Intracellular PK/PD Relationships of Free and Liposomal Doxorubicin: Quantitative Analyses and PK/PD Modeling

Soininen, Suvi K.; Vellonen, Kati‐Sisko; Heikkinen, Aki T.; Auriola, Seppo; Ranta, Veli‐Pekka; Urtti, Arto; Ruponen, Marika

doi:10.1021/acs.molpharmaceut.6b00008

Cited by 29 publications

(14 citation statements)

References 55 publications

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“…Other studies too have used secondary read out effects such as anti-proliferative effects of cancer drugs [67] or changes in the protein expression after siRNA delivery [68] as validation of cargo delivery. In our present study, we demonstrate accurate quantification of intracellular cargo release using LC-MS, like we did previously for liposomes in the cancer cells [69]. To the best of our knowledge, this is the first report that directly quantitates cargo release from conjugated peptide linkers in the intracellular and extracellular space.…”

Section: Accepted Manuscriptsupporting

confidence: 77%

Differentially cleaving peptides as a strategy for controlled drug release in human retinal pigment epithelial cells

Bhattacharya

Sarkhel

Peltoniemi

et al. 2017

Journal of Controlled Release

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Currently, drug delivery to the posterior eye segment relies on intravitreal injections of therapeutics. This approach requires frequent injections and does not guarantee drug delivery to intracellular targets. Controlled release systems and nanoparticles are being investigated to mitigate these challenges but most of these approaches lack translational success to the clinics. In our present study, we report a peptide-based delivery system that utilizes enzyme assisted cleavable linkers to release conjugated cargo within the retinal pigment epithelial (RPE) cells. Peptide linkers with differential cleavage rates were developed and tested in the vitreous humor, RPE cell homogenates and intact RPE cells. Selected peptide linkers were conjugated to cell penetrating peptides and d-peptide cargoes. The peptide-based delivery systems were non-toxic to the RPE cells, chemically stable in porcine vitreous and delivered cargo prototypes (hydrophobic & hydrophilic) to the RPE cells. Importantly, we show quantitatively with LC/MS analytics that the intracellular cargo release is controlled by the sequence of the peptide linker. The controlled cleavage of the peptide linkers is not only a useful strategy for intracellular drug delivery to the RPE targets but might also be useful in utilizing the RPE cells as mediators of drug delivery to intracellular targets and surrounding tissues (such as neural retina and choroid).

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Section: Accepted Manuscriptsupporting

confidence: 77%

Differentially cleaving peptides as a strategy for controlled drug release in human retinal pigment epithelial cells

Bhattacharya

Sarkhel

Peltoniemi

et al. 2017

Journal of Controlled Release

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“…More interestingly, Exo-Dox uptake is much faster and more efficient compared to liposomal formulations. The slow cellular uptake of pegylated liposomal doxorubicin (Doxil) can be explained by the surface presence of PEG, a modification that was specifically introduced to prevent unspecific cellular uptake, to allow longer circulation times and preferential uptake into tumour cells due to the EPR effect [39]. Also non-pegylated liposomal doxorubicin (Myocet) uptake is less efficient than the free drug which is most likely due to the limited interactions that occur between the integral lipids of the liposome and the cell membrane.…”

Section: Discusssionmentioning

confidence: 99%

Exosomal delivery of doxorubicin enables rapid cell entry and enhanced in vitro potency

Schindler¹,

Collinson²,

Matthews³

et al. 2019

PLoS ONE

143

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Doxorubicin is a chemotherapeutic agent that is commonly used to treat a broad range of cancers. However, significant cardiotoxicity, associated with prolonged exposure to doxorubicin, limits its continued therapeutic use. One strategy to prevent the uptake of doxorubicin into cardiac cells is the encapsulation of the drug to prevent non-specific uptake and also to improve the drugs’ pharmacokinetic properties. Although encapsulated forms of doxorubicin limit the cardiotoxicity observed, they are not without their own liabilities as an increased amount of drug is deposited in the skin where liposomal doxorubicin can cause palmar-plantar erythrodysesthesia. Exosomes are small endogenous extracellular vesicles, that transfer bioactive material from one cell to another, and are considered attractive drug delivery vehicles due to their natural origin. In this study, we generated doxorubicin-loaded exosomes and demonstrate their rapid cellular uptake and re-distribution of doxorubicin from endosomes to the cytoplasm and nucleus resulting in enhanced potency in a number of cultured and primary cell lines when compared to free doxorubicin and liposomal formulations of doxorubicin. In contrast to other delivery methods for doxorubicin, exosomes do not accumulate in the heart, thereby providing potential for limiting the cardiac side effects and improved therapeutic index.

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“…In an attempt to improve the therapeutic efficacy of CURC, a combinatory anti-cancer therapy approach is proposed here by using low doses of DOX (in free form) and s form of CURC. The rationale for using free DOX here was that the free drug can enter the cell very quickly by passive diffusion (Soininen et al, 2016) which then facilitates entry of CURC NCs that is otherwise only effective at high doses. This combination therapy approach may offer some advantages over other nanoformulations co-encapsulating both drugs in the same carrier.…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin enhances curcumin’s cytotoxicity in human prostate cancer cells in vitro by enhancing its cellular uptake

Klippstein

Bansal

Al‐Jamal

2016

International Journal of Pharmaceutics

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Doxorubicin (DOX) is a widely used drug in cancer treatment. Despite its popularity, it suffers from systemic side effects and susceptibility to drug resistance. Curcumin (CURC), on the other hand, is a drug that recently gained popularity due to its wide range of biological activities, including anti-inflammatory and anti-cancer activities. Limitations to its clinical translation include its poor water solubility and the need for administration of high doses. Combinatory anti-cancer therapy has been proposed as a common approach to overcome one or more of these challenges. In this work, we propose a combinatory DOX and CURC anti-cancer therapy of prostate cancer cells in vitro. DOX and CURC were administered in the free drug and nanocapsule form, respectively. Cell size and complexity, cytotoxicity and apoptosis were studied by flow cytometry, MTT assay and sub-G1 quantification, respectively. Cellular uptake of CURC nanocapsules (CURC NCs) was quantified by fluorescence microscopy and high-performance liquid chromatography fluorescence detection. Results showed that in vitro treatment with CURC NCs in the presence of subtherapeutic concentrations of DOX, led to significant increase in prostate cancer cells (PC3) apoptosis and death. This was likely due to significantly enhanced CURC uptake by the cells. The study presents a good rationale for pursuing combinatory CURC/DOX therapy in pre-clinical tumor animal models in the near future.

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Intracellular PK/PD Relationships of Free and Liposomal Doxorubicin: Quantitative Analyses and PK/PD Modeling

Cited by 29 publications

References 55 publications

Differentially cleaving peptides as a strategy for controlled drug release in human retinal pigment epithelial cells

Differentially cleaving peptides as a strategy for controlled drug release in human retinal pigment epithelial cells

Exosomal delivery of doxorubicin enables rapid cell entry and enhanced in vitro potency

Doxorubicin enhances curcumin’s cytotoxicity in human prostate cancer cells in vitro by enhancing its cellular uptake

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