mg combined with 200-100 mg ritonavir in a bi-daily weekly schedule (“20-20/200-100 mg”), with IV docetaxel 75 mg/m2 in 21-day cycles. All pts received 5 mg oral prednisone twice daily. Primary endpoint was radiographic progression free survival (rPFS) per PCWG-3 criteria. Secondary objectives included ORR, PSA-PFS, time to skeletal related events, disease control rate, duration of response, and safety assessments. Results: 31 pts were enrolled on IV docetaxel 75 mg/m2 and 31 on ModraDoc006/r 20-20/200-100 mg. Of these, 57 were included in the analysis for rPFS, and 32 pts with measurable disease were included in the ORR analysis. Median PSA was 46 (range 1 to 1460 ng/ml). Prior therapy with enzalutamide in 8 pts, abiraterone in 10 pts. ModraDoc006/r was better tolerated with 0% all grades neutropenia and anemia, as compared to 26% (19% ≥G3) and 16% respectively on IV docetaxel. Neuropathy was significantly reduced at 9.7% G1 only on ModraDoc006/r vs 9.7% G1 and 19.4% G2 on IV docetaxel, whereas alopecia was reduced to 16.1% G1 and 6.5% G2 on ModraDoc006/r vs. 22.6% G1 and 19.4% G2 on IV docetaxel. GI toxicities were broadly comparable with diarrhea 32% (3% ≥G3) vs 29%, nausea 29% vs 13% and stomatitis 3% (G3) vs 13% (3% ≥G3), respectively. Conclusions: ModraDoc006/r demonstrated a favorable safety profile and comparable efficacy to IV docetaxel in pts with mCRPC, thus providing a compelling rationale for conduct of an expanded pivotal program. A key clinical program focus is the comparison of ModraDoc006/r to best available therapy in refractory mCRPC. Studies of ModraDoc006/r in other malignancies are also in active development. Clinical trial information: NCT04028388. [Table: see text]

Reduction in local tumor recurrence in a murine R2 resection model comparing locally administered docetaxel-releasing product, OncoPLEX, versus systemic docetaxel.

e22530 Background: Local recurrence (LR) negatively impacts long-term survival and patients’ quality of life in many solid tumor malignancies, despite advances in surgical techniques and neoadjuvant and adjuvant treatments. Systemic treatment-related morbidity and mortality remains an unmet need, especially if only an R2 resection is achievable. OncoPLEX is a biodegradable, extended-release formulation of docetaxel that is applied in the form of a paste to the resection bed at surgery. We evaluated OncoPLEX efficacy in preventing local recurrence in an R2 tumor resection model generated with cell lines that exhibit high or low docetaxel sensitivity. Methods: Cell lines sensitivity to free docetaxel and OncoPLEX-released docetaxel were determined in a cytotoxic assay. CT26 (murine colorectal carcinoma--resistant) and U-87 (human primary glioblastoma—sensitive) were tested. A murine subcutaneous (SC) tumor resection model using a predetermined tumor size (400-600 mm3) and a standardized R2 resection (̃90%) was developed. OncoPLEX was applied once on the tumor bed post-resection, docetaxel was IV injected every 4 days (6 times total), and animals were followed for tumor regrowth. The overall docetaxel dose in OncoPLEX (0.78 mg docetaxel) is lower than the maximal tolerated dose and non-lethal reported dose (TAXOTERE [10 mg/kg IV]; prescribing information). Results: The IC50 concentrations of free docetaxel in CT26 and U-87 cell lines indicated resistance and sensitivity to docetaxel respectively (112.6 nM vs 4.2 nM). The cytotoxic potency of OncoPLEX-released docetaxel exhibited a similar relationship with greater potency (IC50 values in CT26 56.7 vs. 1.2 nM in U-87). At the completion of the CT26 SC study (37 days), there were more tumor-free animals in the OncoPLEX group (6/8, 75%) compared with the control IV docetaxel treated (3/8, 38%) or the untreated control (0/8, 0%). A similar trend was observed in the U-87 study; OncoPLEX (4/10, 40%), Control intraperitoneal-injected taxel (2/10, 20%), and untreated control (0/10, 0%). In both studies, the average tumor volume was significantly smaller with either OncoPLEX or systemic treatment compared with untreated controls (CT26: 375 mm3, 485 mm3 and 1500 mm3 (p<0.05); U-87, 403 mm3, 780 mm3 and 2059 mm3; p<0.001). There was no effect on behavior or weight in the OncoPLEX treated animals. Conclusions: Locally administered OncoPLEX in this R2 resection model reduced local tumor recurrence and systemic adverse outcomes. OncoPLEX offers a potentially enhanced local adjuvant chemotherapy option with reduced side effects for solid tumors, independent of the tumor sensitivity or resistance to docetaxel.

