Noninvasive Visualization of Pharmacokinetics,Biodistribution and Tumor Targeting of Poly[<Emphasis Type="BoldItalic">N</Emphasis>-(2-hydroxypropyl)methacrylamide] in Mice Using Contrast Enhanced MRI

Purpose To study a non-invasive method of using contrast enhanced magnetic resonance imaging (MRI) to visualize the real-time pharmacokinetics, biodistribution and tumor accumulation of paramagnetically labeled poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) copolymer conjugates with different molecular weights and spacers in tumor-bearing mice. Materials and Methods Paramagnetically labeled HPMA copolymer conjugates were synthesized by free radical copolymerization of HPMA with monomers containing a chelating ligand, followed by complexation with Gd(OAc)₃. A stable paramagnetic chelate, Gd-DO3A, was conjugated to the copolymers via a degradable spacer GlyPheLeuGly and a non-degradable spacer GlyGly, respectively. The conjugates with molecular weights of 28, 60 and 121 kDa and narrow molecular weight distributions were prepared by fractionation with size exclusion chromatography. The conjugates were injected into athymic nude mice bearing MDA-MB-231 human breast carcinoma xenografts via a tail vein. MR images were acquired before and at various time points after the injection with a 3D FLASH sequence and a 2D spin-echo sequence at 3T. Pharmacokinetics, biodistribution and tumor accumulation of the conjugates were visualized based on the contrast enhancement in the blood, major organs and tumor tissue at various time points. The size effect of the conjugates was analyzed among the conjugates. Results Contrast enhanced MRI resulted in a real-time, three-dimensional visualization of blood circulation, pharmacokinetics, biodistribution and tumor accumulation of the conjugates, and the size effect on these pharmaceutical properties. HPMA copolymer conjugates with high molecular weight had a prolonged blood circulation time and high passive tumor targeting efficiency. Non-biodegradable HPMA copolymers with molecular weights higher than the threshold of renal filtration demonstrated higher efficiency for tumor drug delivery than biodegradable poly(L-glutamic acid). Conclusions Contrast enhanced MRI is an effective method for non-invasive visualization of in vivo properties of the paramagnetically labeled polymer conjugates in preclinical studies.     

Contrast-Enhanced MRI-Guided Photodynamic Cancer Therapy with a Pegylated Bifunctional Polymer Conjugate

PURPOSE: To study contrast-enhanced MRI guided photodynamic therapy with a pegylated bifunctional polymer conjugate containing an MRI contrast agent and a photosensitizer for minimally invasive image-guided cancer treatment. METHODS: Pegylated and non-pegylated poly-(L-glutamic acid) conjugates containing mesochlorin e6, a photosensitizer, and Gd(III)-DO3A, an MRI contrast agent, were synthesized. The effect of pegylation on the biodistribution and tumor targeting was non-invasively visualized in mice bearing MDA-MB-231 tumor xenografts with MRI. MRI-guided photodynamic therapy was carried out in the tumor bearing mice. Tumor response to photodynamic therapy was evaluated by dynamic contrast enhanced MRI and histological analysis. RESULTS: The pegylated conjugate had longer blood circulation, lower liver uptake and higher tumor accumulation than the non-pegylated conjugate as shown by MRI. Site-directed laser irradiation of tumors resulted in higher therapeutic efficacy for the pegylated conjugate than the non-pegylated conjugate. Moreover, animals treated with photodynamic therapy showed reduced vascular permeability on DCE-MRI and decreased microvessel density in histological analysis. CONCLUSIONS: Pegylation of the polymer bifunctional conjugates reduced non-specific liver uptake and increased tumor uptake, resulting in significant tumor contrast enhancement and high therapeutic efficacy. The pegylated poly(L-glutamic acid) bifunctional conjugate is promising for contrast enhanced MRI guided photodynamic therapy in cancer treatment.     

