Accumulation of doxorubicin and other lipophilic amines into large unilamellar vesicles in response to transmembrane pH gradients

Harrigan, P.R.; Wong, Kenneth; Redelmeier, Thomas E.; Wheeler, Jeffery J.; Cullis, Pieter R.

doi:10.1016/0005-2736(93)90218-o

Cited by 164 publications

(103 citation statements)

References 21 publications

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“…For example, 66.5% and 29.9% were the percentages of the drug released after 8 h from batches 1 and 5, which were prepared with 5% and 15% (w/w) stearylamine in the lipid pool, respectively. Previous studies have suggested that drug encapsulation and release properties can be explained entirely on the basis of the permeation of the neutral form of the drug (33). If this was also the case with tenofovir, then the presence of a cationic lipid in the membrane would not be expected to affect drug release, since there should be negligible effect of a surface charge on neutral drugs (34).…”

Section: Release Studymentioning

confidence: 99%

Near-Infrared Investigations of Novel Anti-HIV Tenofovir Liposomes

Zidan

Spinks

Fortunak

et al. 2010

AAPS J

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Abstract. Near-infrared (NIR) approaches is considered one of the most well-studied process analyzers evolving from the process analytical technology initiatives. The objective of this study was to evaluate NIR spectroscopy and imaging to assess individual components within a novel tenofovir liposomal formulation. By varying stearylamine, as a positive charge imparting agent, five batches were prepared by the thin film method. Each formulation was characterized in terms of drug entrapment efficiency, release characteristics, particle sizing, and zeta potential. Drug excipients compatibility was tested using Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. The obtained results showed an increase in drug entrapment and a slower drug release by increasing the incorporated percentage of stearylamine. The compatibility testing revealed a significant interaction between the drug and some of the investigated excipients. The developed NIR calibration model was able to assess drug, phospholipid, and stearylamine levels along the batches. The calibration and prediction plots were linear with correlation coefficients of more than 0.9. The root square standard errors of calibration and prediction did not attain 5% of the measured values confirming the accuracy of the model. In contrast, NIR spectral imaging was capable of clearly distinguishing the different batches, both qualitatively and quantitatively. A linear relationship was obtained correlating the actual drug entrapped and the predicted values obtained from the partial least squares images.

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Section: Release Studymentioning

confidence: 99%

Near-Infrared Investigations of Novel Anti-HIV Tenofovir Liposomes

Zidan

Spinks

Fortunak

et al. 2010

AAPS J

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“…Furthermore, lipophilic amino-containing drugs can be partitioned into the lipid bilayer, resulting in a drug gradient through the lipid bilayer that aids the influx of the drug from the outside to the inside. 32) In the present study, we loaded the PtCQ complex into neutral liposomes using a pH gradient and the trans-membrane potential generated by an ammonium sulfate gradient as driving forces. Following hydration of the PtCQ-loaded liposomes using an ammonium sulfate solution, an equal concentration of ammonium sulfate is found outside and inside the liposomes.…”

Section: Fig 4 Effect Of Increasing the Liposomal Content On The Eementioning

confidence: 99%

Effective-Loading of Platinum–Chloroquine into PEGylated Neutral and Cationic Liposomes as a Drug Delivery System for Resistant Malaria Parasites

Ibrahim

Tagami

Ozeki

2017

Biological & Pharmaceutical Bulletin

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The trans platinum-chloroquine diphosphate dichloride (PtCQ) is a new type of antimalarial drug used to fight parasites resistant to traditional drugs. PtCQ is synthesized by mixing platinum and chloroquine diphosphate (CQ). This study examines two efficient methods for forming a nanodrug, PtCQ-loaded liposomes, for use as a potential antimalarial drug-delivery system: the thin drug-lipid film method to incorporate the drug into a liposomal membrane, and a remote-loading method to load the drug into the interior of a cationic liposome. The membranes accordingly comprised PEGylated neutral or cationic liposomes. PtCQ was efficiently loaded into PEGylated neutral and cationic liposomes using the thin drug-lipid film method (encapsulation efficiency, EE: 76.1 6.7% for neutral liposomes, 1 : 14 drug-to-lipid weight ratio; 70.4 9.8% for cationic liposomes, 1 : 14 drug-to-lipid weight ratio). More PtCQ was loaded into PEGylated neutral liposomes using the remote-loading method than by the thin drug-lipid film method and the EE was maximum (96.1 4.5% for neutral liposomes, 1 : 7 (w/w)). PtCQ was encapsulated in PEGylated cationic liposomes comprising various amounts of cationic lipids (0-20 mol%; EE: 96.9-92.3%) using the remote-loading method. PEGylated neutral liposomes and cationic liposomes exhibited minimum leakage of PtCQ after two months' storage at 4°C, and further exhibited little release under in vitro culture conditions at 37°C for 72 h. These results provide a useful framework for the design of future liposome-based in vivo drug delivery systems targeting the malaria parasite.

