All-stage targeted red blood cell membrane-coated docetaxel nanocrystals for glioma treatment.

Challenges for glioma treatment with nanomedicines include physio-anatomical barriers (the blood-brain barrier and blood-brain tumor barrier), low drug loading capacity, and limited circulation time. Here, a red blood cell membrane-coated docetaxel drug nanocrystal (pV-RBCm-NC(DTX)), modified with pHA-VAP (pV) for all-stage targeting of glioma, was designed. The NC(DTX) core exhibited a high drug loading capacity but low in vivo stability, and the RBCm coating significantly enhanced the stability and prolonged in vivo circulation. Moreover, the Y-shaped targeting ligand pV was modified by a mild avidin-biotin interaction, which endowed RBCm-NC(DTX) with superior barrier-crossing ability and therapeutic efficacy. The integration of nanocrystal technology, cell membrane coating, and the avidin-biotin insertion method into this active targeting biomimetic formulation represents a promising drug delivery strategy for glioma.

Pegylated liposome encapsulating docetaxel using microfluidic mixing technique: Process optimization and results in breast cancer models.

The development of nanoparticles could help to improve the efficacy/toxicity balance of drugs. This project aimed to develop liposomes and immunoliposomes using microfluidic mixing technology.Various formulation tests were carried out to obtain liposomes that met the established specifications. The liposomes were then characterized in terms of size, polydispersity index (PDI), docetaxel encapsulation rate and lamellarity. Antiproliferative activity was tested in human breast cancer models ranging from near-negative (MDA-MB-231), positive (MDA-MB-453) to HER2 positive. Pharmacokinetic studies were performed in C57BL/6 mice.Numerous batches of liposomes were synthesised using identical molar ratios and by varying the microfluidic parameters TFR, FRR and buffer. All synthesized liposomes have a size < 200 nm, but only Lipo-1, Lipo-6, Lipo-7, Lipo-8 have a PDI < 0.2, which meets our initial requirements. The size of the liposomes was correlated with the total FRR, for a 1:1 FRR the size is 122.2 ± 12.3 nm, whereas for a 1:3 FRR the size obtained is 163.4 ± 34.0 nm (p = 0.019. Three batches of liposomes were obtained with high docetaxel encapsulation rates > 80 %. Furthermore, in vitro studies on breast cancer cell lines demonstrated the efficacy of liposomes obtained by microfluidic mixing technique. These liposomes also showed improved pharmacokinetics compared to free docetaxel, with a longer half-life and higher AUC (3-fold and 3.5-fold increase for the immunoliposome, respectively).This suggests that switching to the microfluidic process will produce batches of liposomes with the same characteristics in terms of in vitro properties and efficacy, as well as the ability to release the encapsulated drug over time in vivo. This time-efficiency of the microfluidic technique is critical, especially in the early stages of development.

AS1411 aptamer/RGD dual functionalized theranostic chitosan-PLGA nanoparticles for brain cancer treatment and imaging.

