The Use of Cyclodextrin Inclusion Complexes to Increase the Solubility and Pharmacokinetic Profile of Albendazole.

Albendazole is the preferred deworming drug and has strong insecticidal effects on human and animal helminth parasites, showing remarkable activity against hepatocellular carcinoma and colorectal cancer cells. However, it is classified as being in class II in the Biopharmaceutics Classification System due to its poor water solubility (0.2 mg/L) and high permeability, which make the clinical application of albendazole impractical. Through complexation with methyl-ß-cyclodextrin, as the best result so far, albendazole's water solubility was increased by 150,000 times, and albendazole could be 90% released during the first 10 min. In an in vivo pharmacokinetic study, the Cmax and Tmax of the active metabolized sulfoxide were changed from 2.81 µg/mL at 3 h to 10.2 µg/mL at 6 h and the AUC0-48 was increased from 50.72 h⁎µg/mL to 119.95 h⁎µg/mL, indicating that the inclusion complex obtained can be used as a new oral therapeutic anti-anthelmintic and anti-tumor agent formulation.

Cancer-Related Intracellular Signalling Pathways Activated by DOXorubicin/Cyclodextrin-Graphene-Based Nanomaterials.

In the last decade, nanotechnological progress has generated new opportunities to improve the safety and efficacy of conventional anticancer therapies. Compared with other carriers, graphene nanoplatforms possess numerous tunable functionalities for the loading of multiple bioactive compounds, although their biocompatibility is still a debated concern. Recently, we have investigated the modulation of genes involved in cancer-associated canonical pathways induced by graphene engineered with cyclodextrins (GCD). Here, we investigated the GCD impact on cells safety, the HEp-2 responsiveness to Doxorubicin (DOX) and the cancer-related intracellular signalling pathways modulated by over time exposure to DOX loaded on GCD (GCD@DOX). Our studies evidenced that both DOX and GCD@DOX induced p53 and p21 signalling resulting in G0/G1 cell cycle arrest. A genotoxic behaviour of DOX was reported via detection of CDK (T14/Y15) activation and reduction of Wee-1 expression. Similarly, we found a cleavage of PARP by DOX within 72 h of exposure. Conversely, GCD@DOX induced a late cleavage of PARP, which could be indicative of less toxic effect due to controlled release of the drug from the GCD nanocarrier. Finally, the induction of the autophagy process supports the potential recycling of DOX with the consequent limitation of its toxic effects. Together, these findings demonstrate that GCD@DOX is a biocompatible drug delivery system able to evade chemoresistance and doxorubicin toxicity.

Aqueous eye drops containing drug/cyclodextrin nanoparticles deliver therapeutic drug concentrations to both anterior and posterior segment.

Using topical application to deliver therapeutic concentrations of drugs to the posterior segment of the eye remains very challenging. As a result, posterior segment diseases are usually treated by intravitreal injection or implant. While topical treatments are commonly used for anterior segment conditions, they sometimes require frequent applications. Eye drop formulations based on γ-cyclodextrin (γCD)-based nanoparticle aggregates were developed, which in animal models and clinical studies deliver therapeutic concentrations of drugs (dorzolamide and dexamethasone) to both anterior and posterior segments of the eye. An early study in humans showed dorzolamide/γCD eye drops could achieve comparable intraocular pressure decreases to commercial dorzolamide eye drops, but with less frequent application. Pilot studies with dexamethasone/γCD eye drops suggested that they could be effective in a range of conditions, including diabetic macular oedema, cystoid macular oedema and vitritis secondary to uveitis, postcataract surgery inflammation and postoperative treatment in trabeculectomy. Phase II studies with similar dexamethasone/γCD nanoparticle eye drops in diabetic macular oedema and postcataract surgery inflammation have recently been completed. This technology has the potential to be used with other classes of drug molecules and to replace or complement invasive treatments, providing safer, non-invasive therapies, particularly for posterior segment conditions, that can be self-administered as eye drops by patients.

Exploring Charged Polymeric Cyclodextrins for Biomedical Applications.