Design and Evaluation of Two-Step Biorelevant Dissolution Methods for Docetaxel Oral Formulations.

Dissolution is a pivotal tool for oral formulations. Dissolution could be used to either reduce the risk of product failure through quality control or predict and understand in vivo performance of drug formulations. The latter is always challenging because multiple factors such as selection of media, gastrointestinal components, physiological factors, consideration of fasted and fed state are involved. Previously published dissolution methods such as one-step dissolution in individual simulated gastric fluid, simulated intestinal fluid, or phosphate buffer saline did not signify the realistic gastrointestinal transit effect. Docetaxel (DTX), a poorly water-soluble drug, is commercially available only as injectable dosage forms, and thus many publications studied the development of oral DTX formulations. In our previous report, we developed oral lipid-based DTX granules that showed higher oral absorption in rats compared to DTX powder. However, one-step dissolution in simulated gastric fluid showed no difference between DTX granules and DTX powder. Therefore, the present study aimed to develop new two-step biorelevant dissolution methods for DTX oral formulations. In the study, new two-step biorelevant dissolution methods in fasted or fed states with pancreatin were developed and compared with other previously reported dissolution methods. The new two-step biorelevant dissolution methods successfully discriminated the difference of dissolution between DTX granules and DTX powder, which reflected the in vivo difference of absorption of these two formulations. Moreover, food effects were confirmed for DTX. The new dissolution methods have the potential to be used to predict and understand in vivo performance of oral solid dosage forms.

MPEG-PDLLA Micelles Potentiate Docetaxel for Intraperitoneal Chemotherapy in Ovarian Cancer Peritoneal Metastasis.

Ovarian cancer is the second most common cause of gynecological cancer death in women. It is usually diagnosed late and accompanied by peritoneal metastasis. For ovarian cancer with peritoneal metastasis, intraperitoneal (IP) chemotherapy can maintain a high drug concentration in the abdominal cavity and reduce local and systemic toxicity. Recently, docetaxel (DTX) has shown broad-spectrum antitumor activity against various malignant tumors, including ovarian cancer with peritoneal metastasis. However, DTX has limited clinical applications due to its poor water solubility, predisposition to hypersensitivity, fluid retention, and varying degrees of neurotoxicity. In this study, we prepared methoxy-poly(ethylene glycol)-block-poly(D,L-lactide) (mPEG-PDLLA) micelles loaded with DTX and developed an alternative, less toxic, more effective DTX formulation, without Tween 80, and evaluated its pharmacokinetics in the abdominal cavity and its efficacy in ovarian cancer with peritoneal metastasis. The mean diameter of DTX-mPEG-PDLLA was about 25 nm, and the pharmacokinetics of BALB/c mice via IP showed that the plasma exposure of DTX-mPEG-PDLLA was about four times lower than that of DTX. Importantly, DTX-mPEG-PDLLA was significantly more effective than DTX and prolonged the survival period in a SKOV-3 ovarian cancer peritoneal metastasis model. Moreover, the apoptosis rate was significantly increased in vitro. Based on these findings, it is expected that DTX-mPEG-PDLLA can enhance efficacy against ovarian cancer peritoneal metastasis, while reducing toxic side effects, and has the potential to be used in the clinical treatment of peritoneal metastatic cancer.