Conventional chemotherapy and poor targeted delivery in brain cancer resulting to poor treatment and develop resistance to anticancer drugs. Meanwhile, it is quite challenging to diagnose/detection of brain tumor at early stage of cancer which resulting in severity of the disease. Despite extensive research, effective treatment with real-time imaging still remains completely unavailable, yet. In this study, two brain cancer cell specific moieties i.e., AS1411 aptamer and RGD are decorated on the surface of chitosan-PLGA nanoparticles to improve targeted co-delivery of docetaxel (DTX) and upconversion nanoparticles (UCNP) for effective brain tumor therapy and real-time imaging. The nanoparticles were developed by a slightly modified emulsion/solvent evaporation method. This investigation also translates the successful synthesis of TPGS-chitosan, TPGS-RGD and TPGS-AS1411 aptamer conjugates for making PLGA nanoparticle as a potential tool of the targeted co-delivery of DTX and UCNP to the brain cancer cells. The developed nanoparticles have shown an average particle size <200 nm, spherical in shape, high encapsulation of DTX and UCNP in the core of nanoparticles, and sustained release of DTX up to 72 h in phosphate buffer saline (pH 7.4). AS1411 aptamer and RGD functionalized theranostic chitosan-PLGA nanoparticles containing DTX and UCNP (DUCPN-RGD-AS1411) have achieved greater cellular uptake, 89-fold improved cytotoxicity, enhanced cancer cell arrest even at lower drug conc., improved bioavailability with higher mean residence time of DTX in systemic circulation and brain tissues. Moreover, DUCPN-RGD-AS1411 have greatly facilitated cellular internalization and higher accumulation of UCNP in brain tissues. Additionally, DUCPN-RGD-AS1411 demonstrated a significant suppression in tumor growth in brain-tumor bearing xenograft BALB/c nude mice with no impressive sign of toxicities. DUCPN-RGD-AS1411 has great potential to be utilized as an effective and safe theranostic tool for brain cancer and other life-threatening cancer therapies.

Overcoming the Blood-Brain Tumor Barrier with Docetaxel-Loaded Mesoporous Silica Nanoparticles for Treatment of Temozolomide-Resistant Glioblastoma.

While temozolomide (TMZ) has been a cornerstone in the treatment of newly diagnosed glioblastoma (GBM), a significant challenge has been the emergence of resistance to TMZ, which compromises its clinical benefits. Additionally, the nonspecificity of TMZ can lead to detrimental side effects. Although TMZ is capable of penetrating the blood-brain barrier (BBB), our research addresses the need for targeted therapy to circumvent resistance mechanisms and reduce off-target effects. This study introduces the use of PEGylated mesoporous silica nanoparticles (MSN) with octyl group modifications (C8-MSN) as a nanocarrier system for the delivery of docetaxel (DTX), providing a novel approach for treating TMZ-resistant GBM. Our findings reveal that C8-MSN is biocompatible in vitro, and DTX@C8-MSN shows no hemolytic activity at therapeutic concentrations, maintaining efficacy against GBM cells. Crucially, in vivo imaging demonstrates preferential accumulation of C8-MSN within the tumor region, suggesting enhanced permeability across the blood-brain tumor barrier (BBTB). When administered to orthotopic glioma mouse models, DTX@C8-MSN notably prolongs survival by over 50%, significantly reduces tumor volume, and decreases side effects compared to free DTX, indicating a targeted and effective approach to treatment. The apoptotic pathways activated by DTX@C8-MSN, evidenced by the increased levels of cleaved caspase-3 and PARP, point to a potent therapeutic mechanism. Collectively, the results advocate DTX@C8-MSN as a promising candidate for targeted therapy in TMZ-resistant GBM, optimizing drug delivery and bioavailability to overcome current therapeutic limitations.

Darolutamide does not interfere with OATP-mediated uptake of docetaxel.

The addition of darolutamide, an androgen receptor signalling inhibitor, to therapy with docetaxel has recently been approved as a strategy to treat metastatic prostate cancer. OATP1B3 is an SLC transporter that is highly expressed in prostate cancer and is responsible for the accumulation of substrates, including docetaxel, into tumours. Given that darolutamide inhibits OATP1B3 in vitro, we sought to characterise the impact of darolutamide on docetaxel pharmacokinetics. We investigated the influence of darolutamide on OATP1B3 transport using in vitro and in vivo models. We assessed the impact of darolutamide on the tumour accumulation of docetaxel in a patient-derived xenograft (PDX) model and on an OATP1B biomarker in patients. Darolutamide inhibited OATP1B3 in vitro at concentrations higher than the reported Cmax. Consistent with these findings, in vivo studies revealed that darolutamide does not influence the pharmacokinetics of Oatp1b substrates, including docetaxel. Docetaxel accumulation in PDX tumours was not decreased in the presence of darolutamide. Metastatic prostate cancer patients had similar levels of OATP1B biomarkers, regardless of treatment with darolutamide. Consistent with a low potential to inhibit OATP1B3-mediated transport in vitro, darolutamide does not significantly impede the transport of Oatp1b substrates in vivo or in patients. Our findings support combined treatment with docetaxel and darolutamide, as no OATP1B3 transporter based drug-drug interaction was identified.