Over the years, cyclodextrin uses have been widely reviewed and their proprieties provide a very attractive approach in different biomedical applications. Cyclodextrins, due to their characteristics, are used to transport drugs and have also been studied as molecular chaperones with potential application in protein misfolding diseases. In this study, we designed cyclodextrin polymers containing different contents of ß- or γ-cyclodextrin, and a different number of guanidinium positive charges. This allowed exploration of the influence of the charge in delivering a drug and the effect in the protein anti-aggregant ability. The polymers inhibit Amiloid ß peptide aggregation; such an ability is modulated by both the type of CyD cavity and the number of charges. We also explored the effect of the new polymers as drug carriers. We tested the Doxorubicin toxicity in different cell lines, A2780, A549, MDA-MB-231 in the presence of the polymers. Data show that the polymers based on γ-cyclodextrin modified the cytotoxicity of doxorubicin in the A2780 cell line.

Erlotinib entrapped in cholesterol-depleting cyclodextrin nanoparticles shows improved antitumoral efficacy in 3D spheroid tumors of the lung and the liver.

Erlotinib (ERL), a tyrosine kinase inhibitor approved for therapeutic use in non-small cell lung cancer is further researched for eventual liver cancer treatment. However, conventional ERL has important bioavailability problems resulting from oral administration, poor solubility and gastrointestinal degradation into inactive metabolites. Alternative administration routes and nanoparticulate drug delivery systems are studied to prevent or reduce these drawbacks. In this study, ERL-loaded CD nanosphere and nanocapsule formulations capable of cholesterol depletion in resistant cancer cells were evaluated for ERL delivery. Drug loading and release profile depended largely on the surface charge of nanoparticles. Antiproliferative activity data obtained from 2D and 3D cell culture models demonstrated that polycationic ßCD nanocapsules were the most effective formulation for ERL delivery to lung and liver cancer cells. 3D tumour tumoral penetration studies further revealed that nanocapsule formulations penetrated deeper into the tumour through the multilayered cells. Furthermore, all formulations were able to extract membrane cholesterol from lung and liver cancer cell lines, indicating the induction of apoptosis and overcoming drug resistance. In conclusion, given their tumoral penetration and cell membrane cholesterol depletion abilities, amphiphilic CD nanocapsules emerge as promising alternatives to improve the safety and efficiency of ERL treatment of both liver and lung tumours.

Population pharmacokinetic analysis of nanoparticle-bound and free camptothecin after administration of NLG207 in adults with advanced solid tumors.

PURPOSE: NLG207 (formerly CRLX101) is a nanoparticle-drug conjugate (NDC) of the potent topoisomerase I inhibitor, camptothecin (CPT). The present study sought to characterize the complex pharmacokinetics (PK) of NLG207 and better describe CPT release from nanoparticles using a population PK (popPK) model. METHODS: From 27 patients enrolled on two phase II clinical trials (NCT02769962 and NCT03531827), dense sampling was performed up to 48 h post-administration of NLG207 during cycle one and six of treatment; samples were also collected at ~ 360 h post-dose. Conjugated and free CPT concentrations were quantified from each sample, resulting in 477 observations to build a popPK model using non-linear mixed-effects modeling. RESULTS: The PK of NLG207 was characterized by combining two linear two-compartment models with first-order kinetics each to describe nanoparticle-bound (conjugated) and free CPT. Allometric scaling based on body weight provided the best body-size descriptor for all PK parameters. The typical volumes of distribution of the conjugated CPT central and free CPT central compartments were 3.16 L (BSV CV%; 18.1%) and 21.1 L (CV%; 79.8%), respectively. CPT release from the nanoparticle formulation was characterized via an initial rapid clearance of 5.71 L/h (CV%; 62.6%), which decreased via first-order decay (estimated half-life of 0.307 h) to the steady-state value of 0.0988 L/h (CV%; 33.5%) by ~ 4 h after end of infusion. Renal clearance of free CPT was 0.874 L/h (CV%; 42.2%). CONCLUSION: The popPK model confirmed nanoparticle behavior of conjugated CPT and mechanistically characterized CPT release from NLG207. The current analysis provides a strong foundation for future study as a potential predictive tool in ongoing NLG207 clinical trials.

Comparative analysis of solubilization and complexation characteristics for new antifungal compound with cyclodextrins. Impact of cyclodextrins on distribution process.

