You Han Bae

Biodegradable block copolymers as injectable drug-delivery systems.

Polymers that display a physicochemical response to stimuli are widely explored as potential drug-delivery systems. Stimuli studied to date include chemical substances and changes in temperature, pH and electric field. Homopolymers or copolymers of N-isopropylacrylamide, and poly(ethylene oxide)–poly(propylene oxide)–poly(ethylene oxide) (known as poloxamers) are typical examples of thermosensitive polymers, but their use in drug delivery is problematic because they are toxic and non-biodegradable. Biodegradable polymers used for drug delivery to date have mostly been in the form of injectable microspheres or implant systems, which require complicated fabrication processes using organic solvents. Such systems have the disadvantage that the use of organic solvents can cause denaturation when protein drugs are to be encapsulated. Furthermore, the solid form requires surgical insertion, which often results in tissue irritation and damage. Here we report the synthesis of a thermosensitive, biodegradable hydrogel consisting of blocks of poly(ethylene oxide) and poly(L-lactic acid). Aqueous solutions of these copolymers exhibit temperature-dependent reversible gel–sol transitions. The hydrogel can be loaded with bioactive molecules in an aqueous phase at an elevated temperature (around 45 °C), where they form a sol. In this form, the polymer is injectable. On subcutaneous injection and subsequent rapid cooling to body temperature, the loaded copolymer forms a gel that can act as a sustained-release matrix for drugs.

Thermosensitive sol-gel reversible hydrogels

Aqueous polymer solutions that are transformed into gels by changes in environmental conditions, such as temperature and pH, thus resulting in in situ hydrogel formation, have recently attracted the attention of many investigators for scientific interest and for practical biomedical or pharmaceutical applications. When the hydrogel is formed under physiological conditions and maintains its integrity for a desired period of time, the process may provide various advantages over conventional hydrogels. Because of the simplicity of pharmaceutical formulation by solution mixing, biocompatibility with biological systems, and convenient administration, the pharmaceutical and biomedical uses of the water-based sol-gel transition include solubilization of low-molecular-weight hydrophobic drugs, controlled release, labile biomacromolecule delivery, such as proteins and genes, cell immobilization, and tissue engineering. When the formed gel is proven to be biocompatible and biodegradable, producing non-toxic degradation products, it will provide further benefits for in vivo applications where degradation is desired. It is timely to summarize the polymeric systems that undergo sol-gel transitions, particularly due to temperature, with emphasis on the underlying transition mechanisms and potential delivery aspects. This review stresses the polymeric systems of natural or modified natural polymers, N-isopropylacrylamide copolymers, poly(ethylene oxide)/poly(propylene oxide) block copolymers, and poly(ethylene glycol)/poly(D,L-lactide-co-glycolide) block copolymers.

Targeted drug delivery to tumors: Myths, reality and possibility

The ultimate goal of drug delivery research is to help patients by developing clinically useful formulations. During the last several decades controlled drug delivery technology has advanced significantly, leading to the development of various clinical formulations improving patient compliance and convenience [1]. Current technologies allow delivery of drugs at desired release kinetics for extended periods of time ranging from days to years. Oral and transdermal drug delivery systems routinely deliver drugs for 24 h, substantially improving drug efficacy and minimizing side effects. Implantable systems can locally deliver drugs for months, even years. While significant advances have been made, there are still areas where substantial improvements need to be made to reach the next level of clinical relevance. One such area is targeted drug delivery to solid tumors. The clinically significant impact of targeted drug delivery lies in the ability to specifically target a drug or drug carrier to minimize drug-originated systemic toxic effects. Successful translation (from bench to bedside) of potential cancer and gene therapies, particularly small interfering RNA (siRNA) delivery, will largely depend on targeted drug delivery strategies. Overcoming the many challenges of identifying a successful targeted drug delivery strategy requires an understanding of events involving transport of drug or drug carrier to a target site after intravenous (i.v.) administration as well as issues relevant for specific target diseases and the body’s response toward a drug delivery system. The current lack of clear recognition of problems facing the drug delivery field can be anticipated to result in only marginal advances in targeted drug delivery technologies in the coming years. The current unmet needs and challenges in this area were summarized by Professor Alexander T. Florence who is one of the few who raised awareness on the exaggerated claims of the nanoparticle-based drug targeting [2,3]. They need to be better appreciated and understood for achieving greater success in drug targeting to tumors. Thus, it would be profitable to address a variety of issues and factors that could affect the development of improved targeted drug delivery systems. Many terms have been used to describe nano-sized drug delivery systems, and here the term “nanoparticle” is used to represent a spectrum of systems, including nanocarrier, nanovehicle, nanosystem, nanostructure, and other terms used in the literature.