Macrophage derived Exosomal Docetaxel (Exo-DTX) for pro-metastasis suppression: QbD driven formulation development, validation, in-vitro and pharmacokinetic investigation.

Exosomes, biogenic nano-vesicles, are renowned for their ability to encapsulate diverse payloads, however the systematic development and validation of exosomal formulation with significant biological implications have been overlooked. Herein, we developed and validated Exo-DTX, a QbD-driven optimized RAW 264.7 cell derived exosomal anti-cancer formulation of docetaxel (DTX) and evaluate its anti-metastatic and apoptotic efficacy in TNBC 4T1 cells. RAW264.7-derived exosomes were having particle size (112.5 ± 21.48 nm) and zeta-potential (-10.268 ± 3.66 mV) with polydispersity (PDI:0.256 ± 0.03). The statistical optimization of exosomes (200 µg) with Exo: DTX ratio 4:1 confirmed encapsulation of 23.60 ± 1.54 ng DTX/ µg exosomes. Exo-DTX (∼189 nm, -11.03 mV) with 100 ng/ml DTX as payload exhibited ∼5 folds' improvement in IC50 of DTX and distinct cytoskeletal deformation in TNBC 4T1 cells. It also has shown enormous Filamentous actin (F-actin) degradation and triggered apoptosis explained Exo-DTX's effective anti-migratory impact with just 2.6 ± 6.33 % wound closure and 4.56 ± 1.38 % invasion. The western blot confirmed that Exo-DTX downregulated migratory protein EGFR and ß1-integrin but raised cleaved caspase 3/caspase 3 (CC3/C3) ratio and BAX/BCL-2 ratio by about 2.70 and 4.04 folds respectively. The naive RAW 264.7 exosomes also contributed positively towards the effect of Exo-DTX formulation by suppressing ß1-integrin expression and increasing the CC3/C3 ratio in TNBC 4T1 cells as well. Additionally, significant improvement in PK parameters of Exo-DTX was observed in comparison to Taxotere, 6-folds and 3.04-folds improved t1/2 and Vd, proving the translational value of Exo-DTX formulation. Thus, the Exo-DTX so formulated proved beneficial in controlling the aggressiveness of TNBC wherein, naive exosomes also demonstrated beneficial synergistic anti-proliferative effect in 4T1.

Design, development and clinical translation of CriPec®-based core-crosslinked polymeric micelles.

Nanomedicines are used to improve the efficacy and safety of pharmacotherapeutic interventions. Unraveling the biological behavior of nanomedicines, including their biodistribution and target site accumulation, is essential to establish design criteria that contribute to superior performance. CriPec® technology is based on amphiphilic methoxy-poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide lactate] (mPEG-b-pHPMAmLacn) block copolymers, which are designed to upon self-assembly covalently entrap active pharmaceutical ingredients (API) in core-crosslinked polymeric micelles (CCPM). Key features of CCPM are a prolonged circulation time, high concentrations at pathological sites, and low levels of accumulation in the majority of healthy tissues. Proprietary hydrolysable linkers allow for tunable and sustained release of entrapped API, including hydrophobic and hydrophilic small molecules, as well as peptides and oligonucleotides. Preclinical imaging experiments provided valuable information on their tumor and tissue accumulation and distribution, as well as on uptake by cancer, healthy and immune cells. The frontrunner formulation CPC634, which refers to 65 nm-sized CCPM entrapping the chemotherapeutic drug docetaxel, showed excellent pharmacokinetic properties, safety, tumor accumulation and antitumor efficacy in multiple animal models. In the clinic, CPC634 also demonstrated favorable pharmacokinetics, good tolerability, signs of efficacy, and enhanced localization in tumor tissue as compared to conventional docetaxel. PET imaging of radiolabeled CPC634 showed quantifiable accumulation in âˆ¼50 % of tumors and metastases in advanced-stage cancer patients, and demonstrated potential for use in a theranostic setting even when applied at a companion diagnostic dose. Altogether, the preclinical and clinical results obtained to date demonstrate that mPEG-b-pHPMAmLacn CCPM based on CriPec® technology are a potent, tunable, broadly applicable and well-tolerable platform for targeted drug delivery and improved anticancer therapy.

