Novel formulation approaches for optimising delivery of anticancer drugs based on P-glycoprotein modulation

Bansal, Tripta; Akhtar, Naseem; Jaggi, Manu; Khar, Roop K.; Talegaonkar, Sushama

doi:10.1016/j.drudis.2009.07.010

Cited by 147 publications

(72 citation statements)

References 61 publications

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“…There is high inherent toxicity of PGP inhibitors and altered pharmacokinetics and biodistribution of anticancer drugs when coadministered with PGP inhibitors (4,7). Not until recently a number of nanoparticle-based drug delivery systems such as polymer-drug conjugates, polymeric-micelles, and liposomes have been developed to overcome MDR (8).…”

Section: Introductionmentioning

confidence: 99%

“…It is estimated that approximately 500,000 new cases of cancer each year will soon eventually exhibit multidrug resistant phenotype (1). MDR is a complex phenomenon that can result from numerous mechanisms, including overexpressed ATP-dependent efflux pumps, which can diminish intracellular drug concentrations [such as Pglycoprotein (PGP) and multidrug-resistance-associated protein (MRP)], altered activity of specific enzyme systems which can diminish the chemosensitivity of the drug resistant cells (such as glutathione-S-transferase and topoisomerase), altered apoptosis regulation via loss of genes (such as p53) demanded for cell death or overexpression of genes (such as bcl-2) that block cell death, reduced drug uptake via alteration of folate carriers, and increased DNA repair capacity (2)(3)(4). Among these mechanisms, alteration of cell membrane transport (mediated by PGP) is the best clinically studied phenomenon (1).…”

Section: Introductionmentioning

confidence: 99%

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Enhanced Chemotherapy of Cancer Using pH-Sensitive Mesoporous Silica Nanoparticles to Antagonize P-Glycoprotein–Mediated Drug Resistance

Huang

Sun

Cheng

et al. 2011

Molecular Cancer Therapeutics

105

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Multidrug resistance (MDR) is the major clinical obstacle in the management of cancer by chemotherapy. Overexpression of ATP-dependent efflux transporter P-glycoprotein (PGP) is a key factor contributing to multidrug resistance of cancer cells. The purpose of the present study was to use the endosomal pH-sensitive MSN (mesoporous silica nanoparticles; MSN-Hydrazone-Dox) for controlled release of doxorubicin (Dox) in an attempt to overcome the PGP-mediated MDR. In vitro cell culture studies indicate that uptake of MSNHydrazone-Dox by the human uterine sarcoma MES-SA/Dox-resistant tumor (MES-SA/Dx-5) cell occurs through endocytosis, thus bypassing the efflux pump resistance. This improves the efficacy of the drug and leads to significant cytotoxicity and DNA fragmentation evidenced by terminal deoxynucleotidyl transferasemediated dUTP nick end labeling and DNA laddering assays. In vivo studies show that the intratumor injection of MSN-Hydrazone-Dox induces significant apoptosis of MES-SA/Dox-resistant cancer cells. This is validated by active caspase-3 immunohistochemical analysis. However, MSN-Hydrazone, without doxorubicin conjugation, cannot induce apoptosis in vitro and in vivo. In conclusion, both in vitro and in vivo studies show that MSN could serve as an efficient nanocarrier entering cell avidly via endocytosis, thus bypassing the PGP efflux pump to compromise the PGP-mediated MDR. MSN-Hydrazone-Dox could further respond to endosomal acidic pH to release doxorubicin in a sustained manner. Besides the cell study, this is the first report that successfully shows the therapeutic efficacy of using MSN against MDR cancer in vivo. Mol Cancer Ther; 10(5); 761-9. Ó2011 AACR.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhanced Chemotherapy of Cancer Using pH-Sensitive Mesoporous Silica Nanoparticles to Antagonize P-Glycoprotein–Mediated Drug Resistance