Biodistribution and pharmacokinetic studies of bone-targeting N-(2-hydroxypropyl)methacrylamide copolymer-alendronate conjugates

The biodistribution and pharmacokinetics of bone-targeting N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-alendronate conjugates were evaluated following intravenous administration of radioiodinated conjugates to young healthy BALB/c mice. The synthesis of a polymerizable and cathepsin K cleavable alendronate derivative, N-methacryloylglycylglycylprolylnorleucylalendronate, enabled the preparation of HPMA copolymer-alendronate conjugates with varying composition. Using the RAFT (reversible addition-fragmentation chain transfer) polymerization technique, four conjugates with different molecular weight and alendronate content and two control HPMA copolymers (without alendronate) with different molecular weight were prepared. The results of biodistribution studies in mice demonstrated a strong binding capacity of alendronate-targeted HPMA copolymer conjugates to bone. Conjugates with low (1.5 mol%) alendronate content exhibited a similar bone deposition capacity as conjugates containing 8.5 mol % of alendronate. The molecular weight was an important factor in the biodistribution of the HPMA copolymer conjugates. More conjugate structures need to be evaluated, but the data suggest that medium molecular weights (50-100 kDa) might be effective drug carriers for bone delivery.     

Molecular imaging of HPMA copolymers: Visualizing drug delivery in cell,mouse and man

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymers and their drug conjugates are some of the most intensively investigated drug delivery systems for over 30 years. Some of the HPMA copolymer drug conjugates have entered clinical trials. Various molecular imaging technologies have been used to investigate the mechanism of drug delivery with HPMA copolymers. Fluorescence imaging has been used for the study of the process of intracellular drug delivery, including cell binding, subcellular trafficking and intracellular fate, of HPMA copolymers and drug conjugates. Magnetic resonance imaging and nuclear medicine, including γ-scintigraphy, SPECT and PET, have been used for the non-invasive visualization of pharmacokinetics, biodistribution and drug targeting efficiency of HPMA copolymers in animal models. γ-Scintigraphy has been used to study HPMA copolymer drug conjugates in human patients. The application of imaging technologies in the study of HPMA copolymers and properties of the copolymers demonstrated by imaging is summarized in this review.     

Pharmacokinetic and biodistribution studies of a bone-targeting drug delivery system based on N-(2-hydroxypropyl)methacrylamide copolymers

Osteotropicity of novel bone-targeted HPMA copolymer conjugates has been demonstrated previously with bone histomorphometric analysis. The pharmacokinetics and biodistribution of this delivery system were investigated in the current study with healthy young BALB/c mice. The 125I-labeled bone-targeted and control (nontargeted) HPMA copolymers were administered intravenously to mice, and their distribution to different organs and tissues was followed using gamma counter and single photon emission computed tomography (SPECT). Both the invasive and noninvasive data further confirmed that the incorporation of D-aspartic acid octapeptide (D-Asp8) as bone-targeting moiety could favorably deposit the HPMA copolymers to the entire skeleton, especially to the high bone turnover sites. To evaluate the influence of molecular weight, three fractions (Mw of 24, 46, and 96 kDa) of HPMA copolymer-D-Asp8 conjugate were prepared and evaluated. Higher molecular weight of the conjugate enhanced the deposition to bone due to the prolonged half-life in circulation, but it weakened the bone selectivity. A higher content of bone-targeting moiety (D-Asp8) in the conjugate is desirable to achieve superior hard tissue selectivity. Further validation of the bone-targeting efficacy of the conjugates in animal models of osteoporosis and other skeletal diseases is needed in the future.     

In vivo real-time confocal microscopy for target-specific delivery of hyaluronic acid-quantum dot conjugates

Hyaluronic acid (HA), which is a biocompatible, biodegradable, and linear polysaccharide in the body, has been widely used for various biomedical applications. In this work, real-time bioimaging for target-specific delivery of HA derivatives was carried out using quantum dots (QDs). In vitro confocal microscopy of HA-QD conjugates confirmed the intracellular delivery of HA derivatives to B16F1 cells with HA receptors by HA-receptor-mediated endocytosis. Furthermore in vivo real-time confocal microscopy of HA-QD conjugates successfully visualized the target specific delivery and accumulation of HA-QD conjugates from the fluorescence-labeled blood vessels to the liver tissues. The authors could confirm the feasibility of HA derivatives as a target-specific intracellular drug-delivery carrier for the treatment of liver diseases and the in vivo real-time confocal microscopy as a new bioimaging tool for various drug-delivery applications.From the Clinical EditorThis study demonstrates the possibility of labeling hyaluronic acid with quantum dots for visualization and for targeted intracellular drug delivery in liver disease models.     

