Drug delivery systems
Drug delivery systems (DDS) have been developed as a means to resolve the solubility and toxicity issues that almost every potent drug encounters Citation[1]. Extensive preclinical and clinical studies show that DDS not only improve the solubility, but also reduce the toxicity of anticancer drugs significantly. Low toxicity of DDS is attributed to controlled drug distribution in the body. Despite promising achievements, no drug carriers have yet shown therapeutic efficacy more potent than small-molecule drug formulations using conventional dosage forms (e.g., oil, DMSO, Cremophor EL and other excipients). In general, therapeutic efficacy of a drug candidate would be considered as more important than the toxicity in clinical applications. Conventional drug formulations are obviously more toxic than DDS, yet relatively easy to prepare and convenient for injection. For these reasons, DDS are not considered as the first-line therapeutic option for treatment of cancer. These facts indicate that polymer drug carriers are currently facing serious challenges in rationalizing why DDS is necessary and how polymer drug carriers are superior to existing excipients.
Polymer nanoassembly drug carriers
In early DDS development, drugs are covalently conjugated to water-soluble polymers Citation[2]. Unfortunately, this simple type of DDS requires large numbers of polymers to retain solubility of the polymer–drug conjugates. Even if the polymer–drug conjugates showed reasonable solubility in the laboratory, the major problems in vivo, such as hemolysis, opsonization and phagocytic uptake, have not been resolved completely. This is because hydrophobic drug molecules cannot be protected properly by the polymer–drug conjugation approach. Polymer nanoassemblies appeared to be a promising alternative for polymer–drug conjugates. Self-assembling block copolymers are generally used to prepare polymer nanoassemblies, which form cylindrical, micellar and vesicular nanostructures Citation[3]. These polymer nanoassemblies entrap drug molecules stably in the nanostructures with an inner compartment that is enveloped with a biocompatible shell. Polymer micelles and polymersomes are good examples Citation[4,5]. Polymer nanoassemblies can be stabilized by cross-linkers, inducing increased solubility, prolonged plasma retention time and tumor-specific delivery of hydrophobic drugs Citation[6].
Tumor targeting
The performance of DDS is mainly dependent on the drug carriers‘ targeting efficiency of disease lesions. Compared with normal tissues, tumor tissues have leaky blood vessels and immature lymphatic drainage Citation[7]. Polymer–drug carriers that accumulate in tumor tissues through the leaky tumor blood vessels are not cleared from the tumor tissue by the immature lymphatic system for a prolonged period of time. This phenomenon is referred to as the enhanced permeability and retention (EPR) effect Citation[8]. The tumor-targeting approach based solely on the EPR effect is called passive targeting. Although passive targeting rationalizes how polymer drug carriers accumulate in tumor tissues, it is still necessary to overcome limited tissue penetration of polymer drug carriers due to thick fibrosis and low blood vessel density in some tumor tissues Citation[9]. Recently, ligand-mediated tumor targeting, known as active targeting, has drawn attention to improve tumor-targeted drug delivery Citation[10]. Interestingly, DDS researchers are divided into two groups when it comes to addressing the effect of active targeting on tumor-specific accumulation of drug carriers. A string of studies demonstrates that active targeting does not necessarily improve tumor targeting. For instance, when more ligands are installed on the polymer drug carriers, a higher accumulation of polymer drug carriers is observed in the liver and spleen than tumor tissues Citation[11]. Even if ligand-installed polymer drug carriers accumulate in tumor tissues successfully, they are readily taken up by the cancer cells that surround tumor tissues. These cells are adjacent to blood vessels and, thus, less drug molecules are able to reach the deeper central region of the tumor tissue. On the other hand, it is also obvious that active targeting can increase cell cytotoxicity, presumably due to the increased intracellular drug trafficking Citation[12]. These contradictory results clearly demonstrate that effective active targeting cannot be achieved unless drug carriers are suitable for passive targeting.
Controlled drug delivery
The controversial effects of active targeting on the therapeutic efficacy of DDS suggest that controlled drug release is getting more important in DDS design Citation[13]. Controlled drug delivery is designed by using drug-binding linkers, which include acid-labile, hydrolysable, enzymatically degradable and redox-mediated linkers Citation[14]. Among these, the acid-labile linkers appeared to be the most promising because drug release is triggered by protons that are ubiquitous in the body Citation[15]. Protons can penetrate between molecular structures of polymer drug carriers more efficiently than any enzymes or small molecules to trigger the degradation of linkers. Proton concentrations (pH) are also well controlled throughout the human body.
