Advanced liposome and polymersome-based drug delivery systems: Considerations for physicochemical properties, targeting strategies and stimuli-sensitive approaches

Small molecules, peptides, proteins and nucleic acids form an important part of pharmaceutical drugs [1]. When administered, these therapeutics often suffer from poor solubility, low stability, undesirable side effects, short circulation time and ineffective distribution in diseased tissues [1,2]. They are expected to be within a certain concentration range in plasma in order to show the desired therapeutic efficacy. Conventional multiple drug administrations exhibit “peak and valley” pharmacokinetics. On the other hand, the era of drug delivery began with the introduction of the first controlled release systems in the 1960s [3]. With the incorporation of nanotechnology into medicine, improved delivery of poorly water-soluble drugs, targeted drug delivery to specific cells or tissues, drug transcytosis across impenetrable epithelial and endothelial barriers, delivery of large macromolecular drugs to intracellular sites of action, co-delivery of two or more drugs or using different therapeutic modalities for combinational therapy, and visualization of drug delivery sites by such modalities have all become possible by nanocarriers [4].

Among nanocarriers, liposomes stand out for their ease of preparation, size control and relative chemical versatility. Liposomes are described as vesicular self-assembled nanocarriers composed mainly of phospholipids (or other lipid derivatives) and cholesterol [5]. Unlike the micellar aggregates of lipids, they have a bilayer membrane separating the aqueous core (lumen) from the outer aqueous phase. Owing to their vesicular morphology, they can encapsulate both hydrophilic and hydrophobic drugs in the lumen and membrane, respectively. In addition, their chemical versatility, manipulable mechanical properties, and controllable size allow them to be targeted both actively and passively. The year 1995 has been attributed as the milestone of liposomal nanocarriers for clinical translation, with the FDA approval of the liposomal formulation of doxorubicin (DOX; Doxil). In the following years, numerous liposomal drug formulations were approved by the FDA and EMA for the treatment of various cancers, including DaunoXome® (1996), Myocet® (2000), Vyxeos® (2017) and the like (Table 1). These early examples of liposomal formulations relied heavily on the physicochemical properties of nanocarriers to achieve the intended passive targeting of chemotherapeutic small molecules. This technology has been adapted over time to work with complex therapeutic molecules such as plasmid DNA, mRNA, miRNA, and siRNA. As a result of these efforts, Onpattro® became the first liposomal siRNA drug approved for the treatment of hereditary transthyretin amyloidosis-induced polyneuropathies as of 2018 [6]. Preclinical and clinical experience over time has led to the development of mRNA-based liposomal BNT162b2 (Pfizer-Biontech) and mRNA-1273 (Moderna) vaccines against the SARS-CoV-2 pandemic in just months. Today, liposomes remain a hot topic of research, and tremendous efforts are being made to improve the functionality of existing systems and introduce new ones into clinical trials (Table 2). (See Table 3.)

As another class of nanocarriers, polymersomes were first reported in the mid-1990s [7,8]. Even though they are very similar to liposomes in terms of their vesicular morphology and bilayer membrane structure, they differ in their chemical composition, mechanical properties and stability. Polymersomes are colloidal aggregates that self-assemble from amphiphilic polymers. Like liposomes, they have a bilayer membrane that separates the outer aqueous medium from the lumen (Fig. 1A) [9]. The lumen can encapsulate hydrophilic therapeutics such as small molecules (including photo-sensitizers and others), enzymes, proteins, peptides, and nucleic acids, while the bilayer membrane encapsulates hydrophobic therapeutics. Due to current advances in synthetic and polymer chemistry, polymersomes are becoming highly adaptable nanocarrier platforms for various therapeutics. Their physicochemical properties, including size, charge, shape, mechanical, can be tailored to the desired active or passive targeting strategies. In particular, there has been great interest in the development of stimuli-sensitive polymersomes to better control the release of pharmaceuticals by altering the stability and permeability of the membrane. To date, different block copolymers have been employed in the preparation of polymersomes sensitive to stimuli such as pH, temperature, redox, light, magnetic field and glucose concentration. Among these, systems that respond to pH and redox potential particularly draw attention, and preclinical research mainly continues in the fields of diabetes, photodynamic therapy, gene therapy, immunotherapy, and vaccine development.

In this review, current developments and considerations in liposome and polymersome-based nanocarriers will be discussed. First, the basic principles of nano drug delivery systems and the biological barriers that pose a challenge in the drug delivery process will be briefly introduced. In addition, the importance of the physicochemical properties of nanocarriers on drug delivery applications will be emphasized. Following this, active and passive targeting strategies for liposomes and polymersomes will be discussed. Then, stimuli-sensitive systems and their applications will be overviewed. Finally, the current clinical practice, prospective studies, and clinical expectations will be evaluated.

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