Essay: Polymer nanoparticles

Abstract The past half of a century has seen increasing attention focused on the development of polymer nanoparticle based drug delivery systems as being capable of improving the efficacy and obviating the systemic side effects of a wide range of antineoplastic drugs in human cancer therapy. This has led to the emergence of the multifunctional ‘smart’ nanoparticles of carrying the protective polymer capping, targeting ligand, diagnostic label, stimuli-sensitive segments, image contrast agent, and other demanding functional groups. In this article we introduce the basic knowledge and general features of polymer nanoparticles for the purpose of drug delivery. In addition, various types of polymer nanoparticles used in drug delivery systems are presented. The criteria for the development of the required polymer nanoparticles are also summarized.
Keywords Polymer nanoparticles; drug delivery; stimuli responsiveness; controlled release; biodegradable polymer; liposome.
The essence of ”nano-” science and technology is based on the finding that the properties of materials over the size range of 1-100 nm differ from those of the bulk material. The unique properties of these various types of intentionally produced nanomaterials provide them with novel electrical, catalytic, magnetic, mechanical, thermal, and imaging features that are highly desirable for applications in commercial, medical, military, and environmental sectors. These materials may also find their way into more complex nanostructures and systems. As new uses for materials with these special properties are identified, the number of products containing such nanomaterials and their possible applications continues to grow.
In the fields of molecular biology and medicine, cancer has been the leading cause of death and a serious threat to the body health of human beings. Until now, the main techniques to fight the cancer are non-targeted chemotherapy and radiation. However, it is unavoidable to prevent systemic side effects to the human body due to non-specific uptake by normal, healthy, noncancerous tissues because of the instinctive properties of the chemotherapy chemical agent featured with high toxicity and a lack of tumor specificity.
In order to overcome the limitations of free chemotherapeutic agents, targeting of tumors with nanoparticulate drug carriers has received much attention and expectance [1-2]. Nanocarriers can offer many avenues over free drugs for the following aspects [3]: (1) protect the drug from premature degradation; (2) prevent drugs from prematurely interacting with the biological environment; (3) enhance absorption of the drugs into a selected tissue (for example, solid tumour); (4) control the pharmacokinetic and drug tissue distribution profile; and (5) improve intracellular penetration.
Let us first recall the short but rapid development history of drug delivery systems (Figure 1). The first nanotechnology drug delivery system lipid was found in the 1960s, later known as liposomes [4]. After that, biomaterials made of a variety of organic and inorganic substances were developed for drug delivery. In 1976, the first controlled release polymer drug delivery system was reported [5]. In 1980, pH stimuli drug delivery systems to trigger drug release [6] and cell specific targeting of liposomes were reported [7-8]. In 1987, the first long circulating liposome named ‘stealth liposomes’ was described [9]. Subsequently, the use of polyethylene glycol (PEG) was known to increase circulation times for liposomes [10] and polymer nanoparticles [11] in 1990 and 1994, respectively, which established a solid foundation for the development and subsequent approval of DOXIL (doxorubicin liposome) in 1995 for the treatment of epidemic (AIDS-related) Kaposi sarcoma [12].
After fifty-years of development of drug delivery systems, biocompatible polymer nanoparticles have been regarded as a substantial promising effective drug delivery system characterized by the self-assembly of amphiphilic block copolymer surfactants (frozen micelles), dendrimers, vesicles, liposome, emulsions, microemulsion, and latex particles [1]. Drug delivery systems based on polymer nanoparticles generally have the following properties: [13-17] (1) decreased immunogenicity; (2) protection from alteration and inactivation of the active drug; (3) altered biodistribution to reduce systemic toxicity; (4) elimination of multidrug resistance; (5) increased tumor cytotoxicity; (6) passive targeting by enhanced permeability and retention (EPR); and (7) site-specific delivery of drugs by active targeting. On the other hand, in order to reach the rapid and effective clinical translation, these nanocarriers must (1) be made from a material that is biocompatible, well characterized, and easily functionalized; (2) exhibit high differential uptake efficiency in the target cells over normal cells or tissue; (3) be either soluble or colloidal under aqueous conditions for increased effectiveness; and (4) have an extended circulating half-life, a low rate of aggregation, and a long shelf life.
Biodegradable Polymers
Biodegradable polymers used in drug delivery studies can be broadly classified into two categories: natural and synthetic polymers. The majority of investigations into the use of natural polymers as drug delivery systems have concentrated on the use of proteins such as collagen, gelatin, and albumin and polysaccharides such as starch, dextran, insulin, cellulose, and hyaluronic acid.
Various synthetic degradable polymers have been reported for the formulation of controlled drug delivery systems, since they can be synthesized with specific properties to meet particular applications. Probably the most widely investigated biodegradable synthetic polymers are linear aliphatic polyesters based on poly (lactic acid) (PLA), poly (glycolic acid) (PGA), poly(lactic acid-co-glycolide) (PLGA), and poly(��-caprolactone) (PCL). They exhibit important advantages of biocompatibility, predictability of biodegradation kinetics, ease of fabrication, and regulatory approval.
Polyanhydride polymers and copolymers have also received considerable interest for the preparation of drug delivery systems due to their labile anhydride linkages in the polymer structure. In addition, poly (ortho ester)s and polyphosphazenes have generated a lot of research interest for the formulation of nanoparticulate drug delivery systems[18,19]. Poly (ortho ester)s have the advantage of undergoing controllable degradation. The degradation of polyphosphazenes and the linkage of reactive drug molecules to the polymer backbone are controlled by the side-group modification. Langer and coworkers reported a family of synthetic biodegradable poly (polyol sebacate) (PPS) via the bulk polycondensation reactions of the polyol and sebacic acid monomers. [20] Material properties including the physicochemical and mechanical properties as well as the degradation rates of the obtained PPS can be tuned by altering the reacting stiochiometric ratio of monomers polyol and sebacic acid. Through the assessment of biocompatibility in vitro and in vivo, PPS polymers were found have comparable biocompatibility to poly(L-lactic-co-glycolic acid) (PLGA) which is a type of material approved for human use.
Liposome which is the most intensively investigated family of particulate carriers consists of highly ordered lipid molecules in a lamellar arrangement that encapsulates a fraction of the solvent in which they are suspended [21]. As a type of natural biomaterials, liposomes are considered as promising and harmless drug carriers that can circulate in the bloodstream for an extended time [22].

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