Interestingly, cancer tissues are known to be slightly acidic, due to the Warburg effect Citation[16]. According to the Warburg effect, cancer cells consume nutrients (glucose) in a very inefficient way, producing a large amount of lactic acid that decreases the pH. Hypoxia and the necrotic core of tumor tissues also play a role in lowering pH in tumor tissues (pH 6.5–7.2). As seen in live cells, cancer cells possess acidic intracellular compartments such as endosomes and lysosomes (pH 5–6.5). All of these acidic sites in vivo enable the control of drug-release patterns of pH-sensitive drug carriers in both extra- and intra-cellular regions in tumor tissues. Linker chemistry is therefore of crucial importance to control drug-release patterns.
Combination chemotherapy & DDS
Polymer drug carriers are obviously promising formulations for the delivery of hydrophobic and toxic drugs to tumor tissues. The real challenge is that cancer cells‘ response to chemotherapy remains variable. Drug concentrations are known to be the major factor that determines therapeutic effects, yet therapeutic schedules are also responsible for some variable responses of cancer cells Citation[17]. In general, anticancer drugs function in accordance with the cell cycle. Chemotherapy becomes complicated when multiple drugs are involved in the therapy. Simple additive effects are likely to be seen when multiple drugs are added together. However, drugs frequently show either antagonistic or synergistic effects. Antagonistic drug actions would be observed if multiple drugs are competing for an intracellular molecular target. If the therapeutic action of one drug is selective to a certain cell cycle and the other drug functions before and after that cell cycle, either a synergistic or antagonistic effect would be observed depending on which drug is administered first. Even if the optimal drug concentration and schedule are determined, controlling the spatial and temporal distribution of multiple drugs in vivo is highly difficult to achieve using conventional technology. Every drug shows distinctive pharmacokinetic profiles, which are determined by absorption, distribution, metabolism and excretion of drugs. Only DDS is believed to modulate the absorption, distribution, metabolism and excretion of multiple drugs at the same time because concurrent delivery of drugs using the EPR effect would retain initial drug mixing ratios at the time of injection in tumor tissues Citation[18]. Therefore, it is surmised that polymer drug carriers can provide the most convenient way for combination chemotherapy by carrying multiple drugs to tumor tissues. The controlled release of each drug can be controlled further by drug-binding linkers with various hydrolysis rates.
Future DDS
Since DDS has demonstrated potential in clinical applications, drug carriers have evolved from polymer–drug conjugates to polymer nanoassemblies. Recent development of DDS even suggests that integration of multidisciplinary technologies plays a pivotal role in multifunctional drug-carrier design. However, drug carrier design is often overly complicated. It is highly challenging to simultaneously optimize all major factors for drug carrier design, such as bioavailability of polymers, physicochemical properties of polymer nanoassemblies, stability of linkers and spacers and most importantly bioactivity of drug payloads. In order to bring DDS from benchtop to bedside, facile and versatile drug carriers might be more reasonable and practical than complicated ones. Therefore, technologies to control the interaction either between drug carriers or between drug carriers and live cells would become more important in the future to construct multifunctional drug carriers rather than multifunctional DDS. Combination chemotherapy would also benefit from such DDS approaches. It must be noted that the most common criticism that DDS technology is facing at present is the relatively low therapeutic efficacy compared with small-molecule drug formulations. Development cost, time and efforts are also discouraging a wide range of support for DDS. More seriously, drug carriers are often optimized for only a limited number of drugs. From these perspectives, polymer nanoassemblies with improved tumor-targeting capability, feasibility in chemistry and versatility in clinical applications are presumably the most suitable platform to create the ultimate multifunctional DDS that can be used for the detection, diagnosis and treatment of cancers. It is indeed exciting to see how DDS will evolve in the future, replacing conventional toxic and inefficient dosage forms.
Financial & competing interests disclosure
The author acknowledges research support from the Kentucky Lung Cancer Research Program. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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