[Experts' Opinion] Novel formulations of docetaxel, paclitaxel and doxorubicin in the management of metastatic breast cancer

Rajappa, Senthil; Joshi, Anuradha Rajiv; Doval, D.C.; Batra, Ullas; Rajendranath, Rejiv; Deo, Avinash; Biswas, Ghanshyam; Bajpai, Peush; Tilak, Tvsvgk; Kane, Sriram; Kumar, K. V. S. Hari; Kumar, Manish; Talele, Avinash; Devde, Prakash; Gupta, Ashutosh; Joshi, Nisarg; Sejpal, Jaykumar J; Bunger, Deepak; Khan, Mubeen

doi:10.3892/ol.2018.9057

Cited by 12 publications

(11 citation statements)

References 57 publications

(66 reference statements)

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“…In addition, its use in the treatment of glioma is greatly limited because of its poor BBB permeation ability. As a result, most of the available marketed formulations of DTX are not able to cross the BBB efficiently and also accompanied with various side effects, including allergic reactions with some cases of fatal anaphylaxis due to ploysorbate 80 (Tween 80) used in the formulation, lowing of white blood cells count, nephrotoxicity, neurotoxicity, cumulative fluid retention etc, [9,17,18].…”

Section: Introductionmentioning

confidence: 99%

Hyaluronic Acid-Docetaxel Conjugate Loaded Nanoliposomes for Targeting Tumor Cells

Seifu¹,

Nath²,

Dutta³

2020

Int J App Pharm

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Objective: Docetaxel (DTX), a potent anticancer drug, is suffering from non-specificity and drug resistance as major limitations. In this investigation, we developed Hyaluronic acid (HA)-Docetaxel conjugate (HA-DTX) loaded nanoliposomes to target cancer cells via passive and active targeting approaches. Methods: HA-DTX was synthesized and characterized by UV-Visible spectrophotometry, FT-IR spectroscopy, 1H NMR spectroscopy, Differential scanning calorimetry and X-ray diffraction and then loaded into nanoliposomes (L-NLs) by thin-film hydration method. L-NLs were characterized physicochemically and evaluated for anticancer efficacy by in vitro cytotoxicity study in glioma cells (C6 glial cells); cellular uptake and apoptotic effect were investigated by fluorescence microscopy. Results: HA-DTX was successfully synthesized; L-NLs had an average size of 123.0±16.53 nm, polydispersity index of 0.246±0.01 and zeta potential of 44.4±6.79 mV. Also, L-NLs exhibited 90.54%±4.22 of drug loading efficiency and 2.68%±0.12 of drug loading, releasing about 57.72%±1.17 at pH 5.2 and only 14.14%±1.32 at pH 7.4 after 48 h. No significant change instability was observed after storage at 5 °C±3 °C as well as at 25 °C±2 °C/60% RH±5% RH for 6 mo. The cytotoxicity effect of L-NLs was higher by 10% that of marketed formulation at 10 µg/ml docetaxel concentration. Fluorescence microscopic investigation showed that more cellular uptake and apoptotic effect were observed in L-NLs treated C6 glial cells than in those treated with the marketed formulation. Conclusion: HA-DTX loaded nanoliposomes enabled docetaxel to target C6 glial cells with better efficacy and might be effective to treat glioma.

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Section: Introductionmentioning

confidence: 99%

Hyaluronic Acid-Docetaxel Conjugate Loaded Nanoliposomes for Targeting Tumor Cells

Seifu¹,

Nath²,

Dutta³

2020

Int J App Pharm

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“…In addition, premedication with corticosteroids may potentially interfere with the immune response elicited by check-point inhibitors [5] and potentially affect efficacy in combination treatment including chemotherapy and immune therapy, suggesting that chemotherapy not requiring corticosteroid premedication may potentially be advantageous in that specific setting. Therefore, the main goals in the development of novel formulations of paclitaxel is to reduce toxicities associated with Cremophor EL and to decrease the need for premedication with corticosteroids [6, 7].…”

Section: Introductionmentioning

confidence: 99%

Maximum Tolerated Dose and Pharmacokinetics of Paclitaxel Micellar in Patients with Recurrent Malignant Solid Tumours: A Dose-Escalation Study