Huang

Sun

Cheng

et al. 2011

Molecular Cancer Therapeutics

105

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“…On the other hand, it has been described that Pluronics and other non-ionic surfactants inhibit the activity of intestinal Pgp (Batrakova et al, 1998a;1998b). This fact has been explained by a combination of decreased ATPase activity and ATP depletion due to increased membrane fluidity (Batrakova et al, 2004;Bansal et al, 2009). Nonetheless, studies performed on various cell models have shown that polymeric micelles could be internalized, with fluid-phase pinocytosis appearing as a major route (Allen et al, 1999;Luo et al, 2002 (Mathot et al, 2007).…”

Section: Pharmacokinetic Study Of Paclitaxel When Loaded In Stabilizementioning

confidence: 99%

Stabilized micelles as delivery vehicles for paclitaxel

Yoncheva

Calleja

Agüeros

et al. 2012

International Journal of Pharmaceutics

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Paclitaxel is an antineoplastic drug used against a variety of tumors, but its low aqueous solubility and active removal caused by P-glycoprotein in the intestinal cells hinder its oral administration. In our study, new type of stabilized Pluronic micelles were developed and evaluated as carriers for paclitaxel delivery via oral or intravenous route. The pre-stabilized micelles were loaded with paclitaxel by simple solvent/evaporation technique achieving high

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“…The use of 30% of propylene glycol in the present study showed much greater exposure than the reported value, which could be due to increasing the permeability in GI tract. Surfactants like sodium lauryl sulphate, Tween 80 and Cremophor EL were used at ≥10% and were reported to inhibit P-gp and SLS by increasing the fluidity of intestinal membrane resulting in increase in the plasma exposure [20] . Cremophor EL was also reported to increase the permeability by disrupting the intestinal barrier [21] .…”

Section: Table 3: Pharmacokinetic Parameters Of Paromomycin After IV mentioning

confidence: 99%

Investigation of Different Formulation Approaches to Enhance Oral Bioavailability of Paromomycin

Pinjari¹,

Somani²,

Gilhotra³

2017

pharmaceutical-sciences

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Pinjari, et al.: Different Formulation Approach for ParomomycinParomomycin, an aminoglycoside antibiotic, is used to treat visceral leishmaniasis as an intramuscular injection daily for 21 days since it has limited oral bioavailability. The objective of this investigation is to improve the oral bioavailability through formulation development for increased patient compliance and convenience. Comparative pharmacokinetic studies of intravenous and oral administration of paromomycin in mice to evaluate different formulation approaches to increase oral bioavailability were carried out. Following intravenous injection of 15 mg/kg to mice, paromomycin exhibited low plasma clearance (8 ml/min/kg) with elimination half-life of 2.6 h. Following oral administration of 500 mg/kg of a suspension formulation using carboxymethylcellulose to mice, referred to as formulation 1, paromomycin showed very low or negligible oral bioavailability (%F=0.3). Different formulation approaches were made by employing a variety of FDA-approved novel excipients belonging to glycols, fatty acids, alcohols and surfactants alone and in various combinations. In vivo pharmacokinetic studies with these formulations demonstrated improved oral bioavailability of paromomycin in mice. Formulation approaches tested in the present research project were successful in improving the oral bioavailability of paromomycin from 0.3% to a maximum of 9%. Overall, the increase in paromomycin bioavailability ranged 1-30 fold with different formulations compared to carboxymethylcellulose formulation. Formulation with 10% Gelucire 44/14, 10% Solutol HS 15, 30% propylene glycol and 50% normal saline showed higher bioavailability compared to formulation 1. This research provided evidence that improved bioavailability of paromomycin can be achieved through formulation development, which eventually could result in making the most tedious and painful intramuscular therapy redundant.

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Novel formulation approaches for optimising delivery of anticancer drugs based on P-glycoprotein modulation

Cited by 147 publications

References 61 publications

Enhanced Chemotherapy of Cancer Using pH-Sensitive Mesoporous Silica Nanoparticles to Antagonize P-Glycoprotein–Mediated Drug Resistance

Enhanced Chemotherapy of Cancer Using pH-Sensitive Mesoporous Silica Nanoparticles to Antagonize P-Glycoprotein–Mediated Drug Resistance

Stabilized micelles as delivery vehicles for paclitaxel

Investigation of Different Formulation Approaches to Enhance Oral Bioavailability of Paromomycin

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