From a pharmaceutical standpoint, cyclodextrin-based products have deservedly gained substantial market share due to their ability to improve undesirable physicochemical properties of drugs. In this study the solubility of a potenial antifungal compound (L-173) has been improved essentially by addition of ß-cyclodextrin (ß-CD), 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD), and heptakis(2,6-di-O-methyl)-ß-cyclodextrin (DM-ß-CD) in aqueous solutions (pH 2.0 and pH 7.4) at 298.15-313.15 K. The phase solubility diagrams were constructed. The stoichiometric ratio of the complexes was determined as 1:1. The stability constants of L-173 with all three CDs in acidic medium belong to the range optimal for the improvement of the bioavailability of hydrophobic drugs. DM-ß-CD was assigned as the best solubilizer for L-173. The driving forces of the solubilization and complexation process were revealed by evaluating the thermodynamic parameters. The distribution behavior of L-173 in the 1-octanol/buffer and 1-hexane buffer systems at pH 2.0 and pH 7.4 in the presence of different CDs concentrations was studied. The reduction of the distribution coefficients with the increasing of CD concentration was detected due to complex formation. Based on the analysis of the solubility-distribution relationship, the L-173 partitioning between the biological tissues and penetration through the biological membranes in case when cyclodextrins are used as solubilizers was evaluated, and the optimal CD concentrations were proposed.

Characteristic of Cyclodextrins: Their Role and Use in the Pharmaceutical Technology.

About 40% of newly-discovered entities are poorly soluble in water, and this may be an obstacle in the creation of new drugs. To address this problem, the present review article examines the structure and properties of cyclodextrins and the formation and potential uses of drug - cyclodextrin inclusion complexes. Cyclodextrins are cyclic oligosaccharides containing six or more D-(+)- glucopyranose units linked by α-1,4-glycosidic bonds, which are characterized by a favourable toxicological profile, low local toxicity and low mucous and eye irritability; they are virtually non-toxic when administered orally. They can be incorporated in the formulation of new drugs in their natural form (α-, ß-, γ-cyclodextrin) or as chemically-modified derivatives. They may also be used as an excipient in drugs delivered by oral, ocular, dermal, nasal and rectal routes, as described in the present paper. Cyclodextrins are promising compounds with many beneficial properties, and their use may be increasingly profitable for pharmaceutical scientists.

Measurement of NLG207 (formerly CRLX101) nanoparticle-bound and released camptothecin in human plasma.

Camptothecin (CPT), a potent inhibitor of topoisomerase I and HIF-1α, failed to demonstrate utility as an anti-cancer agent in early clinical trial investigations, primarily due to limited clinical activity and significant toxicity attributable to unfavorable physicochemical properties (e.g. low plasma solubility, pH-labile lactone ring). NLG207 (formerly CRLX101), a nanoparticle-drug conjugate (NDC) of CPT designed to optimize plasma pharmacokinetics and facilitate drug delivery to tumors, is included as part of combination treatment in two Phase II clinical trials ongoing at the National Cancer Institute (NCT02769962 and NCT03531827). To better understand the potential for drug-drug interactions and to correlate drug exposure to clinical outcomes and pharmacodynamic biomarkers, a robust analytical method was developed to measure CPT in human plasma. Two sample processing methods were developed to quantify both NDC-bound CPT and free CPT, primarily via alteration of pH conditions. A solid-phase extraction recovered >79 % of CPT prior to quantitative analysis by ultra HPLC-MS/MS. Dynamic calibration ranges of 10 to 10,000 ng/mL and 1 to 1000 ng/mL for total and free CPT, respectively were utilized to capture clinical ranges. NLG207 NDCs demonstrated significant rates of CPT release in human plasma at room temperature after 2 h but were shown to be stable at 4 °C for 24 h and through 4 freeze/thaw cycles. This assay was used to quantitate CPT plasma concentrations in clinical samples to confirm clinical utility following NLG207 treatment in subjects with advanced prostate cancer.

Biopharmaceutical and antifungal properties of ellagic acid-cyclodextrin using an in vitro model of invasive candidiasis.

