Investigation of particle accumulation, chemosensitivity and thermosensitivity for effective solid tumor therapy using thermosensitive liposomes and hyperthermia

Doxorubicin (Dox) loaded thermosensitive liposomes (TSLs) have shown promising results for hyperthermia-induced local drug delivery to solid tumors. Typically, the tumor is heated to hyperthermic temperatures (41-42 °C), which induced intravascular drug release from TSLs within the tumor tissue leading to high local drug concentrations (1-step delivery protocol). Next to providing a trigger for drug release, hyperthermia (HT) has been shown to be cytotoxic to tumor tissue, to enhance chemosensitivity and to increase particle extravasation from the vasculature into the tumor interstitial space. The latter can be exploited for a 2-step delivery protocol, where HT is applied prior to i.v. TSL injection to enhance tumor uptake, and after 4 hours waiting time for a second time to induce drug release. In this study, we compare the 1- and 2-step delivery protocols and investigate which factors are of importance for a therapeutic response. In murine B16 melanoma and BFS-1 sarcoma cell lines, HT induced an enhanced Dox uptake in 2D and 3D models, resulting in enhanced chemosensitivity. In vivo, therapeutic efficacy studies were performed for both tumor models, showing a therapeutic response for only the 1-step delivery protocol. SPECT/CT imaging allowed quantification of the liposomal accumulation in both tumor models at physiological temperatures and after a HT treatment. A simple two compartment model was used to derive respective rates for liposomal uptake, washout and retention, showing that the B16 model has a twofold higher liposomal uptake compared to the BFS-1 tumor. HT increases uptake and retention of liposomes in both tumors models by the same factor of 1.66 maintaining the absolute differences between the two models. Histology showed that HT induced apoptosis, blood vessel integrity and interstitial structures are important factors for TSL accumulation in the investigated tumor types. However, modeling data indicated that the intraliposomal Dox fraction did not reach therapeutic relevant concentrations in the tumor tissue in a 2-step delivery protocol due to the leaking of the drug from its liposomal carrier providing an explanation for the observed lack of efficacy

Hyperthermia-triggered drug delivery from temperature-sensitive liposomes using MRI-guided high intensity focused ultrasound

In the continuous search for cancer therapies with a higher therapeutic window, localized temperature-induced drug delivery may offer a minimal invasive treatment option. Here, a chemotherapeutic drug is encapsulated into a temperature-sensitive liposome (TSL) that is released at elevated temperatures, for example, when passing through a locally heated tumor. Consequently, high drug levels in the tumor tissue can be achieved, while reducing drug exposure to healthy tissue. Although the concept of temperature-triggered drug delivery was suggested more than thirty years ago, several chemical and technological challenges had to be addressed to advance this approach towards clinical translation. In particular, non-invasive focal heating of tissue in a controlled fashion remained a challenge. For the latter, high intensity focused ultrasound (HIFU) allows non-invasive heating to establish hyperthermia (40-45 degrees C) of tumor tissue over time. Magnetic resonance imaging (MRI) plays a pivotal role in this procedure thanks to its superb spatial resolution for soft tissue as well as the possibility to acquire 3D temperature information. Consequently, MRI systems emerged with an HIFU ultrasound transducer embedded in the patient bed (MR-HIFU), where the MRI is utilized for treatment planning, and to provide spatial and temperature feedback to the HIFU. For tumor treatment, the lesion is heated to 42 degrees C using HIFU. At this temperature, the drug-loaded TSLs release their payload in a quantitative fashion. The concept of temperature-triggered drug delivery has been extended to MR image-guided drug delivery by the co-encapsulation of a paramagnetic MRI contrast agent in the lumen of TSLs. This review will give an overview of recent developments in temperature-induced drug delivery using HIFU under MRI guidance

Novel lipidomimetic compounds and uses thereof

\u3cp\u3eDisclosed are lipidomimetic compounds of formula I (I) wherein: G represents a group satisfying formula II: HO-CH2-{CH(OH)-CH2-0}m-CH2-{C(=0)-0-CH2})q- formula II each n independently is an integer from 1-30; m is an integer from 1-10; q is 0 or 1. These compounds can be added to the lipid bilayer of thermosensitive liposomes, for the purpose of aiding in the prevention of leakage of the liposomes' contents at 37 DEG C., and retarding clearance from circulation.\u3c/p\u3

Novel lipidomimetic compounds and uses thereof

\u3cp\u3eDisclosed are lipidomimetic compounds of formula I (I) wherein: G represents a group satisfying formula II: HO-CH2-{CH(OH)-CH2-0}m-CH2-{C(=0)-0-CH2}q- formula II each n independently is an integer from 1-30; m is an integer from 1-10; q is 0 or 1. These compounds can be added to the lipid bilayer of thermosensitive liposomes, for the purpose of aiding in the prevention of leakage of the liposomes' contents at 37°C, and retarding clearance from circulation.\u3c/p\u3