Quantitative and specific molecular imaging of cancer with labeled engineered monoclonal antibody fragments

The high target specificity of antibodies and related constructs makes them excellent scaffolds for molecular-imaging probes. Quantitative data on biodistribution and pharmacokinetics can be acquired by radiolabeling these agents. Such studies demonstrate prolonged circulation times and resulting nonspecific accumulation with high background signal using antibody-based agents. Antibody fragments demonstrate more rapid clearance, but lower tumor uptake. Optical labeling of antibodies provides a basis for developing activatable probes that can image antigens with very high specificity, potentially allowing for the simultaneous visualization of multiple targets. While radioimmunoimaging provides valuable whole-body, quantitative information, activatable optical antibody-based agents could generate real-time diagnostic and prognostic information about near-surface lesions at high-spatial and temporal resolution without requiring ionizing radiation.     

MRI evaluation of the antitumor activity of paramagnetic liposomes loaded with prednisolone phosphate

The design of long circulating liposomes co-loaded with the glucocorticoid prednisolone phosphate (PLP) and the amphiphilic paramagnetic contrast agent Gd-DOTAMA(C(18))(2) allowed the MRI-guided in vivo visualization of the delivery and biodistribution of PLP, as well as the monitoring of drug efficacy. The performance of this theranostic probe was investigated in a mouse model bearing a melanoma B16 syngeneic tumor. The release kinetics of the drug were evaluated in vitro where it displayed a peculiar behavior characterized by a fast process (completed in few hours) involving only a small portion (<5%) of the drug. Interestingly, the incorporation of the amphiphilic imaging reporter in the liposomal bilayer slightly increased the amount of the fast-release portion (<10%), thus suggesting that it could be attributed to a drug fraction embedded in the liposomal bilayer. In fact, the release of a hydrophilic imaging probe encapsulated in the inner core of the same long circulating liposomes formulated for carrying the drug, displayed different, single-step, kinetics. The in vivo monitoring of the antitumor activity of the nanomedicine revealed that the incorporation of the MRI probe into the liposome bilayer did not significantly affect the drug efficacy. The in vivo experiments also indicated a relevant and fast liposome uptake from macrophage-rich organs like spleen and liver, which reduced the tumor accumulation of the liposomes. The accumulation of the amphipatic MRI label caused the occurrence of a long-term residual T(1) contrast still detectable 1week after injection.     

Investigation of targeting mechanism of new dextran-peptide-methotrexate conjugates using biodistribution study in matrix-metalloproteinase-overexpressing tumor xenograft model

We conducted a biodistribution study in HT-1080 bearing mice to investigate the drug targeting mechanism and the cause of side effects of the new dextran-peptide-methotrexate conjugates. HT-1080 is a human fibrosarcoma cell line that is known to overexpress matrix-metalloproteinases (MMPs). The experiments compared conjugates carrying MMP sensitive peptide linkers, conjugates carrying MMP insensitive linkers, and free methotrexate. Passive targeting was evidenced by the prolonged plasma circulation and higher tissue accumulations of both types of the conjugates compared to free methotrexate. Independent of the peptide sequence of the linker, the ratio of drug accumulation at the tumor versus drug accumulation at the major site of side effects (small intestine) for either conjugate was increased by the effect of enhance permeation and retention (EPR). The conjugate released a sufficient amount of peptidyl methotrexate to cause inhibition of tumor growth. There was no significant difference in drug accumulation at the tumor site between the MMP-sensitive and the MMP-insensitive conjugates. We concluded that the tumor targeting effect of the dextran-peptide-methotrexate conjugate was dominantly due to passive targeting and EPR. The difference in the systemic side effects observed for conjugates with different linkers could probably be attributed to their varying susceptibility towards enzymes in normal tissues.     

Poly(L-glutamic acid)--anticancer drug conjugates

Chemotherapy has had limited success in the treatment of cancer over the years, due, in part, to the untoward toxicity of the therapeutic agent to normal cells. The design of tailor-made polymer conjugates provides a synthetic approach that can overcome some of the problems. Several synthetic polymer-based anticancer drug conjugates have entered clinical studies. This report reviews the chemistry, physicochemical properties, and therapeutic applications in cancer therapy of polymeric chemotherapeutic agents based on poly(L-glutamic acid). Targeted delivery of anticancer agents using poly(L-glutamic acid) as the drug carrier is also discussed with emphasis on the design of innovative polymeric constructs.     