Aim: To investigate biopharmaceutical and antifungal properties of pure and complexed ellagic acid. Materials & methods: Caco-2 cells cultured in a Transwell® inserts were infected with Candida albicans to develop an in vitro model. Ellagic acid was complexed with cyclodextrins. Microbial compositions, ellagic acid concentration as function of time and characterization studies of complexes were evaluated. Results: Ellagic acid presented ability to reduce C. albicans invasion, although this was not statistically significant. Its poor water solubility and absorption probably limited this ability. Water solubility was increased after complexation with hydroxypropyl-ß-CD; however, ellagic acid/hydroxypropyl-ß-CD did not improve the antifungal activity. Conclusion: Although ellagic acid presented a promising antifungal activity, its biopharmaceutical properties limit such activity and should be improved.

Preparation, characterization and pharmacokinetic evaluation of rosuvastatin calcium incorporated cyclodextrin-polyanhydride nanoparticles.

Objective: The aim of the study was to formulate, cyclodextrin (CD)-polyanhydride (PA) nanoparticles (CPNs) with rosuvastatin calcium (RCa) in order to enhance the poor oral bioavailability. Methods: CPNs containing RCa/CD complexes were prepared by a modified solvent displacement method and morphological analyses, particle size (PS), polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (EE), DSC, FT-IR, XRD, 1H-NMR analyses were performed. In vitro release properties, release kinetics, cytotoxicity, in vitro permeability and pharmacokinetic studies were also studied. The stability of the formulations were evaluated during the storage period of 3 months. Results: The physicochemical studies showed that the RCa/CD complexes were well incorporated into CPNs resulted in nanosized particles (215.22 and 189.13 nm) with homogenous size distribution (PDI: 0.203 and 0.182) with relatively high incorporation capacity (76.11 and 68.18%) for the CPN1 and CPN2 formulations respectively. Sustained release of RCa from CPNs were achieved. The cytotoxicity values showed that the safety of the formulations. According to permeability studies, pure RCa had lowest permeability data (3.08 × 10-7 cm⋅s-1 Papp value) while CPNs gained higher permeability data (1.36 × 10-5 and 1.12 × 10-5 cm⋅s-1 Papp values) for the CPN1 and CPN2 formulations respectively. CPN2 formulation was selected for pharmacokinetic studies and analyses results demonstrated that approximately 8-fold relative oral bioavailability enhancement compared to the pure RCa was achieved. Conclusion: Considering the analyses results of the study, CPNs can be regarded as suitable, safe, functional oral delivery systems for RCa with enhanced oral bioavailability.

Lipid nanoparticles as carriers of cyclodextrin inclusion complexes: A promising approach for cutaneous delivery of a volatile essential oil.

Solid inclusion complexes with cyclodextrins (CD) may be used to overcome volatility and solubility problems of essential oils of pharmacological interest. However, they lack the many dermatological advantages of lipid nanoparticles. This study intends to evaluate the ability of nanostructured lipid carriers (NLC) to encapsulate hydroxypropyl-ß-cyclodextrin inclusion complexes of Lippia origanoides essential oil (EO) and to maintain the desirable aspects of lipid colloids interaction with the skin, specifically follicular accumulation and controlled delivery. CD and NLC were also evaluated separately. Thymol (TML) was used as the essential oil marker and to produce control formulations. As expected, CD alone, though effective in overcoming volatility and low aqueous solubility of TML, were ineffective in controlling marker release (˜50% of EO released after 3 h, Hixson-Crowell kinetics). Even though NLC controlled drug release (˜20% EO released after 12 h, zero-order kinetics) enabling TML penetration into the skin (> 40 µg/cm2after 12 h), NLC alone were not efficient in preventing TML volatility, especially at higher temperatures (calculated shelf-life of 2 days at 35 °C). The combined approach resulted in a synergistic effect (˜20% EO released after 12 h; shelf life of 6 days). The lack of statistical difference of TML skin penetration from NLC and NLC-CD suggests the developed system maintained all skin interaction aspects of lipid colloids, including follicular accumulation forming a depot for controlled delivery. In conclusion, lipid nanoparticles demonstrated to be promising carriers for inclusion complexes of this particular volatile essential oil.

Nanoporous CD-MOF particles with uniform and inhalable size for pulmonary delivery of budesonide.