Self-Assembled Nanomicellar Formulation of Docetaxel as a Potential Breast Cancer Chemotherapeutic System.

Docetaxel (DTX) is classified as a class IV drug that exhibits poor aqueous solubility (6–7 µg/mL in water) and permeability (P-glycoprotein substrate). The main objective of this study was to construct, characterize, and evaluate docetaxel loaded nanomicellar formulation in vitro for oral delivery to enhance the absorption and bioavailability of DTX, as well as to circumvent P-gp efflux inhibition. Formulations were prepared with two polymeric surfactants, hydrogenated castor oil-40 (HCO-40) and D-α-Tocopherol polyethylene glycol 1000 succinate (VIT E TPGS) with solvent evaporation technique, and the resulting DTX nanomicellar formulations were characterized by proton nuclear magnetic resonance spectroscopy (1H NMR), Fourier Transform Infrared Spectroscopy (FT–IR), X-ray powder diffraction (XRD), and transmission electron microscopy (TEM). Proton NMR, FT–IR, and XRD data indicated that DTX was completely encapsulated within the hydrophobic core of the nanomicelles in its amorphous state. TEM data revealed a smooth spherical shape of the nanomicellar formulation. The optimized formulation (F-2) possessed a mean diameter of 13.42 nm, a zeta potential of −0.19 mV, with a 99.3% entrapment efficiency. Dilution stability study indicated that nanomicelles were stable up to 100-fold dilution with minimal change in size, poly dispersity index (PDI), and zeta potential. In vitro cytotoxicity study revealed higher anticancer activity of DTX nanomicelles at 5 µM compared to the native drug against breast cancer cell line (MCF-7) cells. The LC–MS data confirmed the chemical stability of DTX within the nanomicelles. In vitro drug release study demonstrated faster dissolution of DTX from the nanomicelles compared to the naked drug. Our experimental results exhibit that nanomicelles could be a drug delivery system of choice to encapsulate drugs with low aqueous solubility and permeability that can preserve the stability of the active constituents to provide anticancer activity.

Phase 2 randomized trial of ModraDoc006/r, oral docetaxel plus ritonavir, versus intravenous docetaxel in metastatic castration resistant prostate cancer (mCRPC).

117 Background: Intravenous (IV) docetaxel and oral prednisone is a standard of care regimen in mCRPC. ModraDoc006 is a novel, oral tablet formulation of docetaxel. To enhance bioavailability, it is co-administered with ritonavir (/r), an inhibitor of cytochrome p450 3A4 and P-glycoprotein metabolic enzymes. The oral combination, denoted as ModraDoc006/r, may be superior to IV docetaxel in terms of safety profile, avoiding infusions, patient quality of life (QoL) and overall resource utilization. Safety of ModraDoc006/r in mCRPC was established in a previous phase Ib trial. Methods: We conducted an open label 1:1 randomized study of ModraDoc006/r bi-daily weekly dosing (BIDW) regimen versus IV docetaxel 75 mg/m2 in 21-day cycles. Initially, BIDW 30-20 mg ModraDoc006 combined with 200-100 mg ritonavir was administered on days 1, 8 and 15 of a 21-day cycle. After 39 patients the starting dose was reduced to 20-20 mg BIDW with ritonavir 200 mg in the morning and 100 mg with the evening dose to improve tolerability. All patients received 5 mg oral prednisone twice daily. Primary endpoint was radiographic progression free survival (rPFS) per PCWG-3 criteria. Secondary objectives were ORR, PSA-PFS, time to skeletal related events, disease control rate, duration of response, and safety assessments. Patient reported outcomes and health-related QoL was assessed with treatment satisfaction and FACT-P questionnaires at baseline and after cycles 3, 6 and 10. Results: Enrollment is complete with 101 patients accrued; 49 on IV docetaxel, 52 on ModraDoc006/r (21 on 30-20 mg and 31 on ModraDoc006/r 20-20 mg). 69 patients had measurable disease and median PSA was 67ng/ml (range 0,2 to 1697 ng/ml). IV docetaxel vs ModraDoc006/r 30-20 mg and 20-20 mg demonstrated ORR of 39% vs 50% and 33%, and PSA responses of 57% vs 53% and 48%. All grades neutropenia and neuropathy was noted in 0% and 6% with ModraDoc006/r 20-20 mg therapy and was better than the incidence of 14% (5% ≥G3) and 14% with ModraDoc006/r 30-20 mg, and 27% (20% ≥G3) and 31% respectively on IV docetaxel. Alopecia was also reduced at 23% on ModraDoc006/r 20-20 mg and 29% on ModraDoc006/r 30-20 mg vs 43% on IV docetaxel. GI toxicities were slightly more frequent, but predominantly mild, in the ModraDoc006/r arm: at 20-20 mg dose, all grades diarrhea 32% (3% ≥G3), nausea 29% and stomatitis 3% (G3); at 30-20 mg dose 62% diarrhea (19% ≥G3), 38% nausea and 14% stomatitis (5% ≥G3); and in IV docetaxel, 24% diarrhea, 16% nausea and 10% stomatitis (4% ≥G3). Conclusions: Hematological toxicities and adverse events neuropathy and alopecia were lower with ModraDoc006/r than with IV docetaxel. ModraDoc006/r represents a convenient, oral, tolerable option for patients with mCRPC. ModraDoc006/r has comparable efficacy and a favorable tolerability profile as compared to IV docetaxel and merits further development in patients with mCRPC. Clinical trial information: NCT04028388.

