Elsevier

Journal of Controlled Release

Volume 297, 10 March 2019, Pages 39-47
Journal of Controlled Release

Pharmacokinetics and pharmacodynamics of liposomal chemophototherapy with short drug-light intervals

https://doi.org/10.1016/j.jconrel.2019.01.030Get rights and content

Abstract

Chemophototherapy (CPT) merges photodynamic therapy with chemotherapy and can substantially enhance drug delivery. Using a singular liposomal formulation for CPT, we describe a semi-mechanistic pharmacokinetic-pharmacodynamic (PK/PD) model to investigate observed antitumor effects. Long-circulating, sterically-stabilized liposomes loaded with doxorubicin (Dox) stably incorporate small amounts of a porphyrin-phospholipid (PoP) photosensitizer in the bilayer. These were administered intravenously to mice bearing low-passage, patient-derived pancreatic cancer xenografts (PDX). Dox PK was described with a two-compartment model and tumor drug disposition kinetics were modeled with first-order influx and efflux rates. Tumor irradiation with 665 nm laser light (200 J/cm2) 1 h after liposome administration increased tumor vascular permeabilization and drug accumulation, which was accounted for in the PK/PD model with increased tumor influx and efflux rates by approximately 12- and 4- fold, respectively. This modeling approach provided an overall 7-fold increase in Dox area under the curve in the tumor, matching experimental data (7.4-fold). A signal transduction model based on nonlinear direct cell killing accounted for observed tumor growth patterns. This PK/PD model adequately describes the CPT anti-PDX tumor response based on enhanced drug delivery at the short drug-light interval used.

Introduction

Late-stage pancreatic cancer is typically a lethal disease with poor treatment options [1,2]. Insufficient drug delivery to tumor sites is often a major contributing factor for the poor survival. Pancreatic ductal adenocarcinoma (PDAC) is characterized by low vascular density, perfusion, and permeability as well as amplification of tumor associated stromal tissue (desmoplasia), which together prevent sufficient delivery of chemotherapeutics [3]. Enzymatic degradation of hyaluronan, a major component of stroma, is a promising approach for enhancing drug delivery in PDAC [4] and approaches that reduce hyaluronan density have been shown to enhance liposomal delivery to tumor models [5,6]. Depletion of tumor stromal tissue by inhibition of sonic hedgehog cellular signaling pathway can increase tumor microvessel density and perfusion and enhance delivery of chemotherapeutics and nanotherapeutics [7,8].

Long circulating liposomal chemotherapy can be an effective tumor treatment compared to the free drug [9]. Liposomal irinotecan has recently been approved as a second-line treatment in late-stage pancreatic cancer after favorable phase III trials results in which it was combined with fluorouracil and folinic acid [10,11]. Prior clinical studies in pancreatic cancer with long-circulating liposomal doxorubicin (DOXIL) did not show objective responses when used as a monotherapy [12]. To improve outcomes, numerous approaches have aimed to improve liposomal drug delivery including targeting [13,14], microenvironment-triggered drug release [15], and external stimuli-enhanced delivery [16].

Chemophototherapy (CPT) incorporates two cancer therapy modalities: chemotherapy and phototherapy [17]. Photodynamic therapy has been approved to treat several tumor types [18]. When photosensitizers are circulating in the blood, photodynamic therapy (PDT) is able to permeabilize tumor vasculature and enhance delivery of nanotherapeutics, likely by damaging tumor endothelial cells and augmenting endothelial intercellular gaps [[19], [20], [21]]. By stably incorporating a small amount of porphyrin-phospholipid (PoP) into the bilayer of liposomes, we developed photoactivatable doxorubicin (Dox) encapsulated in PoP liposomes that can be triggered by near infrared light (NIR) and deliver actively-loaded [[22], [23], [24]] or passively-loaded [25] drugs into irradiated tumors. We previously established a long-circulating formulation of Dox in PoP liposomes (termed LC-Dox-PoP) that includes 2 mol% PoP in a DOXIL-like liposome formulation [26]. This work uses the same LC-Dox-PoP formulation. As light has limited tissue penetration, our proposed treatment with LC-Dox-PoP liposomes with laser treatment could be carried out relatively non-invasively using optical fibers that are inserted into large or deep tumors.

Several nanoparticle- and host-related factors impact liposome pharmacokinetics and pharmacodynamics (PK/PD) [27]. PK/PD models of sterically-stabilized Dox liposomes have been reported previously [28], and heat-triggered liposomal Dox release from thermosensitive liposomes has been modeled [29]. However, tumor PK and PK/PD modeling of LC-Dox-PoP liposomes, or other single-agent CPT systems, have not been explored yet.

We assessed LC-Dox-PoP liposomes in a patient-derived xenograft (PDX) PDAC model heterozygous for the G12D KRAS mutation (Fig. S1) and that recapitulates the tumor drug delivery barriers in pancreatic cancer. PDX models are valuable tools for assessing cancer therapeutics [30]. We develop a semi-mechanistic PK/PD model for quantitative analysis of observed PDT-induced vascular permeabilization and the resulting improvement in anti-tumor efficacy.

Section snippets

Liposome preparation

1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC; # LP-R4–076), cholesterol (CHOL; # CH-0355), 1,2-Distearoyl-phosphatidylethanolamine-methyl-polyethyleneglycol conjugate-2000 (PEG-lipid; # LP-R4–039) were ordered from Corden Pharma. NVP-LDE225 (Sonidegib) was from Chemietek. The porphyrin-phospholipid (PoP) used was sn-1-palmitoyl, sn-2-pyropheophorbide phosphatidylcholine and was synthesized as previously reported [22]. PoP liposomes [DSPC:PoP:CHOL:PEG-lipid; 53:2:40:5 mol%] were prepared by

Enhanced Dox uptake via LC-Dox-PoP liposome chemophototherapy

Laser treatment induced drastic enhancement in Dox deposition. Thirty minutes following laser treatment, there was ~5 fold greater Dox deposition in irradiated tumors compared to non-irradiated ones. Twenty-four hr post laser treatment, the drug concentration in the laser-irradiated tumors was nearly 10 fold greater than non-irradiated tumors (Fig. 1A). Dox deposition in key organs was quantified, and the quantity of Dox was high in the spleen and liver, reflecting the removal of circulating

Discussion and conclusions

Pancreatic cancer is characterized by desmoplasia and poor vascularization, which constitute a drug delivery barrier that limits the efficacy of chemotherapy. Therefore, strategies to compromise the drug delivery barrier warrant investigation. The hypovascular PDX tumor model provides an interesting framework to investigate CPT with long-circulating LC-Dox-PoP liposomes. CPT induced a striking increase in Dox accumulation in laser-treated tumors. One caveat of the PDX model is that it

Acknowledgements

This work was supported by the National Institutes of Health (R01EB017270, DP5OD017898, R01CA198096, and R01GM024211), the National Science Foundation (1555220), and utilized Roswell Park Cancer Inst. core facilities supported by NIH/NCIP30CA016056. This research was supported in part by a Graduate Student Fellowship Award for DL from the American Association of Pharmaceutical Scientists Foundation. We acknowledge for the assistance of Dr. Prashant K. Singh for assistance in tumor DNA

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