Background of Drug Delivery System
Drug delivery system (DDS) refers to a formulation technology system that comprehensively regulates the distribution of drugs in the body in terms of time, space and dosage. It can control the release rate of drugs, improve the distribution in the body and improve the targeting of specific cells or tissues. DDS can deliver drugs more accurately, thereby reducing adverse drug reactions and improving the therapeutic effect of drugs, that is, achieving the goal of "reducing toxicity and increasing efficacy". In recent years, the research hotspots of DDS have mainly focused on nano drug delivery systems (NDDS), including the research of nano drug carriers such as liposomes, micelles, and nanoparticles, aiming to achieve targeted drug delivery through these carriers. NDDS can load drugs with poor water solubility, and can also avoid the rapid clearance of drugs to prolong their half-life. And through its unique size effect, it can enhance the targeting of chemotherapeutic drugs to tumor tissues through enhanced permeability and retention effect (EPR).
Figure 1. In vitro drug release and in vivo pharmacokinetic evaluation of PLGA-PEG-PLGA. (Chen X, et al.; 2017)
Poly(lactide-co-glycolide)-block-poly(ethyleneglycol)-block-poly(lactide-co-glycolide) (PLGA-PEG-PLGA) is a triblock pharmaceutical polymer excipient. The nanomicelle or hydrogel system formed by it can be used as DDS for drug delivery, which can effectively improve the targeting of loaded drugs and reduce toxic side effects. Since PLGA-PEG-PLGA is a complex triblock copolymer with high molecular weight and polydispersity, it is extremely challenging to develop full-profile quantitative and qualitative analysis methods for it. Therefore, there is still a blank in the comprehensive pharmacokinetic evaluation of PLGA-PEG-PLGA, which greatly restricts the design and development of DDS based on PLGA-PEG-PLGA polymer excipients.
PLGA-PEG-PLGA Structure and Characteristics
PLGA-PEG-PLGA is a triblock copolymer synthesized by ring-opening copolymerization of D, L-lactide (LA) and glycolide (GA) monomers with PEG as an initiator under the catalysis of stannous isooctanoate. At present, PLGA-PEG-PLGA has been widely used in the fields of cell culture, tissue engineering, in vivo imaging, wound repair, postoperative adhesion prevention and DDS, and has good development prospects. PLGA-PEG-PLGA has amphiphilic structural characteristics and can self-assemble in aqueous solution to form micelles for drug delivery; there are also studies using PLGA-PEG-PLGA to prepare nanoparticles or microspheres for the development of related preparations. In addition, when the molecular parameters of PLGA-PEG-PLGA are appropriate, its aqueous solution has reverse temperature-sensitive gelation characteristics. The formation of this hydrogel system is mainly due to the fact that PLGA-PEG-PLGA micelles aggregate in aqueous solution due to hydrophobic interactions as the temperature rises, forming a percolating micelle network with hydrophobic interactions as crosslinking points. At this time, the aqueous solution is transformed into an immobile gel state on a macroscopic scale; when the temperature is further increased, the percolating micelle network structure is destroyed and polymer precipitation is formed. Unlike the low-temperature gel and high-temperature sol of the forward hydrogel, the aqueous solution of PLGA-PEG-PLGA is in a flowable state under low temperature conditions, and it turns into a gel state when the temperature rises above the gelation temperature. This reverse temperature-sensitive feature avoids the disadvantage that the drug may be inactivated by high temperature during the process of drug loading in the high-temperature sol state of the traditional forward hydrogel. However, not all PLGA-PEG-PLGA can form a hydrogel system. Only when the conditions such as molecular weight, molecular weight distribution, hydrophilic and hydrophobic block ratio and polymer concentration are suitable, can it have ideal thermal gelation performance. When its gelation temperature is between room temperature and body temperature, it can be used for in vivo injection. This gelation system can form a drug reservoir at the injection site, prolong the drug release time, reduce the frequency of drug injections, increase patient compliance, and reduce drug toxicity.
