A chemotherapeutic approach targeting the acidic tumor microenvironment: combination of a proton pump inhibitor and paclitaxel for statistically optimized nanotherapeutics

Bhattacharya, Saswati; Khanam, Jasmina; Sarkar, Pradipta; Pal, Tapan Kumar

doi:10.1039/c8ra08924h

Cited by 14 publications

(8 citation statements)

References 63 publications

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“…Since V-ATPases are located in every eukaryotic cell,31 in order to increase the efficacy of inhibitors, it is important to target drugs directly to neoplastic cells. Recently, Bhattacharya designed a dual nanocarrier system loaded with paclitaxel and LANSO.…”

Section: Discussionmentioning

confidence: 99%

<p>Proton Pump Inhibitors Modulate Transport Of Doxorubicin And Its Liposomal Form Into 2D And 3D Breast Cancer Cell Cultures</p>

Paškevičiūtė¹,

Petrikaitė²

2019

CMAR

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PurposeThe purpose of our study was to evaluate the influence of two PPIs (omeprazole (OME) and lansoprazole (LANSO)) on weakly basic anticancer drug doxorubicin (DOX) and pegylated liposomal doxorubicin (PLD) delivery to monolayer-cultured 4T1 murine breast cancer cells and tumor spheroids.MethodsThe effect of PPIs on cell viability was evaluated by MTT assay. 3D cell cultures (spheroids) were formed using 3D bioprinting method. DOX and PLD penetration into cancer cells and spheroids at pH 6.0 and 7.4 was assessed using fluorescence microscopy.ResultsBoth OME and LANSO did not reduce the viability of 4T1 cells at 100 μM and lower concentrations, and therefore, in further experiments, 100 μM of PPIs was used. At pH 7.4, both tested PPIs did not enhance DOX (5 µM) and PLD (concentration corresponding to 5 µM DOX) delivery into 2D cell cultures. However, in acidic conditions, both PPIs increased the amount of drug in cancer cells and their nucleus. At physiological pH they were not effective at improving DOX delivery into spheroids, but after 2 hrs of incubation, OME slightly increased PLD delivery into edge and middle zones. At pH 6.0, both tested PPIs significantly enhanced DOX and PLD transport into spheroids, but the positive effect on delivery was observed only within the first 4 hrs of incubation.ConclusionBoth OME and LANSO increased DOX and PLD penetration into monolayer-cultured cells at acidic conditions but did not show a positive effect on drug delivery at physiological pH. Also, pretreatment with tested PPIs slightly increased DOX and PLD delivery in the edge and middle zones of tumor spheroids. Thus, OME and LANSO are promising transport modulators of weakly basic drugs.

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Section: Discussionmentioning

confidence: 99%

<p>Proton Pump Inhibitors Modulate Transport Of Doxorubicin And Its Liposomal Form Into 2D And 3D Breast Cancer Cell Cultures</p>

Paškevičiūtė¹,

Petrikaitė²

2019

CMAR

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“…The significant range of each independent variable was established by performing initial screening, which was presented in table 2. Results (table 4) indicate BBD was found as a suitable statistical design for the development work in a limited number of experimental runs [3,26]. The model suggested 17 experimental runs with five centre points (table 3).…”

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…As directed, the combinations were used to prepare an optimized formulation. The values obtained from predicted and experimental formulations were compared and the error percentages were evaluated [26]. Chemical integrity between PLGA, drug and other excipient (PVA) of the NPs was determined by identifying specific bond vibration of each ingredient using FTIR spectroscopy (model: Nicolet iS10, Thermo Fisher Scientific, USA).…”

Section: Optimization and Validation Of The Designmentioning

confidence: 99%

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Application of statistical design to evaluate critical process parameters and optimize formulation technique of polymeric nanoparticles