Real-time imaging and kinetics measurements of focused ultrasound-induced extravasation in skeletal muscle using SPECT/CT

Drugs need to overcome several biological barriers such as the endothelium and cellular membranes in order to reach their target. Promising new therapeutics, many of which are charged and macromolecular, are not able to passively extravasate, let alone cross cell membranes, and stay mainly in the blood pool upon intravenous injection until clearance. Using focused ultrasound (fUS) in combination with circulating microbubbles (MBs) leads to temporary localized tissue permeabilization allowing extravasation of (macro) molecules from the vascular system. Thus, fUS is a promising approach for localized drug delivery. However, little is known about the permeabilization kinetics in skeletal muscle. In this study, we used single photon emission computed tomography (SPECT) to characterize the kinetics of extravasation of In-111-labeled bovine serum albumin (BSA), a model macromolecular drug, in muscle treated with fUS and MBs. The same fUS protocol was applied to 6 groups of mice with different times, Delta t, between fUS application and BSA injection (Delta t = -10, 2.5, 10, 30, 60, 90 min) followed by SPECT imaging. For Delta

Targeting the peritoneum with novel drug delivery systems in peritoneal carcinomatosis:a review of the literature

\u3cp\u3eThe Peritoneal cavity is a well-known metastatic site for several intra-abdominal malignancies, such as stomach, colon, pancreas and rectal cancer. For long, it was thought that treatment with curative intent was impossible but that was challenged by the introduction of cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC). Although their effectiveness has been proven both experimentally and clinically, there is need for improvement. Firstly, a significant proportion of patients develop recurrent disease. Secondly, HIPEC demands presence of dedicated perfusion devices not readily available in most hospitals. Since intraperitoneal administration of chemotherapy is thought to play a crucial role, new modalities to deliver effective chemotherapeutics to the peritoneum are developed. The current review aims to present an overview of the experimental data on new drug delivery systems (DDS) in peritoneal cancer.\u3c/p\u3

Temperature-sensitive liposomes for doxorubicin delivery under MRI guidance

Local drug delivery of doxorubicin holds promise to improve the therapeutic efficacy and to reduce toxicity profiles. Here, we investigated the release of doxorubicin and [Gd(HPDO3A)(H2O)] from different temperature-sensitive liposomes for applications in temperature-induced drug delivery under magnetic resonance image guidance. In particular, two temperature-sensitive systems composed of DPPC:MPPC:DPPE-PEG2000 (low temperature-sensitive liposomes, LTSL) and DPPC:HSPC:cholesterol:DPPE-PEG2000 (traditional temperature-sensitive liposomes, TTSL) were investigated. The co-encapsulation of [Gd(HPDO3A)(H2O)], a clinically approved MRI contrast agent, did not influence the encapsulation and release of doxorubicin. The LTSL system showed a higher leakage of doxorubicin at 37 °C, but a faster release of doxorubicin at 42 °C compared to the TTSL system. Furthermore, the rapid release of both doxorubicin and the MRI contrast agent from the liposomes occurred near the melting phase transition temperature, making it possible to image the release of doxorubicin using MRI

Paramagnetic liposomes for molecular MRI and MRI-guided drug delivery

Liposomes are a versatile class of nanoparticles with tunable properties, and multiple liposomal drug formulations have been clinically approved for cancer treatment. In recent years, an extensive library of gadolinium (Gd)-containing liposomal MRI contrast agents has been developed for molecular and cellular imaging of disease-specific markers and for image-guided drug delivery. This review discusses the advances in the development and novel applications of paramagnetic liposomes in molecular and cellular imaging, and in image-guided drug delivery. A high targeting specificity has been achieved in vitro using ligand-conjugated paramagnetic liposomes. On targeting of internalizing cell receptors, the effective longitudinal relaxivity r1 of paramagnetic liposomes is modulated by compartmentalization effects. This provides unique opportunities to monitor the biological fate of liposomes. In vivo contrast-enhanced MRI studies with nontargeted liposomes have shown the extravasation of liposomes in diseases associated with endothelial dysfunction, such as tumors and myocardial infarction. The in vivo use of targeted paramagnetic liposomes has facilitated the specific imaging of pathophysiological processes, such as angiogenesis and inflammation. Paramagnetic liposomes loaded with drugs have been utilized for therapeutic interventions. MR image-guided drug delivery using such liposomes allows the visualization and quantification of local drug delivery. Copyright (c) 2013 John Wiley & Sons, Ltd