It is essential to optimize a carrier of dry powder inhalation (DPI) for the aerodynamic deposition in vitro to achieve pulmonary delivery of drug molecules in vivo. In this study, neutralized nanoporous γ-cyclodextrin metal-organic framework (CD-MOF) crystals with cubic morphology and uniform inhalation size were developed and modified as a DPI carrier for budesonide (BUD). Cholesterol (CHO) and leucine (LEU)-poloxamer were used to modify the CD-MOF powder for the improvement of flowability and particle aerodynamic behaviour, for which the particle size distribution, Carr's index and in vitro pulmonary deposition were assessed. Compared to CD-MOF or LEU-CD-MOF-BUD, CHO-CD-MOF had a superior mass median aerodynamic diameter (4.35 ±â€¯0.04 µm) and inhalable performance (fine particle fraction of 30.60 ±â€¯0.76%), which were maintained after budesonide loading (4.47 ±â€¯0.30 µm, 24.95 ±â€¯4.33%). The crystallinity, cytotoxicity and in vivo deposition of drug loaded samples (CHO-CD-MOF-BUD) were then investigated by powder X-ray diffraction (PXRD), cell viability study, in vivo fluorescence imaging and pharmacokinetic studies in rats. The characteristic PXRD crystallinity peaks of budesonide disappeared after being loaded into CHO-CD-MOF, potentially indicating the molecular incorporation of budesonide into the pores of CD-MOF. The cell viability of A549 cell was more than 90% for CHO-CD-MOF-BUD as a result of the good biocompatibility of CD-MOF. When Rhodamine B was carried by the DPI particles, the fluorescence signal at the lung tissue was markedly improved after cholesterol modification compared with CD-MOF, whilst the bioavailability of CHO-CD-MOF-BUD in rat was equivalent with that of the commercial product of Pulmicort Turbuhaler. Therefore, the CD-MOF powders modified by cholesterol can be used as a promising inhalable carrier for pulmonary delivery of drugs with small dose.

Development of self-assembled multi-arm polyrotaxanes nanocarriers for systemic plasmid delivery in vivo.

Polyrotaxane (PRX) is a promising supramolecular carrier for gene delivery. Classic PRX exhibits a linear structure in which the amine-functionalized α-cyclodextrin (CD) is threaded along the entire polyethylene glycol (PEG) backbone. While promising in vitro, the absence of free PEG moieties after CD threading compromised the in vivo implementation, due to the unfavorable pharmacokinetics (PK) and biodistribution profile. Herein, we developed a multi-arm PRX nanocarrier platform, which has been designed for protective nucleic acid encapsulation, augmented biodistribution and PK, and suitable for intravenous (IV) administration. A key design was to introduce cationic CD rings onto a multi-arm PEG backbone in a spatially selective fashion. The optimal structural design was obtained through iterative rounds of experimentation to determine the appropriate type and density of cationic charge on CD ring, the degree of PEGylation, the size and structure of polymer backbone, etc. This allowed us to effectively deliver large size reporter and therapeutic plasmids in cancer mouse models. Post IV injection, we demonstrated that our multi-arm polymer design significantly enhanced circulatory half-life and PK profile compared to the linear PRX. We continued to use the multi-arm PRX to formulate a therapeutic plasmid encoding an immunomodulatory cytokine, IL-12. When tested in a colon cancer syngeneic mouse model with same background, the IL-12 plasmid was protected by the multi-arm PRX and delivered through the tail vein to the tumor site, leading to a significant tumor inhibition effect. Moreover, our delivery system was devoid of major systemic toxicity.

Molecular Imprinting of Cyclodextrin Supramolecular Hydrogels Improves Drug Loading and Delivery.

Cyclodextrin-based controlled delivery materials have previously been developed for controlled release of different therapeutic drugs. In this study, a supramolecular hydrogel made from cyclodextrin-based macromonomers is subjected to molecular imprinting to investigate the impact on release kinetics and drug loading, when compared with non-imprinted, or alternately imprinted hydrogels. Mild synthesis conditions are used to molecularly imprint three antibiotics-novobiocin, rifampicin, and vancomycin-and to test two different hydrogel chemistries. The release profile and drug loading of the molecularly imprinted hydrogels are characterized using ultraviolet spectroscopy over a period of 35 days and compared to non-imprinted, and alternately imprinted hydrogels. While only modest differences are observed in the release rate of the antibiotics tested, a substantial difference is observed in the total drug-loading amount possible for hydrogels releasing drugs which has been templated by those drugs. Hydrogels releasing drugs which are templated by other drugs do not show improved release or loading. Analysis by FTIR does not show substantial incorporation of drug into the polymer. Lastly, bioactivity assays confirmed long-term stability and release of incorporated antibiotics.