Poly(ethylene glycol) conjugated drugs and prodrugs: a comprehensive review

Low molecular weight Poly(ethylene glycol) (PEG) (< 20,000)-drug conjugates, prepared over a 20-year period, have been scrutinized and their properties and efficacy reviewed. No commercial products have thus far been reported for these types of compounds. However, during the past 5 years a renaissance in the field of PEG-(anticancer) drug conjugates has taken place, initiated by the use of higher molecular weight PEGs (> 20,000), especially 40,000, which is estimated to have a plasma circulating half-life of approximately 8-9 h. This recent resuscitation of small organic molecule delivery by high molecular weight PEG conjugates was founded on meaningful in vivo testing using established tumor models and has led to a clinical candidate. Recent applications of high molecular weight PEG prodrug strategies to amino-containing drugs are also detailed.     

Recent progress in drug delivery systems for anticancer agents

Recent progress in understanding the molecular basis of cancer brought out new materials such as oligonucleotides, genes, peptides and proteins as a source of new anticancer agents. Due to their macromolecular properties, however, new strategies of delivery for them are required to achieve their full therapeutic efficacy in clinical setting. Development of improved dosage forms of currently marketed anticancer drugs can also enhance their therapeutic values. Currently developed delivery systems for anticancer agents include colloidal systems (liposomes, emulsions, nanoparticles and micelles), polymer implants and polymer conjugates. These delivery systems have been able to provide enhanced therapeutic activity and reduced toxicity of anticancer agents mainly by altering their pharmacokinetics and biodistribution. Furthermore, the identification of cell-specific receptor/antigens on cancer cells have brought the development of ligand- or antibody-bearing delivery systems which can be targeted to cancer cells by specific binding to receptors or antigens. They have exhibited specific and selective delivery of anticancer agents to cancer. As a consequence of extensive research, clinical development of anticancer agents utilizing various delivery systems is undergoing worldwide. New technologies and multidisciplinary expertise to develop advanced drug delivery systems, applicable to a wide range of anticancer agents, may eventually lead to an effective cancer therapy in the future.     

Targeted multifunctional lipid-based nanocarriers for image-guided drug delivery

Lipid-based nanocarriers have proven successful in the delivery of mainly chemotherapeutic agents, and currently they are being applied clinically in the treatment of various types of cancer. These drug delivery systems achieve increased therapeutic efficacy by altering the pharmacokinetics and biodistribution of encapsulated drugs, resulting in decreased drug toxicity and enhanced accumulation in tumor tissue. This increased accumulation is due to the relatively leaky immature vasculature of a tumor. After the clinical relevance of such drug delivery systems was demonstrated, research in this area focused on optimization, both by cell specific targeting and including controlled and triggered release concepts within the carrier. These more advanced targeted nanocarriers in general have clearly shown their potential in various animal tumor models and await clinical application. The development of targeted nanocarriers in which therapeutic and imaging agents are merged into a single carrier will certainly be of importance in the near future. Indeed, scientists active in the field of imaging (e.g. nuclear and magnetic resonance imaging) have already started to exploit nanocarriers for molecular imaging. Image-guided drug delivery using these multifunctional nanocarriers, containing therapeutic and imaging agents, will ultimately allow for online monitoring of tumor location, tumor targeting levels, intratumoral localization and drug release kinetics prior and during radio- and/or chemotherapeutic treatment. This review describes the current status and challenges in the field of nanocarrier-aided drug delivery and drug targeting and discusses the opportunities of combining imaging probes with these drug carriers and the potential of these multifunctional lipid-based nanocarriers within image-guided drug delivery.     

Pharmacokinetics and in vivo fate of drug loaded chitosan nanoparticles

Chitosan is a natural polysaccharide which is generally biodegradable, biocompatible and mucoadhesive, thus, attracting considerable interest of scientific researchers. The application of chitosan as nanocarriers for drug delivery thrived. And some of their pharmacokinetics and biodistribution profiles were studied, which are crucial to develop a promising drug delivery system. In this article, we will first give an introduction for the chitosan as drug delivery system, especially as nanoparticles. Then, we focus on pharmacokinetics studies of various chitosan nanoparticles both in vitro and in vivo. In a following part, we refer to researches on biodistribution properties of chitosan nanoparticles. Here we crucially discuss the in vivo fate of chitosan nanoparticles. And finally, toxicity issue is discussed and conclusions are drawn.     