Novel Self-Assembled Micelles With Increased Tumor Penetration and Anti-Tumor Efficiency Against Breast Cancer.

PURPOSE: Recently, docetaxel (DTX) micelles based on retinoic acid derivative surfactants showed lower systemic toxicity and bioequivalence to polysorbate-solubilized docetaxel (Taxotere®) in a phase II clinical study. However, the poor stability of these surfactants in vitro and in vivo led to extremely harsh storage conditions with methanol, and the formed micelles were quickly disintegrated with rapid drug burst release in vivo. To further enhance the stability and accumulation in tumors of DTX micelles, a novel surfactant based on acitretin (ACMeNa) was synthesized and used to prepare DTX micelles to improve anti-tumor efficiency. METHODS: Novel micelle-forming excipients were synthesized, and the micelles were prepared using the thin film hydration technique. The targeting effect in vitro, distribution in the tumor, and its mechanism were observed. Pharmacokinetics and anti-tumor effect were further investigated in rats and tumor-bearing female mice, respectively. RESULTS: The DTX-micelles prepared with ACMeNa (ACM-DTX) exhibited a small size (21.9 ± 0.3 nm), 39% load efficiency, and excellent stability in vitro and in vivo. Long circulation time, sustained and steady accumulation, and strong penetration in the tumor were observed in vivo, contributing to a better anti-tumor effect and lower adverse effects. CONCLUSIONS: The micelles formed by ACMeNa showed a better balance between anti-tumor and adverse effects. It is a promising system for delivering hydrophobic molecules for cancer therapy.

Multifunctional exosome-mimetics for targeted anti-glioblastoma therapy by manipulating protein corona.

Targeted drug delivery to the glioblastoma (GBM) overcoming blood-brain barrier (BBB) has been challenging. Exosomes are promising vehicles for brain tumor drug delivery, but the production and purification hinder its application for nanomedicine. Besides, the formation of protein corona (PC) may affect the behaviour of nanocarriers. Here, multifunctional exosomes-mimetics (EM) are developed and decorated with angiopep-2 (Ang) for enhancing GBM drug delivery by manipulating PC. Docetaxel (DTX)-loaded EM with Ang modification (DTX@Ang-EM) show less absorption of serum proteins and phagocytosis by macrophages. Ang-EM show enhanced BBB penetration ability and targeting ability to the GBM. Ang-EM-mediated delivery increase the concentration of DTX in the tumor area. The multifunctional DTX@Ang-EM exhibits significant inhibition effects on orthotopic GBM growth with reduced side effects of the chemotherapeutic. Findings from this study indicate that the developed DTX@Ang-EM provide a new strategy for targeted brain drug delivery and GBM therapy.

Reversed-phase high-performance liquid chromatography: A fast and efficient analytical method to quantify docetaxel-loaded pegylated liposomes in release study.