Effects of Docetaxel Injection and Docetaxel Micelles on the Intestinal Barrier and Intestinal Microbiota.

Increasing evidence has suggested that chemotherapeutics affect the integrity of the intestinal barrier and alter the intestinal microbiota, thus limiting the therapeutic outcomes of cancer chemotherapy. Docetaxel (DTX) is used for breast cancer treatment and has gastrointestinal side effects, but the influence of DTX formulations on the intestinal barrier and intestinal microbiota remains unknown. Therefore, in this work, the influence of DTX injection (free DTX, commercial formulation) and DTX/methoxy poly(ethylene glycol)‐b lock‐poly(D,L‐lactide) (mPEG‐PDLLA) (DTX micelles, nanoformulation) on the integrity of the intestinal barrier and the intestinal microbiota is investigated. It is found that the free DTX causes significantly greater intestinal barrier damage than the DTX micelles. The diversity of the intestinal microbiota, and the relative abundance of Akkermansia muciniphila and Ruminococcus gnavus in the DTX micelle‐treated group is significantly higher than that in the free DTX‐treated group. Moreover, the tumor growth rate is elevated in antibiotic mixture‐pretreated mice, demonstrating that the diversity and composition of the intestinal microbiota may be associated with tumor progression. This work demonstrates that different formulations of chemotherapeutics have different effects on the integrity of the intestinal barrier and the intestinal microbiota.

Enhancement of Docetaxel Absorption Using Ritonavir in an Oral Milk-Based Formulation.

The current study aimed to develop a novel milk-based formulation of docetaxel, a sparingly soluble antineoplastic agent, administered so far exclusively by the intravenous route and evaluate its oral bioavailability. Pre-formulation studies included the determination of docetaxel solubility in water-alcohol mixtures as well as short-term content uniformity experiments of the final formulation. The pharmacokinetic (PK) performance of the developed milk-based formulations was further evaluated in vivo in mice using ritonavir, a potent P-glycoprotein inhibitor, as an absorption enhancer of docetaxel and the marketed intravenous docetaxel formulation, Taxotere®, as a control. In vivo PK results in mice showed that all the administered oral docetaxel formulations had limited absorption in the absence of ritonavir. On the contrary, ritonavir co-administration given as pre-treatment significantly enhanced oral bioavailability of both the marketed and milk-based docetaxel formulations; an even more marked increase in drug exposure was observed when ritonavir was incorporated within the docetaxel milk-based formulation. The fixed-dose combination also showed a more prolonged absorption of the drug compared to separate administrations. The current study provides insights for the discovery of a novel milk-based formulation that could potentially serve as an alternative, non-toxic and patient-friendly carrier for an acceptable docetaxel oral chemotherapy.

