Enhancing near-infrared fluorescence intensity and stability of PLGA-b-PEG micelles by introducing Gd-DOTA at the core boundary.

Micelles have been extensively used in biomedicine as potential carriers of hydrophobic fluorescent dyes. Their small diameters can potentially enable them to evade recognition by the reticuloendothelial system, resulting in prolonged circulation. Nevertheless, their lack of stability in physiological environments limits the imaging utility of micelles. In particular, when a dye sensitive to water, such as IR-1061, is encapsulated in the micelle core, the destabilized structure leads to interactions between water and dye, degrading the fluorescence. In this study, we investigated a method to improve micelle stability utilizing the electrical effect of gadolinium (Gd3+ ) and tetraazacyclododecane tetraacetic acid (DOTA), introduced into the micelles. Three micellar structures, one containing a poly(lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-b-PEG) block copolymer, and two other structures, including PLGA-b-PEG with DOTA or Gd-DOTA introduced at the boundary of PLGA and PEG, were prepared with IR-1061 in the core. Structures that contained DOTA at the border of the PLGA core and PEG shell exhibited much higher fluorescence intensity than probes without DOTA. With Gd3+ ions at the DOTA center, fluorescence stability was enhanced remarkably in physiological environments. Most interesting is the finding that fluorescence is enhanced with increased Gd-DOTA concentrations. In conclusion, we found that overall fluorescence and stability are improved by introducing Gd-DOTA at the boundary of the PLGA core and PEG shell. Improving micelle stability is crucial for further biomedical applications of micellar probes such as bimodal fluorescence and magnetic resonance imaging.

Glucose microenvironment sensitive degradation of arginine modified calcium sulfate reinforced poly(lactide-co-glycolide) composite scaffolds.

Poly(lactide-co-glycolide) (PLGA) and calcium sulfate composites are promising biodegradable biomaterials but are still challenging to use in people with high levels of blood glucose or diabetes. To date, the influence of glucose on their degradation has not yet been elucidated and thus calls for more research attention. Herein, a novel calcium sulfate whisker with L-arginine was used to effectively tune its crystal morphology and was employed as a reinforced phase to construct the PLGA-based composite scaffolds (ArgCSH/PLGA) with a sleeve porous structure. ArgCSH/PLGA showed excellent elastic modulus and strength in the compression and bending models. Moreover, an in vitro immersion test showed that ArgCSH/PLGA possessed degradation and redeposition behaviors sensitive to glucose concentration, and the adsorbed Arg played a crucial role in the degradation process. The subsequent cell functional evaluation showed that ArgCSH could effectively protect cells from damage caused by AGEs and promote osteogenic differentiation. The corresponding degradation products of ArgCSH/PLGA displayed the ability to regulate osteoblast bone differentiation and accelerate matrix mineralization. These findings provide new insights into the interaction between biomaterials and the physiological environment, which may be useful in expanding the targeted choice of efficient bone graft biodegradable materials for diabetic osteoporosis.

Liposomes Affect Protein Release and Stability of ITA-Modified PLGA-PEG-PLGA Hydrogel Carriers for Controlled Drug Delivery.

Fat grafting, a key regenerative medicine technique, often requires repeat procedures due to high-fat reabsorption and volume loss. Addressing this, a novel drug delivery system uniquely combines a thermosensitive, FDA-approved hydrogel (itaconic acid-modified PLGA-PEG-PLGA copolymer) with FGF2-STAB, a stable fibroblast growth factor 2 with a 21-day stability, far exceeding a few hours of wild-type FGF2's stability. Additionally, the growth factor was encapsulated in "green" liposomes prepared via the Mozafari method, ensuring pH protection. The system, characterized by first-order FGF2-STAB release, employs green chemistry for biocompatibility, bioactivity, and eco-friendliness. The liposomes, with diameters of 85.73 ± 3.85 nm and 68.6 ± 2.2% encapsulation efficiency, allowed controlled FGF2-STAB release from the hydrogel compared to the unencapsulated FGF2-STAB. Yet, the protein compromised the carrier's hydrolytic stability. Prior tests were conducted on model proteins human albumin (efficiency 80.8 ± 3.2%) and lysozyme (efficiency 81.0 ± 2.7%). This injectable thermosensitive system could advance reconstructive medicine and cosmetic procedures.

Design of experiments approach for the development of a validated method to determine the exenatide content in poly(lactide-co-glycolide) microspheres.