Intratumoral delivery of paclitaxel using a thermosensitive hydrogel in human tumor xenografts

Poly(organophosphazene), a novel thermosensitive hydrogel, is an injectable drug delivery system (DDS) that transforms from sol to gel at body temperature. Paclitaxel (PTX) is a mitotic inhibitor used in the treatment of various solid tumors. Due to its poor solubility in water and efflux systems in the gastrointestinal tract, PTX is a good candidate for local DDS. Here, we evaluated the penetration kinetics of PTX released from the PTX-poly(organophosphazene) hydrogel mixture in multicellular layers (MCLs) of human cancer cells. We also investigated the tumor pharmacokinetics of PTX (60 mg/kg) when administered as an intratumoral injection using poly(organophosphazene) in mice with human tumor xenografts. When PTX was formulated at 0.6 % w/w into a 10 % w/w hydrogel, the in vitro and in vivo release were found to be 40 and 90 % of the dose, respectively, in a sustained manner over 4 weeks. Exposure of MCLs to PTX-hydrogel showed time-dependent drug penetration and accumulation. In mice, the hydrogel mass was well retained over 6 weeks, and the PTX concentration in the tumor tissue was maximal at 14 days, which rapidly decreased and coincided with rebound tumor growth after 14 days of suppression. These data indicate that PTX-hydrogel should be intratumorally injected every 14 days, or drug release duration should be prolonged in order to achieve a long-term antitumor effect. Overall, poly(organophosphazene) represents a novel thermosensitive DDS for intratumoral delivery of PTX, which can accommodate a large dose of the drug in addition to reducing its systemic exposure by restricting biodistribution to tumor tissue alone.     

In vivo imaging for biodistribution and metabolism evaluations of new chemical entities

Due to numerous technical developments, in vivo imaging is suitable for pharmacokinetic and metabolism studies of new chemical entities as well as for evaluating their pharmacological or biological effects. MRI, nuclear medicine, X-Ray, ultrasound and optical imaging are available for both clinical and experimental imaging with even higher performance. For all these imaging modalities, diagnostic agents are useful to improve contrast and specificity. Specific targeting of biological events is addressed by molecular imaging. From a pharmacodynamic perspective, radiolabeling of a new chemical entity allows in vivo visualization quantitative measure of its biodistribution, its elimination and its specific molecular binding. Non-invasive imaging methods are useful for longitudinal investigations of biological changes. Based on nanotechnologies, specificity of drug delivery can be monitored by imaging. New developments in hybrid imaging technologies as well as multimodal contrast agents reinforce in vivo experimental and clinical proof of mechanism of new chemical entities.     

Novel star HPMA-based polymer conjugates for passive targeting to solid tumors

Novel star polymer-doxorubicin conjugates designed for passive tumor targeting have been developed and their potential for treatment of cancer has been investigated. In the present study the synthesis, physico-chemical characterization, drug release, bio-distribution and preliminary data of in vivo efficacy of the conjugates are described. In the water-soluble conjugates the core of a molecule formed by poly(amido amine) (PAMAM) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers bearing doxorubicin (Dox) attached by hydrazone bonds enabling intracellular pH-controlled hydrolytic drug release, or by GFLG sequence susceptible to enzymatic degradation. The controlled synthesis utilizing semitelechelic copolymer precursors facilitated preparation of polymer conjugates in a broad range of molecular weights (1.1–3.0·10⁵ g/mol). In contrast to free drug or linear conjugates the star polymer-Dox conjugates exhibited prolonged blood circulation and enhanced tumor accumulation in tumor-bearing mice indicating important role of the EPR effect. The star polymer-Dox conjugates showed significantly higher anti-tumor activity in vivo than Dox·HCl or its linear or graft polymer conjugates, if treated with a single dose 15 or 5?mg Dox eq./kg. Method of tumor initialization (acute or chronic experimental tumor models) significantly influenced effectiveness of the treatment with much lower success in treatment of mice bearing chronic tumors.     