Docetaxel encapsulation in nanoscale assembly micelles of folate-PEG-docetaxel conjugates for targeted fighting against metastatic breast cancer in vitro and in vivo

Due to the high frequency and mortality of breast cancer, developing efficient targeted drug delivery systems for frightening against this malignancy is among cancer research priorities.The aim of this study was to synthesize a targeted micellar formulation of docetaxel (DTX) using DTX, folic acid (FA) and polyethylene glycol (PEG) conjugates as building blocks.In the current study, two therapeutic polymers consisting of FA-PEG-DTX and PEG-DTX conjugates were synthesized and implemented to form folate-targeted and non-targeted micelles. Dissipative particle dynamics (DPD) method was used to simulate the behavior of the nanoparticle.The anti-cancer drug, DTX was loaded in to the micelles via solvent switching method in order to increase its solubility and stability. The cytotoxicity of the targeted and non-targeted formulations was evaluated against 4T1 and CHO cell lines. In vivo therapeutic efficiency was studied using ectopic tumor model of metastatic breast cancer, 4T1, in Female BALB/c mice. The successful synthesis of therapeutic polymers, FA-PEG-DTX and PEG-DTX were confirmed implementing 1HNMR spectral analysis. The size of DTX-loaded non-targeted and targeted micelles were 176.3 ± 8.3 and 181 ± 10.1 nm with PDI of 0.23 and 0.17, respectively. Loading efficiencies of DTX in non-targeted and targeted micelles were obtained to be 85% and 82%, respectively. In vitro release study at pH = 7.4 and pH = 5.4 showed a controlled and continuous drug release for both formulations, that was faster at pH = 5.4 (100% drug release within 120 h) than at pH = 7.4 (80% drug release within 150 h). The targeted formulation showed a significant higher cytotoxicity against 4T1 breast cancer cells (high expression of folate receptor) within the range of 12.5 to 200 μg/mL in comparison with no-targeted one. However, there was no significant difference between the cytotoxicity of the targeted and non-targeted formulations against CHO cell line as low-expressed cell line. In accordance with in vitro investigation, in vivo studies verified the ideal anti-tumor efficacy of the targeted formulation compared to Taxotere and non-targeted formulation. Based on the obtained data, FA-targeted DTX-loaded nano-micelles significantly increased the therapeutic efficacy of DTX and therefore can be considered as a new potent platform for breast cancer chemotherapy.

Novel Gellan Gum-Based In Situ Nanovesicle Formulation of Docetaxel for Its Localized Delivery Using Depot Formation.

In the present study, different in situ hydrogel formulations of docetaxel (DTX) based on biocompatible polymers such as Hyaluronic Acid (HA), poloxamer-407, chitosan and gellan gum were formulated to increase its therapeutic efficacy and reduce toxicity. DTX was loaded in nanovesicles (20 mg/mL equivalent to commercial strength) and further incorporated into the hydrogel bases to possess a dual rationale of protection against burst release and enhanced solubility of the drug. The optimized hydrogel formulation (NV-TPGS-3-GG-4) showed ideal rheological behavior and in situ characteristics at 37±0.5°C with sustained release of more than 144 h. The optimized formulation had instant in vitro gelation (2.8±0.3 min) with good injectability in comparison to the conventional commercial DTX injectable formulation having instant release (<2 h). Additionally, developed formulation exhibited an improved biodisponibility (25.1±0.2 h) in comparison to the commercially available formulation (1.7±0.1 h). The Solid Tumor Carcinoma model in Swiss albino mice revealed that the optimized formulation (based on gellan gum) showed better tumor reduction (85.7±1.2%) and lower toxicity as compared to the commercial formulation (77.3±1.3%). Pharmacokinetic and biodistribution studies demonstrated 3 to 4 times higher localization of drug in tumors. Our findings suggested that injectable gellan gum-based in situ hydrogel formulation can be an effective delivery system for DTX with enhanced solubility, reduced toxicity, and better targeting to the tumors for improved therapeutics.Graphical abstract.