Due to the lack of pharmacopeia guidelines for injectable microspheres based on poly (D, L-lactide-co-glycolide) (PLGA), an internal method validation is a critical prerequisite for quality assurance. One of the essential issues of developing peptide-based drugs loaded PLGA microspheres is the precise determination of the amount of peptide drug entrapped in the microspheres. The aim of this study is the development and optimization of a method for measuring the drug content loading of PLGA microspheres using exenatide as a model peptide drug. Exenatide-loaded PLGA microspheres were prepared by a double emulsion solvent evaporation method. The extraction method to determine exenatide content in microspheres was optimized using Design of Experiments (DoE) approach. After the initial screening of six factors, using Fractional Factorial design (FFD), four of them, including type of organic solvent, buffer/organic solvent ratio (v/v), shaking time and pH, exhibited significant effects on the response, namely the exenatide loading, and a Box-Behnken design (BBD) was subsequently applied to obtain its optimum level. The optimum level for organic solvent volume, buffer/organic solvent ratio, shaking time, and pH were 4 ml, 1, 5.6 hrs, and pH 6, respectively. The exenatide content in microspheres under these conditions was 6.4 ± 0.0 (%w/w), whereas a value of 6.1% was predicted by the derived equation. This excellent agreement between the actual and the predicted value demonstrates that the fitted model can thus be used to determine the exenatide content.

An In vivo Investigation of Ascorbic Acid Tethered Polymeric Nanoparticles for Effectual Brain Transport of Rivastigmine.

INTRODUCTION: The goal of this study was to see if ascorbic acid grafted polylactic glycolic acid-b-polyethylene glycol nanoparticles (PLGA-b-PEG NPs) might boost the carrying or transport capacity of rivastigmine(RSM) to the brain via choroid plexus Sodium-dependent vitamin C transporter 2 (SVCT2 transporters). The IR and 1H NMR, were used to characterise the PLGA-b-PEG copolymer. METHODS: Nanoprecipitation method was used to make PLGA-b-PEG NPs. To promote SVCT2- mediated transportation of ascorbic acid (Asc) into the brain, PLGA-b-PEG NPs of acceptable size, polydispersity, and drug loading were bound with ascorbic acid (PLGA-b-PEG-Asc). When compared to PLGA-b-mPEG NPs, the surface functionalization of NPs with ascorbic acid dramatically improved the cellular uptake of NPs in SVCT2 expressing NIH/3T3 cells. Radial Arm Maze Test, and Acetylcholinesterase (AChE) activity in scopolamine-induced amnetic rats were used to assess in vivo pharmacodynamic effectiveness. RESULTS: In vivo pharmacodynamic tests revealed that drug loaded PLGA-b-PEG-Asc NPs had much greater therapeutic and sustained activity than free drugs, and PLGA-b-mPEG NPs to the brain. CONCLUSION: As a consequence, the findings revealed that using ascorbic acid grafted PLGA-b-PEG NPs to deliver bioactives to the brain is a potential strategy.

Synthesis and Preliminary Biological Assessment of Carborane-Loaded Theranostic Nanoparticles to Target Prostate-Specific Membrane Antigen.

Boron neutron capture therapy (BNCT) is an encouraging therapeutic modality for cancer treatment. Prostate-specific membrane antigen (PSMA) is a cell membrane protein that is abundantly overexpressed in prostate cancer and can be targeted with radioligand therapies to stimulate clinical responses in patients. In principle, a spatially targeted neutron beam together with specifically targeted PSMA ligands could enable prostate cancer-targeted BNCT. Thus, we developed and tested PSMA-targeted poly(lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-b-PEG) nanoparticles (NPs) loaded with carborane and tethered to the radiometal chelator deferoxamine B (DFB) for simultaneous positron emission tomography (PET) imaging and selective delivery of boron to prostate cancer. Monomeric PLGA-b-PEGs were covalently functionalized with either DFB or the PSMA ligand ACUPA. Different nanoparticle formulations were generated by nanoemulsification of the corresponding unmodified and DFB- or ACUPA-modified monomers in varying percent fractions. The nanoparticles were efficiently labeled with 89Zr and were subjected to in vitro and in vivo evaluation. The optimized DFB(25)ACUPA(75) NPs exhibited strong in vitro binding to PSMA in direct binding and competition radioligand binding assays in PSMA(+) PC3-Pip cells. [89Zr]DFB(25) NPs and [89Zr]DFB(25)ACUPA(75) NPs were injected to mice with bilateral PSMA(-) PC3-Flu and PSMA(+) PC3-Pip dual xenografts. The NPs demonstrated twofold superior accumulation in PC3-Pip tumors to that of PC3-Flu tumors with a tumor/blood ratio of 25; however, no substantial effect of the ACUPA ligands was detected. Moreover, fast release of carborane from the NPs was observed, resulting in a low boron delivery to tumors in vivo. In summary, these data demonstrate the synthesis, characterization, and initial biological assessment of PSMA-targeted, carborane-loaded PLGA-b-PEG nanoparticles and establish the foundation for future efforts to enable their best use in vivo.