Inclusion complexes and self-assembled cyclodextrin aggregates for increasing the solubility of benzimidazoles

Albendazole and fenbendazole are imidazole derivatives that exhibit broad spectrum activity against parasites, but the low solubility of these drugs considerably reduces their effectiveness. Complexation of albendazole and fenbendazole with cyclodextrins (ß-cyclodextrin and hydroxypropyl-ß-cyclodextrin) in both water and an aqueous solution of polyvinylpyrrolidone (PVP-k30) was studied to determine if it could increase the solubility and dissolution rate of the drugs. In an aqueous solution, ß-cyclodextrin increased the solubility of albendazole from 0.4188 to ~93.47 µg mL-1 (223×), and of fenbendazole from 0.1054 to 45.56 µg mL-1 (432×); hydroxypropyl-ß-cyclodextrin, on the other hand, increased solubility to ~443.06 µg mL-1 (1058×) for albendazole and ~159.36 µg mL-1 (1512×) for fenbendazole. The combination of hydroxypropyl-ß-cyclodextrin and polyvinylpyrrolidone enabled a solubility increase of 1412× (~591.22 µg mL-1) for albendazole and 1373× (~144.66 µg mL-1) for fenbendazole. The dissolution rate of the drugs was significantly increased in binary and ternary systems, with hydroxypropyl-ß-cyclodextrin proving to be more effective. The presence of the water-soluble PVP-k30 increased the dissolution rate and amorphization of the complexes. Analysis of the changes in displacement and the profile of the cyclodextrin bands in the 1H NMR spectra revealed a molecular interaction and pointed to an effective complexation in the drug/cyclodextrin systems. Monomeric forms and nanoclusters of cyclodextrins were observed in the drug/cyclodextrin systems, suggesting that the increase in solubility of the drugs in the presence of cyclodextrins should not be attributed only to the formation of inclusion complexes, but also to the formation of cyclodextrin aggregates

Enhanced oral bioavailability of fluvastatin by using nanosuspensions containing cyclodextrin.

BACKGROUND: In this study, fluvastatin (FVT) nanosuspensions containing cyclodextrin were developed to improve oral bioavailability. METHODS: FVT nanosuspensions containing cyclodextrin were prepared by a high pressure homogenization technique. The nanosuspensions system was then characterized by transmission electron microscopy (TEM), particle size, differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD). In addition, in vitro drug release properties, pharmacokinetics and pharmacodynamics were also investigated in detail. RESULTS: After lyophilization, the nanosuspensions could be redispersed gently and with a narrow particle size distribution, but the particle size has no obvious change. The powder X-ray diffraction and differential scanning calorimetry of FVT nanosuspensions showed that FVT existed in amorphous form in nanosuspensions. In vitro release, FVT nanosuspensions have sustained-release properties. Meanwhile, FVT nanosuspensions could significantly modify the pharmacokinetic profile and increase the bioavailability of FVT by more than 2.4-fold in comparison with the FVT capsules group. In vivo irritation test showed that there was almost no evidence of hemorrhagic mucosal erosion and intestinal villus destruction in rat gastric mucosa. CONCLUSION: The combination of nanocrystallization and cyclodextrin complexation techniques is a new attempt to formulate poorly water-soluble FVT.

Potent in vivo lung cancer Wnt signaling inhibition via cyclodextrin-LGK974 inclusion complexes.