Docetaxel is an anticancer that belongs to the family of taxanes and acts in the inhibition of cell proliferation through the polymerization of microtubules. The aim of this study was the development and validation of a fast method by reversed-phase high-performance liquid chromatography for quantitative analysis of docetaxel encapsulated in pegylated liposomes. The analytical method was validated for the following recognized specifications: system suitability, precision (repeatability and intermediate precision), linearity, accuracy, selectivity, detection and quantification limits, and robustness. The reversed phase-high-performance liquid chromatography analyses were performed at a temperature of 45°C (isocratic mode). The mobile phase was composed of acetonitrile and water (65:35, v/v) and the flow rate was fixed at 0.8 mL/min. The running time and wavelength were 8 min and 230 nm, respectively. The method was found to be linear, precise, selective, precise, robust, accurate, in the range of 1-75 µg/mL (R2 = 0.9999) and the values of detection and quantification limits were 2.35 and 7.84 µg/mL, respectively. The release rates of docetaxel in pegylated liposomes were lower compared to docetaxel in solution. The reversed phase high-performance liquid chromatography method developed proved to be adequate and can be effectively used to determine the in vitro release profile of docetaxel transported by pegylated liposomes.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Nanocrystal-Loaded Micelles for the Enhanced In Vivo Circulation of Docetaxel.

Prolonging in vivo circulation has proved to be an efficient route for enhancing the therapeutic effect of rapidly metabolized drugs. In this study, we aimed to construct a nanocrystal-loaded micelles delivery system to enhance the blood circulation of docetaxel (DOC). We employed high-pressure homogenization to prepare docetaxel nanocrystals (DOC(Nc)), and then produced docetaxel nanocrystal-loaded micelles (DOC(Nc)@mPEG-PLA) by a thin-film hydration method. The particle sizes of optimized DOC(Nc), docetaxel micelles (DOC@mPEG-PLA), and DOC(Nc)@mPEG-PLA were 168.4, 36.3, and 72.5 nm, respectively. The crystallinity of docetaxel was decreased after transforming it into nanocrystals, and the crystalline state of docetaxel in micelles was amorphous. The constructed DOC(Nc)@mPEG-PLA showed good stability as its particle size showed no significant change in 7 days. Despite their rapid dissolution, docetaxel nanocrystals exhibited higher bioavailability. The micelles prolonged the retention time of docetaxel in the circulation system of rats, and DOC(Nc)@mPEG-PLA exhibited the highest retention time and bioavailability. These results reveal that constructing nanocrystal-loaded micelles may be a promising way to enhance the in vivo circulation and bioavailability of rapidly metabolized drugs such as docetaxel.

Active Tumoral/Tumor Environmental Dual-Targeting by Non-Covalently Arming with Trispecific Antibodies or Dual-Bispecific Antibodies on Docetaxel-Loaded mPEGylated Nanocarriers to Enhance Chemotherapeutic Efficacy and Minimize Systemic Toxicity.

PURPOSE: This study was aimed at developing the trispecific antibodies (anti-EGFR/anti-FAP/anti-mPEG, TsAb) or dual bispecific antibodies (anti-EGFR/anti-mPEG and anti-FAP/anti-mPEG) docetaxel (DTX)-loaded mPEGylated lecithin-stabilized micelles (mPEG-lsbPMs) for improving the targeting efficiency and therapeutic efficacy. METHODS: mPEG-lsbPMs were simply prepared via thin film method. The trispecific antibodies or bispecific antibodies bound the mPEG-lsbPMs by anti-mPEG Fab fragment. The formulations were characterized by DLS and TEM; in vitro and in vivo studies were also conducted to evaluate the cellular uptake, cell cytotoxicity and therapeutic efficacy. RESULTS: The particle sizes of mPEG-lsbPMs with or without the antibodies were around 100 nm; the formulations showed high encapsulation efficiencies of 97.12%. The TsAb and dual bispecific antibodies were fabricated and demonstrated their targeting ability. Two EGFR-overexpressed cell lines (HT-29 and MIA PaCa-2) were co-cultured with FAP-overexpressed WS1 cells (HT-29/WS1; MIA PaCa-2/WS1) to mimic a tumor coexisting in the tumor microenvironment. Cellular binding study revealed that the binding of anti-FAP micelles to three co-culture ratios (4:1, 1:1, and 1:4) of HT-29/EGFR to WS1/FAP was significantly higher than that for TsAb micelles and dual (1:1) micelles, and the binding of those targeting antibodies to WS1/FAP and MIA PaCa-2/EGFR was equally efficacious resulting in a similar binding amount of the TsAb and dual BsAbs (1:1) with the co-culture of MIA PaCa-2/EGFR and WS1/FAP at a 1:1 ratio. Antitumor efficacy study showed that treatment with DTX-loaded mPEG-lsbPMs modified with or without BsAbs, dual BsAbs (1:1), and TsAbs was enhanced in inhibiting tumor growth compared with that for Tynen® while showing fewer signs of adverse effects. CONCLUSION: Active targeting of both tumors and TAF-specific antigens was able to increase the affinity of DTX-loaded mPEG-lsbPMs toward tumor cells and TAFs leading to successive uptake by tumor cells or TAFs which enhanced their chemotherapeutic efficacy against antigen-positive cancer cells.