Recent progress in tumor pH targeting nanotechnology

pH-sensitive polymeric micelles and nanogels have recently been developed to target slightly acidic extracellular pH environment of solid tumors. The pH targeting approach is regarded as a more general strategy than conventional specific tumor cell surface targeting approaches, because the acidic tumor microclimate is most common in solid tumors. When nanosystems are combined with triggered release mechanisms by endosomal or lysosomal acidity plus endosomolytic capability, the nanocarriers demonstrated to overcome multidrug resistance of various tumors. This review highlights recent progress of the pH-sensitive nanotechnology developed in Bae research group.

Polymeric micelle for tumor pH and folate-mediated targeting.

Novel pH-sensitive polymeric mixed micelles composed of poly(L-histidine) (polyHis; M(w) 5000)/PEG (M(n) 2000) and poly(L-lactic acid) (PLLA) (M(n) 3000)/PEG (M(n) 2000) block copolymers with or without folate conjugation were prepared by diafiltration. The micelles were investigated for pH-dependent drug release, folate receptor-mediated internalization and cytotoxicity using MCF-7 cells in vitro. The polyHis/PEG micelles showed accelerated adriamycin release as the pH decreased from 8.0. When the cumulative release for 24 h was plotted as a function of pH, the gradual transition in release rate appeared in a pH range from 8.0 to 6.8. In order to tailor the triggering pH of the polymeric micelles to the more acidic extracellular pH of tumors, while improving the micelle stability at pH 7.4, the PLLA/PEG block copolymer was blended with polyHis/PEG to form mixed micelles. Blending shifted the triggering pH to a lower value. Depending on the amount of PLLA/PEG, the mixed micelles were destabilized in the pH range of 7.2-6.6 (triggering pH for adriamycin release). When the mixed micelles were conjugated with folic acid, the in vitro results demonstrated that the micelles were more effective in tumor cell kill due to accelerated drug release and folate receptor-mediated tumor uptake. In addition, after internalization polyHis was found to be effective for cytosolic ADR delivery by virtue of fusogenic activity. This approach is expected to be useful for treatment of solid tumors in vivo.

Drug release from biodegradable injectable thermosensitive hydrogel of PEG-PLGA-PEG triblock copolymers

An aqueous solution of newly developed low-molecular-weight PEG-PLGA-PEG triblock copolymers with a specific composition is a free flowing sol at room temperature but becomes a gel at body temperature. Two model drugs, ketoprofen and spironolatone, which have different hydrophobicities, were released from the PEG-PLGA-PEG triblock copolymer hydrogel formed in situ by injecting the solutions into a 37 degrees C aqueous environment. Ketoprofen (a model hydrophilic drug) was released over 2 weeks with a first-order release profile, while spironolactone (a model hydrophobic drug) was released over 2 months with an S-shaped release profile. The release profiles were simulated by models considering degradation and diffusion, and were better described by a model assuming a core-shell structure of the gel.