2019

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In advanced medication, drug-loaded polymeric nanoparticles (NPs) appeared as a novel drug delivery system with lots of advantages over conventional medicines. Despite all the advantages, NPs do not gain popularity for manufacturing hurdles. The study focused on the formulation difficulties and implementation of statistical design to establish an effective model for manufacturing NPs. In this study, physico-chemical properties of the drug and polymer (PLGA) were incorporated to understand the mechanistic insights of nanoformulations. Primarily, the process controlling parameters were screened by Plackett–Burman design and the critical process parameters (Cpp) were further fabricated by Box–Behnken design (BBD). The TLM-PLGA-NPs (telmisartan loaded PLGA NPs) exhibited particle size, encapsulation efficiency and zeta potential of 232.4 nm, 79.21% and −9.92 mV respectively. The NPs represented drug loading of 76.31%. Korsmeyer–Peppas model ( R 2 = 0.925) appeared to be the best fitted model for in vitro release kinetics of NPs. The model identified Fickian diffusion of TLM from the polymeric nanoparticles. The ANOVA results of variables indicate that BBD is a suitable model for the development of polymeric NPs. The study successfully identified and evaluated the correlation of significant parameters that were directly or indirectly influencing the formulations which deliberately produce desired nanoparticles with the help of statistical design.

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“…Structure-activity relationship studies provided the pharmacophoric model of PTX which consists of the taxane ring, the C-13 side chain and the benzoyl residue at C-2 [16,18]. Its bulky chemical structure, low aqueous solubility (<0.01 mg/mL) and, consequently, high lipophilicity (logP ⁓4) make its delivery a challenge [19]. Indeed, the absence of ionizable functional groups represents a serious drawback in this respect because modulation of the pH may promote the solubility of the drug in polar media, as has been true for other compounds such as doxorubicin [20][21][22] and vancomycin [23].…”

Section: Introduction 1paclitaxel In Anti-cancer Therapymentioning

confidence: 99%

Recent Advances of Taxol-Loaded Biocompatible Nanocarriers Embedded in Natural Polymer-Based Hydrogels

Voci

Gagliardi

Molinaro

et al. 2021

Gels

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The discovery of paclitaxel (PTX) has been a milestone in anti-cancer therapy and has promoted the development and marketing of various formulations that have revolutionized the therapeutic approach towards several malignancies. Despite its peculiar anti-cancer activity, the physico-chemical properties of PTX compromise the administration of the compound in polar media. Because of this, since the development of the first Food and Drug Administration (FDA)-approved formulation (Taxol®), consistent efforts have been made to obtain suitable delivery systems able to preserve/increase PTX efficacy and to overcome the side effects correlated to the presence of some excipients. The exploitation of natural polymers as potential materials for drug delivery purposes has favored the modulation of the bioavailability and the pharmacokinetic profiles of the drug, and in this regard, several formulations have been developed that allow the controlled release of the active compound. In this mini-review, the recent advances concerning the design and applications of natural polymer-based hydrogels containing PTX-loaded biocompatible nanocarriers are discussed. The technological features of these formulations as well as the therapeutic outcome achieved following their administration will be described, demonstrating their potential role as innovative systems to be used in anti-tumor therapy.

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A chemotherapeutic approach targeting the acidic tumor microenvironment: combination of a proton pump inhibitor and paclitaxel for statistically optimized nanotherapeutics

Abstract: Development of statistically optimized, paclitaxel–lansoprazole, dual drug loaded PLGA nanoparticles as a promising tumor acidic microenvironment targeted chemotherapeutic approach.

Cited by 14 publications

References 63 publications

<p>Proton Pump Inhibitors Modulate Transport Of Doxorubicin And Its Liposomal Form Into 2D And 3D Breast Cancer Cell Cultures</p>

<p>Proton Pump Inhibitors Modulate Transport Of Doxorubicin And Its Liposomal Form Into 2D And 3D Breast Cancer Cell Cultures</p>

Application of statistical design to evaluate critical process parameters and optimize formulation technique of polymeric nanoparticles

Recent Advances of Taxol-Loaded Biocompatible Nanocarriers Embedded in Natural Polymer-Based Hydrogels

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