ADME gene polymorphisms do not influence the pharmacokinetics of docetaxel: Results from a population pharmacokinetic study in Indian cancer patients.

BACKGROUND: Pharmacokinetics (PK) of docetaxel is characterized by high inter-individual variability (IIV). While covariate models that explain the PK variability of docetaxel exist, not much is known about the effects of genetic variations on docetaxel disposition. METHODS: Fifty patients with head and neck or prostate cancer were enrolled of whom two patients withdrew consent before the start of the study. Docetaxel was administered at either 50 or 75 mg/m2 as intravenous infusion over 1 h. One pharmacogenetic sample and a series of PK samples, either intensive (N = 5; 13 samples each) or sparse (N = 43; 6 samples each), were collected from each patient. Docetaxel levels were estimated using a validated HPLC method. Polymorphic loci on the Absorption, Distribution, Metabolism, and Elimination (ADME) genes were identified using the PharmacoScan array platform. Population pharmacokinetic analysis was carried out using NONMEM v7.2. RESULTS: Docetaxel PK was well characterized by a three-compartment model. Clearance (Cl) was found to be 18 L/h with an IIV of 45.3%. None of the genetic variants showed significant covariate effect on the Cl of docetaxel. Patients with abnormal alanine aminotransferase (ALT) were found to have 25% lower Cl as compared to patients with normal ALT values. However, the covariate effect could not be established in the final model possibly due to lack of adequate number of patients with abnormal ALT. CONCLUSION: Genetic polymorphisms in the ADME gene do not explain the IIV in PK of docetaxel. However, patients with abnormal liver function might require dose reduction. CLINICAL TRIAL REGISTRATION: Not applicable since participants in this study received treatment that was standard of care.

Chitosan-based nanoparticle co-delivery of docetaxel and curcumin ameliorates anti-tumor chemoimmunotherapy in lung cancer.

The application of traditional chemotherapy drugs for lung cancer has obvious limitations, such as toxic side effects, uncontrolled drug-release, poor bioavailability, and drug-resistance. Thus, to address the limitations of free drugs and improve treatment effects, we developed novel T7 peptide-modified nanoparticles (T7-CMCS-BAPE, CBT) based on carboxymethyl chitosan (CMCS), which is capable of targeted binding to the transferrin receptor (TfR) expressed on lung cancer cells and precisely regulating drug-release according to the pH value and reactive oxygen species (ROS) level. The results showed that the drug-loading content of docetaxel (DTX) and curcumin (CUR) was approximately 7.82% and 6.48%, respectively. Good biosafety was obtained even when the concentration was as high as 500 µg/mL. More importantly, the T7-CMCS-BAPE-DTX/CUR (CBT-DC) complexes exhibited better in vitro and in vivo anti-tumor effects than DTX monotherapy and other nanocarriers loaded with DTX and CUR alone. Furthermore, we determined that CBT-DC can ameliorate the immunosuppressive micro-environment to promote the inhibition of tumor growth. Collectively, the current findings help lay the foundation for combinatorial lung cancer treatment.