Current Status of Research on the Pharmacokinetics of PLGA-PEG-PLGA in vivo
In the past formulation development process, pharmaceutical polymer excipients were generally considered to be bioinert substances, that is, they have no biological effects in vivo. However, with the extensive research and application of polymer excipients in recent years, more and more studies have found that some pharmaceutical polymer excipients that were generally considered to be bioinert can also interact with the body, thereby producing active or toxic side effects. At present, many literatures point out that allergic reactions caused by some preparations are likely to be caused by polymer excipients added to the preparations. In addition, there are also studies showing that excipients may interact with the body's immune system, thereby causing a series of side effects. From this point of view, whether at the level of national drug registration and supervision regulations or from the level of DDS design and development, it is necessary to conduct pharmacokinetic research on pharmaceutical polymer excipients, which plays a very important and direct guiding role in evaluating the in vivo biosafety of pharmaceutical polymer excipients and improving the success rate of clinical transformation of DDS.
The researchers connected rhodamine B to both ends of PLGA-PEG-PLGA by fluorescent labeling, and studied the degradation behavior of PLGA-PEG-PLGA in mice by fluorescence imaging. The results showed that the fluorescence signals were mainly detected in the spleen, liver and gallbladder, suggesting that PLGA-PEG-PLGA and its degradation products may be mainly eliminated through the above organs. The complete in vivo pharmacokinetics of PLGA-PEG-PLGA carrier materials, including the absorption, distribution, metabolism and excretion processes in the body, have not yet been elucidated, which seriously limits the rapid development of related drug preparations using PLGA-PEG-PLGA as carrier materials. Therefore, it is urgent to establish an accurate and reliable quantitative and qualitative analysis method for the full profile components of PLGA-PEG-PLGA in vivo, so as to comprehensively analyze the pharmacokinetic behavior of PLGA-PEG-PLGA and provide comprehensive and accurate pharmacokinetic technical support for the design, development and bioeffect evaluation of triblock PLGA-PEG-PLGA carrier material delivery systems.
Current Status of in Vivo Analysis Methods for PLGA-PEG-PLGA
The inability to achieve full-profile in vivo accurate quantitative and qualitative analysis of polymers after they enter the body is a major obstacle to the development of polymer pharmacokinetics. As a triblock copolymer, PLGA-PEG-PLGA has a complex chemical structure, a large molecular weight and a polydisperse mass distribution. It is more difficult and challenging to perform full-profile accurate quantitative analysis on it than on single-block or diblock polymers. Therefore, it is urgent to develop more accurate in vivo full-profile analysis technology for polymers, which is the key to breaking through the technical bottleneck of PLGA-PEG-PLGA pharmacokinetic research. At present, some literature uses fluorescent labeling to study the tissue distribution of PLGA-PEG-PLGA in mice through fluorescence imaging and explores the degradation behavior of PLGA-PEG-PLGA. However, as an indirect quantitative method, the fluorescent labeling method needs to detect the fluorescence intensity of the fluorescent marker to indirectly determine the concentration of the analyte. There are still the following insurmountable problems in technology: 1) The introduction of fluorescent labeling groups will change the original chemical structure of the analyte, thereby affecting its true pharmacokinetic process. It has been reported in the literature that even if 3H is used to replace 1H in the compound, its pharmacokinetic behavior will be affected; 2) The fluorescent labeling method cannot distinguish whether the observed fluorescent signal comes from the polymer to be tested or its metabolites; 3) If the fluorescent labeling group is metabolized or detached, a false positive result will be produced. In addition to the fluorescent labeling method, there are no reports on other quantitative analysis methods for PLGA-PEG-PLGA. However, the quantitative methods of other polymer excipients have certain reference value for the development of PLGA-PEG-PLGA quantitative methods. In the past, the most commonly used quantitative method for polymers was radioactive labeling, that is, radioactive isotopes were used to label the polymers, and the radioactivity intensity in the biological samples was detected to indirectly perform quantitative analysis on the polymers.
References
- Chen X, et al.; PLGA-PEG-PLGA triblock copolymeric micelles as oral drug delivery system: In vitro drug release and in vivo pharmacokinetics assessment. J Colloid Interface Sci. 2017, 490:542-552.
- Song Z, et al.; Curcumin-loaded PLGA-PEG-PLGA triblock copolymeric micelles: Preparation, pharmacokinetics and distribution in vivo. J Colloid Interface Sci. 2011, 354(1):116-23.