Albumin-Coated Mesoporous Silica Nanoparticles of Docetaxel: Preparation, Characterization, and Pharmacokinetic Evaluation.

The potential of albumin-coated hollow mesoporous silica nanoparticles (A-HMSNs) to optimize the chemotherapeutic efficacy of docetaxel (DTX) was explored. The synthesized A-DTX-HMSNs had a nanometric size range, offered large surface area with numerous pores, and offered high drug entrapment and loading, that is, 79.18% ± 1.4% and 19.11% ± 1.30%, respectively. Fourier transform infrared spectroscopy and differential scanning calorimetry studies confirmed drug loading and the presence of albumin onto the developed systems, and the drug release followed Higuchi profile. A-HMSNs significantly enhanced the pharmacokinetic profile of DTX by eightfold vis-à-vis the pure DTX. The enhanced plasma levels (Cmax, Tmax, area under the curve), prolonged drug release, long circulation time, lower clearance, hemocompatability, and substantially higher drug loading offered by these nanocarriers inherit promise of a safer and efficacious formulation of DTX.

Novel pegylated liposomal formulation of docetaxel with 3-n-pentadecylphenol derivative for cancer therapy

The taxanes are commonly used in the treatment of many types of cancer. The disadvantages of using taxanes in therapy are their low solubility in water, the toxicity or relatively poor pharmacokinetics of existing formulations. Using liposomes as carriers would help in overcoming these problems, however, their use is limited by the low incorporation efficiency of taxane molecules within bilayer and by subsequent drug crystallization. Most of published taxanes liposomal formulations use natural soy phosphatidylcholine (PC) as main liposomes lipid. This allows a relatively good drug retention during the liposomes storage, but on the other hand, the use of liposomes with more liquid bilayer facilitates fast drug release after its intravenous administration. In order to decrease the drug release from liposomes in circulation, we used pegylated HSPC (hydrogenated soy PC) liposomes containing a novel synthetic 3-n-pentadecylphenol derivative – KW101, that showed a remarkably stabilizing action for the docetaxel (DTX) dopped HSPC liposomes over 30 days, expressed by the inhibition of DTX crystallization. The resulting liposomes with DTX showed similar cytotoxicity on MCF-7 and MDA-MB-231 breast cancer cell lines and higher toxicity in drug-resistant NCI/ADR-RES cell line in comparison with the free DTX. Moreover, this formulation has good pharmacokinetics in mice, in comparison to control pegylated DTX formulation composed of egg phosphatidylcholine (ePC). This novel liposomal formulation of docetaxel consisting of HSPC with the stabilizing compound KW101, appears to be a promising carrier for DTX cancer therapy.

Pharmacokinetics of docetaxel and ritonavir after oral administration of ModraDoc006/r in patients with prostate cancer versus patients with other advanced solid tumours.