Docetaxel loaded mPEG-PLA nanoparticles for sarcoma therapy: preparation, characterization, pharmacokinetics, and anti-tumor efficacy.

Sarcoma represents one of the most common malignant tumors with poor treatment outcomes and prognosis. Docetaxel (DTX) is acknowledged as one of the most important chemotherapy agents. The aim of this study was to improve the efficacy of docetaxel by incorporation into the mPEG-PLA nanoparticle (DTX NP) for the treatment of sarcoma. The DTX NP was prepared by emulsion solvent diffusion method and the prescription and preparation process were optimized through a single factor experiment. The optimized DTX NP was characterized by drug loading, encapsulation efficiency, drug release, etc. Then, the pharmacokinetics was conducted on rats and tumor-bearing ICR mice. Finally, the anti-tumor efficacy of DTX NP with different dosages was evaluated on tumor-bearing ICR mice. The optimized DTX NP was characterized by around 100 nm sphere nanoparticles, sustained in vitro drug release with no obvious burst drug release. Compared with DTX injection, the AUC of DTX NP increased by 94.7- and 35.1-fold on the rats and tumor-bearing ICR mice models, respectively. Moreover, the intra-tumoral drug concentration increased by 5.40-fold. The tumor inhibition rate of DTX NP reached 94.66%, which was 1.24 times that of DTX injection (76.11%) at the same dosage, and the bodyweight increase rate was also higher than the DTX injection. The study provided a DTX NP, which could significantly improve the bioavailability and therapeutic efficacy of DTX as well as reduced its toxicity. It possessed a certain prospect of application for sarcoma treatment.

Safety and pharmacokinetics of docetaxel in combination with pegvorhyaluronidase alfa in patients with non-small cell lung cancer.

This open-label, phase Ib study (NCT02346370) assessed the effect of pegvorhyaluronidase alfa (PVHA; PEGPH20) on the plasma pharmacokinetics (PKs) and safety of docetaxel in 15 patients with stage IIIB/IV non-small cell lung cancer (NSCLC). The docetaxel PK profile from this study was consistent with simulations from a published docetaxel population PK model, and did not demonstrate an effect of PVHA on docetaxel PK. A maximum a posteriori Bayesian fit of the literature PK model to the docetaxel PK appeared unbiased. Adverse events (AEs) were generally consistent with previous reports for docetaxel monotherapy in NSCLC, except for higher incidence of musculoskeletal events, including myalgias, with PVHA plus docetaxel. The most common AEs were fatigue (87%), muscle spasms (60%), and myalgia (53%). Four patients experienced thromboembolic events (27%), three leading to treatment discontinuation. PVHA appeared to demonstrate an acceptable safety profile when given with docetaxel without significantly changing the plasma PK of docetaxel in patients with stage IIIB/IV NSCLC.

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.

A Phase I study of the safety, pharmacokinetics and efficacy of navitoclax plus docetaxel in patients with advanced solid tumors.

Aim: This Phase I study investigated safety of navitoclax and docetaxel in patients (n = 41) with advanced solid tumors. Patients & methods: Two navitoclax plus docetaxel dosing schedules (21 and 28 days) were evaluated. Maximum tolerated dose, dose-limiting toxicities and preliminary antitumor activity were assessed. Results: Ten (24%) patients experienced dose-limiting toxicities; dose-escalation cohorts: n = 7 (21-day schedule: n = 5; 28-day schedule: n = 2) and 21-day expanded safety cohort: n = 3. Navitoclax 150-mg days 1-5 every 21 days with docetaxel 75 mg/m2 day 1 was the maximum tolerated dose and optimal schedule. Adverse events included thrombocytopenia (63%), fatigue (61%), nausea (59%) and neutropenia (51%). Four confirmed partial responses occurred. Conclusion: Navitoclax 150-mg orally once/day was safely administered with docetaxel. Myelosuppression limited dose escalation; antitumor activity was observed. Clinical trial registration: NCT00888108 (ClinicalTrials.gov).