Activation of the Wnt signaling pathway promotes lung cancer progression and contributes to poor patient prognosis. The porcupine inhibitor LGK974, a novel orally bioavailable cancer therapeutic in Phase I clinical trials, induces potent Wnt signaling inhibition and leads to suppressed growth and progression of multiple types of cancers. The clinical use of LGK974, however, is limited in part due to its low solubility and high toxicity in tissues that rely on Wnt signaling for normal homeostasis. Here, we report the use of host-guest chemistry to enhance the solubility and bioavailability of LGK974 in mice through complexation with cyclodextrins (CD). We assessed the effects of these complexes to inhibit Wnt signaling in lung adenocarcinomas that are typically driven by overactive Wnt signaling. 2D 1H NMR confirmed host-guest complexation of CDs with LGK974. CD:LGK974 complexes significantly decreased the expression of Wnt target genes in lung cancer organoids and in lung cancer allografts in mice. Further, CD:LGK974 complexes increased the bioavailability upon oral administration in mice compared to free LGK974. In a mouse lung cancer allograft model, CD:LGK974 complexes induced potent Wnt signaling inhibition with reduced intestinal toxicity compared to treatment with free drug. Collectively, the development of these complexes enables safer and repeated oral or parenteral administration of Wnt signaling inhibitors, which hold promise for the treatment of multiple types of malignancies.

In vitro evaluation of a biomaterial-based anticancer drug delivery system as an alternative to conventional post-surgery bone cancer treatment.

Patients diagnosed with osteosarcoma are currently treated with intravenous injections of anticancer agents after tumor resection. However, due to remaining neoplastic cells at the site of tumor removal, cancer recurrence often occurs. Successful bone regeneration combined with the control of residual cancer cells presents a challenge for tissue engineering. Cyclodextrins loaded with chemotherapeutic drugs reversibly release the drugs over time. Hydroxyapatite bone biomaterials coated with doxorubicin-loaded cyclodextrin should release the drug with time after implantation directly at the original tumor site and may be a way to eliminate residual neoplastic cells. In the present study, we have carried out in vitro studies to evaluate such a drug-delivery system and have shown that doxorubicin released from cyclodextrin-coated hydroxyapatite retained biological activity and exhibited longer and higher cytotoxic effects on both cancer (osteosarcoma cells) and healthy cells (primary osteoblasts and endothelial cells) compared to biomaterials without cyclodextrin loaded with doxorubicin. Furthermore, doxorubicin released from biomaterials with cyclodextrin moderately induced the expression of tumor suppressor protein p53 whereas p21 expression was similar to control cells. In addition, hypoxic conditions, which occur after implantation until blood-flow to the area is regenerated, protected endothelial cells and primary osteoblasts from doxorubicin-induced cytotoxicity. This chemo-protective effect was far less prominent for the osteosarcoma cells. These findings indicate that a hydroxyapatite-cyclodextrin-doxorubicin chemotherapeutic strategy may enhance the drug-targeting effect on tumor cells while protecting the more sensitive healthy cells for a period of time after implantation. A successful integration of such a drug delivery system might allow healthy cells to initially survive during the doxorubicin exposure period, while eliminating residual neoplastic cells.

Linear Cyclodextrin Polymer Prodrugs as Novel Therapeutics for Niemann-Pick Type C1 Disorder.

Niemann-Pick Type C1 disorder (NPC) is a rare lysosomal storage disease characterized by the accumulation of cholesterol in lysosomes. NPC has no FDA approved treatments yet, however 2-hydroxypropyl-ß-cyclodextrin (HPßCD) has shown efficacy for treating the disease in both mouse and feline NPC models and is currently being investigated in late stage clinical trials. Despite promising results, therapeutic use of HPßCD is limited by the need for high doses, ototoxicity and intrathecal administration. These limitations can be attributed to its poor pharmacokinetic profile. In the attempt to overcome these limitations, we have designed a ß-cyclodextrin (ßCD) based polymer prodrugs (ORX-301) for an enhanced pharmacokinetic and biodistribution profile, which in turn can potentially provide an improved efficacy at lower doses. We demonstrated that subcutaneously injected ORX-301 extended the mean lifespan of NPC mice at a dosage 5-fold lower (800 mg/kg, body weight) the HPßCD dose proven efficacious (4000 mg/kg). We also show that ORX-301 penetrates the blood brain barrier and counteracts neurological impairment. These properties represent a substantial improvement and appear to overcome major limitations of presently available ßCD-based therapy, demonstrating that this novel prodrug is a valuable alternative/complement for existing therapies.