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“…[6][7][8][9][10] The effectiveness of this formulation approach is dependent on the rate of drug release from the liposomes. Liposomes that rapidly release their contents in vivo will not improve delivery of drugs to target sites 2); for therapeutic value, it is important that drugs are retained in liposomes in vivo for an appropriate time.11,12) Weakly basic drugs can be actively concentrated inside liposomes using a transmembrane pH gradient [13][14][15] or an ammonium sulfate gradient.16) However, the retention of drugs in liposomes is drug-dependent and can vary dramatically. For example, the anticancer drugs doxorubicin and epirubicin are well retained inside liposomes, [17][18][19] whereas the anticancer drug vincristine and the antibiotic ciprofloxacin tend to leak out rapidly.…”

mentioning

confidence: 99%

“…11,12) Weakly basic drugs can be actively concentrated inside liposomes using a transmembrane pH gradient [13][14][15] or an ammonium sulfate gradient.…”

mentioning

confidence: 99%

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Release of Drugs from Liposomes Varies with Particle Size

Yamauchi

Tsutsumi

Abe

et al. 2007

Biological & Pharmaceutical Bulletin

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Administration of liposomes loaded with active drugs can result in enhanced therapeutic activity 1,2) and reduced toxic side effects. [3][4][5] For example, liposomes are widely used to improve the delivery of many anticancer, antibiotic and antifungal drugs, such as doxorubicin, epirubicin, vincristine and ciprofloxacin. [6][7][8][9][10] The effectiveness of this formulation approach is dependent on the rate of drug release from the liposomes. Liposomes that rapidly release their contents in vivo will not improve delivery of drugs to target sites 2); for therapeutic value, it is important that drugs are retained in liposomes in vivo for an appropriate time.11,12) Weakly basic drugs can be actively concentrated inside liposomes using a transmembrane pH gradient [13][14][15] or an ammonium sulfate gradient.16) However, the retention of drugs in liposomes is drug-dependent and can vary dramatically. For example, the anticancer drugs doxorubicin and epirubicin are well retained inside liposomes, [17][18][19] whereas the anticancer drug vincristine and the antibiotic ciprofloxacin tend to leak out rapidly. 14,19,20) In order to obtain homogenous preparations, liposomes are often extruded through polycarbonate filters of 0.4, 0.2 and 0.1 mm pore size. A high proportion of liposomes that are passed through 0.2 mm filters remain as multilamellar vesicles. On the other hand, extrusion of liposomes through 0.1 mm filters produces mainly unilamellar vesicles.21) Zhang et al. 22) reported that the release of the amphiphilic drug 5-carboxyfluorescein (CF) was greater from unilamellar liposomes than from multilamellar liposomes of similar particle size. The curvature of small unilamellar vesicles (SUVs) is greater, and packing between lipids in the membranes is looser, compared with large unilamellar vesicles. For this reason, SUVs are believed to release drugs more readily. 23,24) The aim of the present study was to identify the causes of the rapid release of drugs, such as vincristine, from liposomes and then to apply this knowledge to the development of more stable formulations. Initially, we investigated the effect of particle size on the leakage of drugs from liposomes incubated in fetal bovine serum (FBS); for these studies, doxorubicin and vincristine were used as examples of wellretained and readily released drugs, respectively. MATERIALS AND METHODS MaterialsEgg yolk phosphatidylcholine (EPC) was purchased from Nippon oil and fat (Tokyo, Japan). Vincristine and doxorubicin were acquired from Sigma-Aldrich (St. Louis, MO, U.S.A.) and Kyowa Hakko (Tokyo, Japan), respectively. FBS was obtained from GIBCO BRL (Grand Island, NY, U.S.A.). Nuclepore polycarbonate filters and Sepharose CL-6B were purchased from Corning (Acton, MA, U.S.A.) and Amersham Pharmacia Biotech (Uppsala, Sweden), respectively. All other chemicals were of analytical grade quality.Preparation of Liposomes EPC liposomes were formed by hydrating the lipid with the following buffers: (i) 100 mmol/l citric acid (pH 4.0), (ii) 10 mmol/l Tris-HCl (pH 7.3...

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Accumulation of doxorubicin and other lipophilic amines into large unilamellar vesicles in response to transmembrane pH gradients

Cited by 164 publications

References 21 publications

Near-Infrared Investigations of Novel Anti-HIV Tenofovir Liposomes

Near-Infrared Investigations of Novel Anti-HIV Tenofovir Liposomes

Effective-Loading of Platinum–Chloroquine into PEGylated Neutral and Cationic Liposomes as a Drug Delivery System for Resistant Malaria Parasites

Release of Drugs from Liposomes Varies with Particle Size

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