Liposomes as carriers of hydrophilic small molecule drugs: Strategies to enhance encapsulation and delivery

Highlights

• Many hydrophilic small molecule drugs undergo suboptimal encapsulation and delivery.

• We review liposomal loading of hydrophilic small molecule drugs.

• Lipid composition, drug/lipid ratio, charge and loading method affect encapsulation.

• Liposomal targeted and triggered delivery enhance efficacy of hydrophilic drugs.

Abstract

Although hydrophilic small molecule drugs are widely used in the clinic, their rapid clearance, suboptimal biodistribution, low intracellular absorption and toxicity can limit their therapeutic efficacy. These drawbacks can potentially be overcome by loading the drug into delivery systems, particularly liposomes; however, low encapsulation efficiency usually results. Many strategies are available to improve both the drug encapsulation efficiency and delivery to the target site to reduce side effects. For encapsulation, passive and active strategies are available. Passive strategies encompass the proper selection of the composition of the formulation, zeta potential, particle size and preparation method. Moreover, many weak acids and bases, such as doxorubicin, can be actively loaded with high efficiency. It is highly desirable that once the drug is encapsulated, it should be released preferentially at the target site, resulting in an optimal therapeutic effect devoid of side effects. For this purpose, targeted and triggered delivery approaches are available. The rapidly increasing knowledge of the many overexpressed biochemical makers in pathological sites, reviewed herein, has enabled the development of liposomes decorated with ligands for cell-surface receptors and active delivery. Furthermore, many liposomal formulations have been designed to actively release their content in response to specific stimuli, such as a pH decrease, heat, external alternating magnetic field, ultrasound or light. More than half a century after the discovery of liposomes, some hydrophilic small molecule drugs loaded in liposomes with high encapsulation efficiency are available on the market. However, targeted liposomes or formulations able to deliver the drug after a stimulus are not yet a reality in the clinic and are still awaited.

Introduction

Most drugs are small molecules under 500 Da [1]. However, small molecules are affected by rapid clearance and suboptimal biodistribution, resulting in toxic side effects [2]. In addition, the in vivo efficacy of high polarity drugs may be limited due to low intracellular absorption [3].

Drug encapsulation in colloidal delivery systems is an efficient approach to improve the pharmacokinetics of hydrophilic drugs. These carriers encompass a broad range of dispersion systems ranging from submicron emulsions to colloidal particles, such as polymeric and lipid nanoparticles, micelles and liposomes, aiming to protect the drug against degradation, sustain drug release, increase patient comfort by avoiding repetitive bolus injections or the use of perfusion pumps and reduce side effects [2], [4]. For the treatment of cancer, nanocarriers take advantage of the enhanced permeability and retention (EPR) effect of the leaky vasculature of tumours and thus can be passively accumulated in the tumour [5]. Moreover, the possibility of modifications in the surface of nanocarriers, for example, pegylation, can be used to form “stealth” nanoparticles that can escape from rapid uptake by mononuclear phagocyte system, enabling an extended circulation time [6], [7]. Hydrophilic drug encapsulation in polymer-based nanoparticles has been previously reviewed, and the authors observed that drug encapsulation in polymeric nanoparticles can provide a better pharmacokinetic profile and bioavailability, enhance the anticancer effect and reduce toxicity compared with drug administration without a carrier [2].

Among nanocarriers, liposomes, which are vesicles composed of phospholipid bilayers surrounding an aqueous compartment, allow the encapsulation of both lipophilic and hydrophilic drugs [8]. Although hydrophilic drugs can be easily dissolved in the external aqueous phase during liposome preparation using the common thin layer hydration method, the drug is usually encapsulated with low efficiency due to the large volume of hydration medium compared with the volume that is entrapped as the aqueous cavity of the liposome, which may impede clinical developments [9]. Hence, strategies are available to increase hydrophilic drug encapsulation in liposomes. Xu and collaborators [10], for instance, developed a mathematical model to predict drug encapsulation in unilamellar liposomes and observed an inverse correlation between the media ionic strength and the drug encapsulation efficiency. Furthermore, some liposome preparation methods have been reported to enhance hydrophilic drug encapsulation, such as the reverse phase evaporation and freeze and thaw cycling [11], [12]. Remote-loading methods are available for active encapsulation with a high efficiency for weakly basic drugs, such as doxorubicin [13], [14]. These strategies and others that will be discussed in this review made liposomes the most successful nanocarrier to deliver hydrophilic drugs, with different marketed products available for different routes of injection.

For a therapeutic effect, the drug must be delivered by the liposomes at the target site with a high concentration. Therefore, an optimal formulation should have maximum drug encapsulation, limited leakage during storage and systemic circulation, and effective release at the target site. To achieve the maximum drug encapsulation with limited leakage, the incorporation of high-transition temperature lipids and/or cholesterol may be considered. However, the necessity to effectively release the drug opposes the need for limited leakage; thus, some alternatives must be considered to optimise drug release specifically at the site of action, which can be achieved by exploiting the local environmental characteristics of the target site [15]. In this context, targeted delivery, in which ligands, such as antibodies, are coupled to the liposome surface to direct it for recognition by receptors at the pathological site, and triggered release, in which liposomes are specially designed to respond to a signal, such as a decrease in pH, hyperthermia, an external alternating magnetic field or ultrasound, to release their aqueous content, are used with consequent therapeutic efficacy enhancement [16].

Because this paper focuses on liposomes as carriers of hydrophilic small drugs, it was of importance to select which drugs to include in this review. The United States pharmacopeia (USP) hydrophilic drugs classification was used, which considers as hydrophilic drugs those classified between very soluble (solubility range > 1000 mg/mL) to soluble (solubility range from 33 to 100 mg/mL). Some exceptions of sparingly soluble drugs (solubility range from 10 to 33 mg/mL) were considered because doxorubicin is included in this category, and it was the first FDA approved drug available in liposomal carriers (Doxil^®). Herein, our aim is to review the most relevant papers in the literature on hydrophilic small molecule drug-loaded liposomes and discuss the effect of the lipid membrane composition and permeability, phospholipid chain length, drug-to-lipid ratio, charge, particle size, remote-loading and different liposome preparation methods on the encapsulation efficiency. Furthermore, the key aspects that can direct drug delivery to the target and consequently improve its efficacy will be discussed, such as targeted and triggered delivery.