Enhancement of the targeting capabilities of the Paclitaxel-loaded pluronic nanoparticles with a glycol chitosan/heparin composite

An enhancement of tumor-targeting capability was demonstrated with paclitaxel (PTX)-loaded Pluronic nanoparticles (NPs) with immobilized glycol chitosan and heparin. The PTX-loaded Pluronic NPs were prepared as described in our previous report by means of a temperature-induced phase transition in a mixture of Pluronic F-68 and liquid polyethylene glycol (PEG; molecular weight: 400) containing PTX. The liquid PEG is used as the solubilizer of PTX, and Pluronic F-68 is the polymer that encapsulates the PTX. The glycol chitosan and heparin were immobilized on the surface of the Pluronic NPs in an aqueous medium, and a powdery form of the glycol chitosan/heparin immobilized Pluronic NPs (composite NPs) was obtained by freeze-drying. Field emission scanning electron microscopy and a particle size analyzer were used to observe the morphology and size distribution of the prepared NPs. To apply the composite NPs as a delivery system for the model anticancer drug PTX, the release pattern and pharmacokinetic parameters were observed, and the tumor growth was monitored by injecting the composite NPs into the tail veins of tumor-bearing mice. An enhancement of tumor-targeting capability of NPs was verified by using noninvasive live animal imaging technology to observe the time-dependent excretion profile, the in vivo biodistribution, circulation time, and the tumor-targeting capability of composite NPs.     

酸敏感靶向的阿霉素聚酰胺-胺型树枝状高分子的抗肿瘤研究(英文)

聚酰胺-胺型树枝状高分子是近年来新出现的一种表面有多官能团的药物载体。本研究中,顺-4,7,10,13,16,19-二十二碳六烯酸(DHA)和阿霉素(DOX)共价连接到2.5代的PAMAM分子上。通过这种设计,载体结构可以优化药物在血液中的循环,药物和载体之间的酸敏感键可以优化药物的释放。体外实验结果表明,pH4.5条件下阿霉素的12小时累积释放量约为pH7.4条件下的两倍。这种酸敏感的药物释放可以提高药效。药动学研究表明,DHA-PAMAM-DOX能提高药物浓度-时间曲线下面积。在荷B16黑色素瘤小鼠模型中,实验构建的DHA-PAMAM-DOX抑瘤效果优于同等剂量(5 mg/kg)的阿霉素溶液。研究表明DHA-PAMAM-DOX在肿瘤药物靶向给药方面有很好的发展前景。     

Delivery of peptides to the blood and brain after oral uptake of quaternary ammonium palmitoyl glycol chitosan nanoparticles

The clinical development of therapeutic peptides has been restricted to peptides for non-CNS diseases and parenteral dosage forms due to the poor permeation of peptides across the gastrointestinal mucosa and the blood-brain barrier. Quaternary ammonium palmitoyl glycol chitosan (GCPQ) nanoparticles facilitate the brain delivery of orally administered peptides such as leucine(5)-enkephalin, and here we examine the mechanism of GCPQ facilitated oral peptide absorption and brain delivery. By analyzing the oral biodistribution of radiolabeled GCPQ nanoparticles, the oral biodistribution of the model peptide leucine(5)-enkephalin and coherent anti-Stokes Raman scattering microscopy tissue images after an oral dose of deuterated GCPQ nanoparticles, we have established a number of facts. Although 85-90% of orally administered GCPQ nanoparticles are not absorbed from the gastrointestinal tract, a peak level of 2-3% of the oral GCPQ dose is detected in the blood 30 min after dosing, and these GCPQ particles appear to transport the peptides to the blood. Additionally, although peptide loaded nanoparticles from low (6 kDa) and high (50 kDa) molecular weight GCPQ are taken up by enterocytes, polymer particles with a polymer molecular weight greater than 6 kDa are required to facilitate peptide delivery to the brain after oral administration. By examining our current and previous data, we conclude that GCPQ particles facilitate oral peptide absorption by protecting the peptide from gastrointestinal degradation, adhering to the mucus to increase the drug gut residence time and transporting GCPQ associated peptide across the enterocytes and to the systemic circulation, enabling the GCPQ stabilized peptide to be transported to the brain. Orally administered GCPQ particles are also circulated from the gastrointestinal tract to the liver and onward to the gall bladder, presumably for final transport back to the gastrointestinal tract.