Lipid-based nanosystems: the next generation of cancer immune therapy.

Immunotherapy has become an important part of the oncotherapy arsenal. Its applicability in various cancer types is impressive, as well as its use of endogenous mechanisms to achieve desired ends. However, off-target or on-target-off-tumor toxicity, limited activity, lack of control in combination treatments and, especially for solid tumors, low local accumulation, have collectively limited clinical use thereof.

Liposomal Drug Delivery Systems for Cancer Therapy: The Rotterdam Experience.

At the Nanomedicine Innovation Center (NICE) at the Erasmus MC in Rotterdam, we have approached the treatment of cancer by starting with a vision of first establishing a platform that enables us to overcome the low levels of drugs delivered to tumors and the issue of dose-limiting toxicity. Showing that a reduction of the volume of distribution, and a lowering of toxicity and side-effects, accompanied by augmented intratumoral drug delivery, could change outcomes in patients, paved the way to target, not only localized disease, but also systemic and metastasized cancers. In particular, the detailed studies with intravital microscopy we performed at NICE provided us with the necessary insights and affected to a large extent our program on liposome-based cancer therapy.

Temperature-sensitive polymers to promote heat-triggered drug release from liposomes: Towards bypassing EPR.

Heat-triggered drug release from temperature-sensitive nanocarriers upon the application of mild hyperthermia is a promising approach to achieve site-specific delivery of drugs. The combination of mild hyperthermia (41-42 °C) and temperature-sensitive liposomes (TSL) that undergo lipid phase-transition and drug release has been studied extensively and has shown promising therapeutic outcome in a variety of animal tumor models as well as initial indications of success in humans. Sensitization of liposomes to mild hyperthermia by means of exploiting the thermal behavior of temperature-sensitive polymers (TSP) provides novel opportunities.

An Updated Review on EPR-Based Solid Tumor Targeting Nanocarriers for Cancer Treatment.

The enhanced permeability and retention (EPR) effect in cancer treatment is one of the key mechanisms that enables drug accumulation at the tumor site. However, despite a plethora of virus/inorganic/organic-based nanocarriers designed to rely on the EPR effect to effectively target tumors, most have failed in the clinic. It seems that the non-compliance of research activities with clinical trials, goals unrelated to the EPR effect, and lack of awareness of the impact of solid tumor structure and interactions on the performance of drug nanocarriers have intensified this dissatisfaction.

Increased Targeting Area in Tumors by Dual-Ligand Modification of Liposomes with RGD and TAT Peptides.

Modification with polyethylene glycol (PEGylation) and the use of rigid phospholipids drastically improve the pharmacokinetics of chemotherapeutics and result in more manageable or reduced side-effects. A major drawback is retarded cellular delivery of content, which, along with tumor heterogeneity, are the two main obstacles against tumor targeting. To enhance cellular delivery and reach a bigger area of a tumor, we designed liposomes decorated with two ligands: one for targeting tumor vasculature via a cyclic-pentapeptide containing arginine-glycine-aspartic acid (RGD), which impacts tumor independent of passive accumulation inside tumors, and one for extravascular targeting of tumor cells via a cell-penetrating peptide derived from human immunodeficiency virus type 1 transactivator of transcription (TAT).

Antinociceptive effect of N-acetyl glucosamine in a rat model of neuropathic pain.

Objective: This study was aimed at evaluating the efficacy of glucosamine and potential mechanisms of actions in a neuropathic pain model in rats.

Methods: Glucosamine (500, 1000 and 2000 mg/kg) was administered via gavage route, 1 day before the chronic constriction injury (CCI) of sciatic nerve and daily for 14 days (prophylactic regimen), or from days 5 to 14 post-injury (therapeutic regimen), as the indicators of neuropathic pain, mechanical allodynia, cold allodynia and thermal hyperalgesia were assessed on days 0, 3, 5, 7, 10 and 14 after ligation. Inducible nitric oxide synthase (iNOS) and tumour necrosis factor alpha (TNF-α) gene expressions were measured by real-time polymerase chain reaction.

Preclinical Studies in Small Animals for Advanced Drug Delivery Using Hyperthermia and Intravital Microscopy.

This paper presents three devices suitable for the preclinical application of hyperthermia via the simultaneous high-resolution imaging of intratumoral events. (Pre)clinical studies have confirmed that the tumor micro-environment is sensitive to the application of local mild hyperthermia. Therefore, heating is a promising adjuvant to aid the efficacy of radiotherapy or chemotherapy.

Drug transport kinetics of intravascular triggered drug delivery systems.

Intravascular triggered drug delivery systems (IV-DDS) for local drug delivery include various stimuli-responsive nanoparticles that release the associated agent in response to internal (e.g., pH, enzymes) or external stimuli (e.

The effect of RGD-targeted and non-targeted liposomal Galbanic acid on the therapeutic efficacy of pegylated liposomal doxorubicin: From liposomal preparation to in-vivo studies.