Borgå¹,

Henriksson

Bjermo

et al. 2019

Adv Ther

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IntroductionA water-soluble Cremophor EL-free formulation of paclitaxel, in which retinoic acid derivates solubilize paclitaxel by forming micelles (paclitaxel micellar), was studied for the first time in man to establish the maximum tolerated dose (MTD) and to characterize the pharmacokinetics (PK).MethodsThis was an open-label, one-arm, dose-escalating study in patients with advanced solid malignant tumours, for which no standard therapy was available or had failed. Paclitaxel micellar was given as 1-h intravenous infusion every 21 days for 3 cycles, mainly without premedication. Plasma samples were collected during 24 h at the first cycle and paclitaxel concentrations were assayed by high-performance liquid chromatography. PK was evaluated using a two-compartment model.ResultsThirty-four patients received paclitaxel micellar at doses ranging between 90 and 275 mg/m2. MTD was established as 250 mg/m2. Fatigue and neuropathy were the most frequent dose-limiting toxicities. No hypersensitivity reactions were observed. PK of paclitaxel was evaluated in 25 data sets. Paclitaxel micellar had a rapid initial distribution phase, mean half-life 0.55 h, estimated to be completed 3 h after dosing and a mean terminal half-life of 8.8 h. Mean clearance was 13.4 L/h/m2 with fivefold interindividual variability. The residual areas after 10 h and 24 h were 15.7 ± 8.6% and 5.7 ± 3.9% of the area under the plasma concentration–time curve to infinite time (AUCinf), respectively.ConclusionNo new side effects unknown for paclitaxel were observed. Maximum plasma concentration (Cmax) and AUCinf showed a tendency to increase linearly with dose within the 150–275 mg/m2 dose range. The possibility to administer paclitaxel micellar without steroid premedication makes it an attractive candidate for further studies in combination with immunotherapy.Trial RegistrationEudraCT no: 2004-001821-54.FundingOasmia Pharmaceutical AB.

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“…In order to evaluate the chemotherapy resistance mechanisms driving TNBC recurrence, we grew four TNBC cell lines MDA-MB-231, Bt549, Hs578t and MDA-MB-468 and exposed them to the frontline therapy combination of doxorubicin and docetaxel (ratio 100:1) starting at 0.1 nM docetaxel and 10 nM doxorubicin and concluding with 2 nM docetaxel and 200 nM doxorubicin. The concentration was chosen to mimic the clinical administration of bolus doxorubicin and infusion of docetaxel (17). Resistance was achieved over 6-8 months with escalating doses of the chemotherapy combination.…”

Section: Resultsmentioning

confidence: 99%

Genome Instability and Pressure on Non-Homologous end Joining drives Chemotherapy Resistance via a DNA Repair Crisis Switch in Triple Negative Breast Cancer.

Wiegmans

Ward

Ivanova

et al. 2020

Preprint

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Background: Chemotherapy intensifies pressure on the DNA repair pathways that can lead to deregulation. There is an urgent clinical need to be able to track the emergence of chemotherapy resistance and tailor patient staging appropriately. This is especially evident in the triple negative breast cancer (TNBC) subtype, of which standard of care is chemotherapy with tumours displaying high levels of inherent genome instability. TNBC has an overall poor prognosis for survival. There have been numerous studies into single agent chemoresistance but to date no study has elucidated in detail the roles of the key DNA repair components in resistance associated with the frontline clinical combination of anthracyclines and taxanes together. Methods: In this study, we hypothesized that the emergence of chemotherapy resistance is driven by changes in functional signaling in the DNA repair pathways. We identified the importance of the DNA repair pathways in chemoresistant clinical samples and characterized the emergence of chemoresistance in TNBC cell lines. We utilized classical DNA repair assays and specific targeting of key DNA repair proteins to elucidate a new mechanism for adaptation to the combination of doxorubicin and docetaxel. Results: We identified that consistent pressure on the non-homologous end joining pathway in the presence of genome instability causes failure of the key kinase DNA-PK, loss of p53 and compensation by p73. In-turn a switch to reliance on the homologous recombination pathway and RAD51 recombinase occurs to repair residual double strand DNA breaks. Conclusions: We demonstrate that RAD51 is an actionable target for resensitization to chemotherapy in resistant cells with a matched gene expression profile of resistance highlighted by homologous recombination.

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[Experts' Opinion] Novel formulations of docetaxel, paclitaxel and doxorubicin in the management of metastatic breast cancer

Cited by 12 publications

References 57 publications

Hyaluronic Acid-Docetaxel Conjugate Loaded Nanoliposomes for Targeting Tumor Cells

Hyaluronic Acid-Docetaxel Conjugate Loaded Nanoliposomes for Targeting Tumor Cells

Maximum Tolerated Dose and Pharmacokinetics of Paclitaxel Micellar in Patients with Recurrent Malignant Solid Tumours: A Dose-Escalation Study

Genome Instability and Pressure on Non-Homologous end Joining drives Chemotherapy Resistance via a DNA Repair Crisis Switch in Triple Negative Breast Cancer.

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