ModraDoc006 is a novel oral formulation of docetaxel. The clearance of intravenous docetaxel is higher in medically castrated prostate cancer patients as compared to patients with other types of solid tumours. Oral docetaxel requires co-administration ritonavir (r), which might further impact the pharmacokinetics (PK). We now compare the PK of docetaxel and ritonavir between patients with Hormone Sensitive Prostate Cancer (HSPC), metastatic Castration-Resistant Prostate Cancer (mCRPC) and other metastatic solid tumours, treated on the same dose and weekly schedule of ModraDoc006/r. The docetaxel and ritonavir PK were compared between four patient groups from three clinical phase I trials, including eight male and eight female patients with different types of solid tumours (study 1), seven patients with HSPC (study 2) and five patients with mCRPC (study 3). All patients were treated with ModraDoc006 30mg and ritonavir 100mg in the morning, followed by ModraDoc006 20mg and ritonavir 100mg in the evening (ModraDoc006/r 30-20/100-100). For comparative purposes, the PK of six mCRPC patients that received 30-20/200-100 in study 3 were also evaluated. The maximum plasma concentration (Cmax) was significantly lower for both docetaxel and ritonavir in the prostate cancer patients as compared to the patients with other types of solid tumours treated at ModraDoc006/r 30-20/100-100. The docetaxel area under the plasma concentration versus time curve (AUC) was significantly different at this dose, with a mean AUC0-48 of 1359 ± 374ng/mL*h (N = 8) in female patients and 894 ± 223ng/mL*h (N = 8) in male patients with different solid tumours (study 1), 321 ± 81 (N = 7) in HSPC (study 2) and 367 ± 182ng/mL*h (N = 5) in mCRPC (study 3). A similar pattern was observed for ritonavir. ModraDoc006/r 30-20/200-100 in six mCRPC patients led to a comparable ritonavir exposure as compared to the patients at 30-20/100-100 in study 1 and increased the docetaxel AUC0-48 to 1266 ± 473ng/mL*h (N = 6). The exposure to docetaxel and ritonavir was significantly lower in prostate cancer patients as compared to patients with other types of solid tumours, treated on ModraDoc006/r 30-20/100-100. An increase of the ritonavir dose increased the docetaxel exposure in mCRPC patients. Therefore, a different RP2D of ModraDoc006/r is pursued in castrated prostate cancer patients as compared to patients with other types of solid tumours. Study 1: ClinicalTrials.gov Identifier NCT01173913, date of registration August 2, 2010. Study 2: ClinicalTrials.gov Identifier NCT03066154, date of registration February 28, 2017. Study 3: ClinicalTrials.gov Identifier NCT03136640, date of registration May 2, 2017.

Phase IIb trial of oral ModraDoc006/r as a tolerable and effective option in comparison with intravenous docetaxel in metastatic castration-resistant prostate cancer (mCRPC).

132 Background: ModraDoc006 is a novel, oral tablet formulation of docetaxel. To enhance bioavailability, it is co-administered with ritonavir (r), an inhibitor of cytochrome P450 3A4 and P-glycoprotein. The oral combination, denoted ModraDoc006/r, has potential advantages in terms of patient convenience, elimination of infusion-related reactions and avoiding prophylactic steroid administration, as well as safety benefits. Safety and preliminary efficacy of ModraDoc006/r in mCRPC were established in a prior phase Ib trial. Methods: This is an open label 1:1 randomized phase IIb trial of ModraDoc006/r bi-daily once weekly (BIDW) regimen versus IV docetaxel 75 mg/m2 q day 21. Initially, BIDW 30-20 mg ModraDoc006 combined with 200-100 mg ritonavir was administered on days 1, 8 and 15 of a 21-day cycle. After 39 patients, the dose of ModraDoc006 was reduced to 20-20 mg BIDW to improve GI tolerability. All patients received 5 mg oral prednisone BID. Imaging is obtained every 8-9 weeks for the first 24 weeks, every 12 weeks thereafter. Initially mCRPC patients with RECIST 1.1 measurable disease were eligible; this was amended to evaluable disease per Prostate Cancer Working Group 3 (PCWG3) to allow for wider recruitment. No prior taxane therapy is allowed. The primary efficacy endpoint is radiographic progression free survival (rPFS) per PCWG3 criteria. Secondary objectives include objective response rate, PSA-PFS, time to skeletal related events, disease control rate, duration of response and safety. Patient reported outcomes, QoL and FACT-P questionnaires are assessed. It is expected that ModraDoc006/r will be as effective as IV docetaxel. A sample size of approximately 50 evaluable patients per arm will provide a point estimate of the primary endpoint of rPFS for this study. Results: At the data cut-off of 30 Nov 2020, 90 patients were enrolled in US and EU: 44 patients had been randomized to IV docetaxel and 46 to ModraDoc006/r, with 58 patients currently on treatment. Preliminary PSA response rates and rPFS were noted to be comparable in both treatment arms. ModraDoc006/r was mainly associated with mild and reversible GI-toxicity, of which grade and incidence were reduced at 20-20 mg compared to the initial dose-level of 30-20 mg ModraDoc006. Myelosuppression and neurotoxicity were low to negligible in the ModraDoc006/r arm, with low accompanying levels of alopecia. Conclusions: Adverse events of cytopenias and alopecia were lower with ModraDoc006/r, and preliminary efficacy appears comparable in both arms. Oral chemotherapy option has become critically important during the COVID-19 pandemic. Preliminary data reveals that ModraDoc006/r is an attractive oral option in mCRPC with favorable toxicity profile and comparable efficacy. Clinical trial information: NCT04028388.