The anti-cancer therapeutic application of Galbanic acid (Gba) as a strong antiangiogenic sesquiterpene coumarin has been limited due to its low water solubility. This issue necessitates developing new liposomal formulations for the efficient delivery of Gba in vivo. In this study, various liposomal formulations were prepared by a thin-film hydration method, and Gba was incorporated into the liposomal bilayers, which consequently increased its release profile compared to formulations in our previous study prepared by remote loading methods.

Hyperthermia and Temperature-Sensitive Nanomaterials for Spatiotemporal Drug Delivery to Solid Tumors.

Nanotechnology has great capability in formulation, reduction of side effects, and enhancing pharmacokinetics of chemotherapeutics by designing stable or long circulating nano-carriers. However, effective drug delivery at the cellular level by means of such carriers is still unsatisfactory. One promising approach is using spatiotemporal drug release by means of nanoparticles with the capacity for content release triggered by internal or external stimuli.

Author Correction: Liposomal formulation of Galbanic acid improved therapeutic efficacy of pegylated liposomal Doxorubicin in mouse colon carcinoma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Neuroprotective effects of clavulanic acid following permanent bilateral common carotid artery occlusion in rats.

We investigated whether clavulanic acid could improve learning and memory, in rats underwent bilateral occlusion of common carotid artery (2VO). Seventy male Wistar rats were subjected to 2VO, with a 1-week interval between right and left artery occlusions. After 2VO, animals received clavulanic acid (10, 20, 40 mg/kg, intraperitoneally), from day 8 to 20.

Liposomal formulation of Galbanic acid improved therapeutic efficacy of pegylated liposomal Doxorubicin in mouse colon carcinoma.

Galbanic acid (Gba), a sesquiterpene coumarin, with strong antiangiogenic activity could serve as an excellent anti-cancer agent. However, Gba is a poor water-solube which hampered its clinical application. In this study, a pegylated liposomal Gba (PLGba) with HSPC/Cholesterol/mPEG-DSPE (56.

Regulation of in vivo behavior of TAT-modified liposome by associated protein corona and avidity to tumor cells.

Introduction: PEGylated liposomes are widely used and studied as carriers for chemotherapeutics. While pharmacokinetics of the encapsulated drug is drastically altered resulting in favorable circulation time, improved tumor accumulation, and better manageable or reduced side effects, therapeutic efficacy has been disappointing. Major drawbacks are a failure to reach the tumor cell, limited penetration depth, and impaired uptake by tumor cells.

Development of a novel cyclic RGD peptide for multiple targeting approaches of liposomes to tumor region.

Liposomes containing cytotoxic agents and targeted with Arg-Gly-Asp based peptides have frequently been used against αvβ3 integrin on tumor neovasculature. However, like many other ligand modified liposomes these preparations suffered from enhanced uptake by the reticulo endothelial system (RES) and off-targeted interaction with integrin receptors vastly expressed in normal organs causing poor biodistribution and toxic effects. Here we mainly focus on development of a RGD-modified liposomal delivery system to enhance both targeting selectivity and tumor uptake.

Enhanced Specificity and Drug Delivery in Tumors by cRGD-Anchoring Thermosensitive Liposomes.

Purpose: To develop RGD-targeted thermosensitive liposomes with increased tumor retention, improving drug release efficiency upon mild hyperthermia (HT) in both tumor and angiogenic endothelial cells.

Methods: Standard termosensitive liposomes (TSL) and TSL containing a cyclic Arg-Gly-Asp (cRGD) pentapeptide with the sequence Arg-Cys-D-Phe-Asp-Gly (RGDf[N-Met]C) were synthetized, loaded with Dox and characterized. Temperature- and time-dependent drug release profiles were assessed by fluorometry.

Improvement of pharmacokinetic and antitumor activity of PEGylated liposomal doxorubicin by targeting with N-methylated cyclic RGD peptide in mice bearing C-26 colon carcinomas.

Cyclic Arg-Gly-Asp (cRGD) pentapeptides engrafted liposomes have attracted considerable attention for targeting integrin receptors on tumor vasculature. In this study PEGylated liposomal doxorubicin (PLD) was decorated with three cRGD peptides including Arg-Gly-Asp-D-Tyr-Cys (RGDyC), Arg-Gly-Asp-D-Phe-Lys (RGDfK) and Arg-Gly-Asp-D-Phe-[N-Methyl]Lys (RGDf[N-Met]K). The in vitro liposome-cell-association and cytotoxicity experiments demonstrated the RGD-PLDs capability of internalization into integrin expressing HUVEC cells via receptor mediated endocytosis.

Impact of chitosan coating of anionic liposomes on clearance rate, mucosal and systemic immune responses following nasal administration in rabbits.

Liposomes have been identified as effective immunological adjuvants and have potential for the intranasal and oral delivery of protein antigen. Anionic MLV liposomes were prepared by dehydration-rehydration method. For coating, liposomes were incubated in chitosan solution.