Hydrogels: Swelling, drug loading, and release

Hydrogels have been used by many investigators in controlled-release drug delivery systems because of their good tissue compatibility and easy manipulation of swelling level and, thereby, solute permeability. The desired kinetics, duration, and rate of solute release from hydrogels are limited to specific conditions, such as hydrogel properties, amount of incorporated drug, drug solubility, and drug–polymer interactions. This review summarizes the compositional and structural effects of polymers on swelling, loading, and release and approaches to characterize solute release behavior in a dynamic state. A new approach is introduced to compensate drug effects (solubility and loading) with the release kinetics by varying the structure of heterogeneous polymers. Modulated or pulsatile drug delivery using functional hydrogels is a recent trend in hydrogel drug delivery.

Polymer Architecture and Drug Delivery

Polymers occupy a major portion of materials used for controlled release formulations and drug-targeting systems because this class of materials presents seemingly endless diversity in topology and chemistry. This is a crucial advantage over other classes of materials to meet the ever-increasing requirements of new designs of drug delivery formulations. The polymer architecture (topology) describes the shape of a single polymer molecule. Every natural, seminatural, and synthetic polymer falls into one of categorized architectures: linear, graft, branched, cross-linked, block, star-shaped, and dendron/dendrimer topology. Although this topic spans a truly broad area in polymer science, this review introduces polymer architectures along with brief synthetic approaches for pharmaceutical scientists who are not familiar with polymer science, summarizes the characteristic properties of each architecture useful for drug delivery applications, and covers recent advances in drug delivery relevant to polymer architecture.

Poly(l-histidine)–PEG block copolymer micelles and pH-induced destabilization

Poly(L-histidine)-poly(ethylene glycol) diblock copolymers (polyHis-b-PEG) were prepared and used for the construction of polymeric micelles responding to local pH changes in the body. PolyHis was synthesized by ring opening polymerization of L-histidine N-carboxyanhydride, the imidazole amine group of which was protected by the dinitrophenyl group. The resulting polymer (M(n): 5,000 g/mole) was coupled to poly(ethylene glycol) (M(n): 2,000 g/mole) via an amide linkage using the dicyclohexyl carbodiimide and N-hydroxysuccinimide-mediated reaction. The block copolymer in dimethyl sulfoxide formed polymeric micelles on diafiltration against a borate buffer at pH 8. Dynamic light scattering and atomic force microscopy showed the micelles were spherical, diameter approximately 114 nm, with a unimodal distribution. The critical micelle concentration (CMC) at pH 8.0 was 2.3 mg/l. The CMC increased markedly on decreasing the pH of the diafiltration medium below 7.2. Micelles prepared at pH 8.0 were gradually destabilized below pH 7.4, as evidenced by a slight increase in light transmittance, an alteration in size distribution, and a decrease in the pyrene fluorescence intensity. It was concluded that the ionization of the polyHis block forming the micelle core determined the pH-dependent CMC and stability. After further optimization of the pH-sensitivity, pH-sensitive micelles are expected to have application for solid tumor treatment, exploiting the fact that most solid tumors have an acidic extracellular pH.

EPR: Evidence and fallacy.

The enhanced permeability and retention (EPR) of nanoparticles in tumors has long stood as one of the fundamental principles of cancer drug delivery, holding the promise of safe, simple and effective therapy. By allowing particles preferential access to tumors by virtue of size and longevity in circulation, EPR provided a neat rationale for the trend toward nano-sized drug carriers. Following the discovery of the phenomenon by Maeda in the mid-1980s, this rationale appeared to be well justified by the flood of evidence from preclinical studies and by the clinical success of Doxil. Clinical outcomes from nano-sized drug delivery systems, however, have indicated that EPR is not as reliable as previously thought. Drug carriers generally fail to provide superior efficacy to free drug systems when tested in clinical trials. A closer look reveals that EPR-dependent drug delivery is complicated by high tumor interstitial fluid pressure (IFP), irregular vascular distribution, and poor blood flow inside tumors. Furthermore, the animal tumor models used to study EPR differ from clinical tumors in several key aspects that seem to make EPR more pronounced than in human patients. On the basis of this evidence, we believe that EPR should only be invoked on a case-by-case basis, when clinical evidence suggests the tumor type is susceptible.