Bile Acid Tethered Docetaxel‐Based Nanomicelles Mitigate Tumor Progression through Epigenetic Changes

AbstractIn this study, we describe the engineering of sub‐100 nm nanomicelles (DTX‐PC NMs) derived from phosphocholine derivative of docetaxel (DTX)‐conjugated lithocholic acid (DTX‐PC) and poly(ethylene glycol)‐tethered lithocholic acid. Administration of DTX‐PC NMs decelerate tumor progression and increase the mice survivability compared to Taxotere (DTX‐TS), the FDA‐approved formulation of DTX. Unlike DTX‐TS, DTX‐PC NMs do not cause any systemic toxicity and slow the decay rate of plasma DTX concentration in rodents and non‐rodent species including non‐human primates. We further demonstrate that DTX‐PC NMs target demethylation of CpG islands of Sparcl1 (a tumor suppressor gene) by suppressing DNA methyltransferase activity and increase the expression of Sparcl1 that leads to tumor regression. Therefore, this unique system has the potential to improve the quality of life in cancer patients and can be translated as a next‐generation chemotherapeutic.

Bile Acid Tethered Docetaxel-Based Nanomicelles Mitigate Tumor Progression through Epigenetic Changes.

In this study, we describe the engineering of sub-100 nm nanomicelles (DTX-PC NMs) derived from phosphocholine derivative of docetaxel (DTX)-conjugated lithocholic acid (DTX-PC) and poly(ethylene glycol)-tethered lithocholic acid. Administration of DTX-PC NMs decelerate tumor progression and increase the mice survivability compared to Taxotere (DTX-TS), the FDA-approved formulation of DTX. Unlike DTX-TS, DTX-PC NMs do not cause any systemic toxicity and slow the decay rate of plasma DTX concentration in rodents and non-rodent species including non-human primates. We further demonstrate that DTX-PC NMs target demethylation of CpG islands of Sparcl1 (a tumor suppressor gene) by suppressing DNA methyltransferase activity and increase the expression of Sparcl1 that leads to tumor regression. Therefore, this unique system has the potential to improve the quality of life in cancer patients and can be translated as a next-generation chemotherapeutic.

Self-assembled supramolecular nanomicelles from a bile acid-docetaxel conjugate are highly tolerable with improved therapeutic efficacy.

Herein, we present the engineering of a supramolecular nanomicellar system that is composed of self-assembled units of the PEGylated lithocholic acid (LCA)-docetaxel (DTX) conjugate (LCA-DTX-PEG). We tethered a short polyethylene glycol unit to LCA and used an esterase-sensitive ester linkage between DTX and LCA. The LCA-DTX-PEG conjugate formed nanomicelles (LCA-DTX-PEG NMs) with ∼160 nm hydrodynamic diameter that are sensitive to cellular esterases and maximized the release of DTX under high esterase exposure. LCA-DTX-PEG NMs were found to be effective as the parent drug in breast cancer cells by stabilizing tubulin and arresting the cells in the G2/M phase. We determined the maximum tolerated dose (MTD) and systemic and vital organ toxicity of LCA-DTX-PEG NMs in mice, rats, and rabbits. LCA-DTX-PEG NMs showed a MTD of >160 mg kg-1 and are found to be safe in comparison with their parent FDA-approved drug formulation (Taxotere® or DTX-TS) that is highly toxic. LCA-DTX-PEG NMs effectively reduced the tumor volume and increased the survival of 4T1 tumor-bearing mice with improved blood circulation time of the drug and its higher accumulation in tumor tissues. Therefore, this study highlights the potential of PEGylated bile acid-drug conjugate based nanomicelles for the development of next generation cancer therapeutics.