Effect of Dioxane and N-Methyl-2-pyrrolidone as a Solvent on Biocompatibility and Degradation Performance of PLGA/nHA Scaffolds

Background: Solvent casting/particulate leaching is one of the most conventional methods for fabricating polymer/ceramic composite scaffolds. In this method, the solvent generally affects resulting scaffold properties, including porosity and degradation rate. Methods: Herein, composite scaffolds of PLGA (poly(lactide-co-glycolide))/ nano-hydroxyapatite (nHA) with different percentages of nHA (25, 35, and 45 wt. %) were prepared by the solvent casting/particle leaching combined with freeze drying. The effects of two different solvents, 1,4-dioxane (DIO) and N-methyl-2-pyrrolidone (NMP), on morphology, porosity, bioactivity, degradation rate, and biocompatibility of the resulting scaffolds were investigated. Results: The results revealed that increasing the nano-hydroxyapatite (nHA) percentages had no significant effect on the porosity and interconectivity of scaffolds (p > 0.05), whereas altering the solvent from DIO into NMP decreased the porosity from about 87% into 71%, respectively. Moreover, scaffolds of DIO illustrated the high results of cell proliferation compared to those of NMP; the cell viability of GD25 decreased from 85% to 65% for GN25. The findings also indicated that scaffolds prepared by NMP had a higher rate of losing weight in comparison to DIO. Adding nHA to PLGA had a significant effect on the bioactivity of scaffolds (p < 0.05), composite scaffolds with 45 wt % nHA had at least 30% more weight gain compared to the neat polymer scaffolds. Conclusion: The DIO scaffolds have higher rates of porosity, interconnectivity, bioactivity, and biocompatibility than NMP scaffolds due to its high evaporation rate.

A cell-free ROS-responsive hydrogel/oriented poly(lactide-co-glycolide) hybrid scaffold for reducing inflammation and restoring full-thickness cartilage defectsin vivo.

The modulation of inflammation in tissue microenvironment takes an important role in cartilage repair and regeneration. In this study, a novel hybrid scaffold was designed and fabricated by filling a reactive oxygen species (ROS)-scavenging hydrogel (RS Gel) into a radially oriented poly(lactide-co-glycolide) (PLGA) scaffold. The radially oriented PLGA scaffolds were fabricated through a temperature gradient-guided phase separation and freeze-drying method. The RS Gel was formed by crosslinking the mixture of ROS-responsive hyperbranched polymers and biocompatible methacrylated hyaluronic acid (HA-MA). The hybrid scaffolds exhibited a proper compressive modulus, good ROS-scavenging capability, and cell compatibility.In vivotests showed that the hybrid scaffolds significantly regulated inflammation and promoted regeneration of hyaline cartilage after they were implanted into full-thickness cartilage defects in rabbits for 12 w. In comparison with the PLGA scaffolds, the neo-cartilage in the hybrid scaffolds group possessed more deposition of glycosaminoglycans and collagen type II, and were well integrated with the surrounding tissue.

Effect and Biocompatibility of a Cross-Linked Hyaluronic Acid and Polylactide-co-glycolide Microcapsule Vehicle in Intratympanic Drug Delivery for Treating Acute Acoustic Trauma.

The treatment of acute hearing loss is clinically challenging due to the low efficacy of drug delivery into the inner ear. Local intratympanic administration of dexamethasone (D) and insulin-like growth factor 1 (IGF1) has been proposed for treatment, but they do not persist in the middle ear because they are typically delivered in fluid form. We developed a dual-vehicle drug delivery system consisting of cross-linked hyaluronic acid and polylactide-co-glycolide microcapsules. The effect and biocompatibility of the dual vehicle in delivering D and IGF1 were evaluated using an animal model of acute acoustic trauma. The dual vehicle persisted 10.9 times longer (8.7 days) in the middle ear compared with the control (standard-of-care vehicle, 0.8 days). The dual vehicle was able to sustain drug release over up to 1 to 2 months when indocyanine green was loaded as the drug. One-third of the animals experienced an inflammatory adverse reaction. However, it was transient with no sequelae, which was validated by micro CT findings, endoscopic examination, and histological assessment. Hearing restoration after acoustic trauma was satisfactory in both groups, which was further supported by comparable numbers of viable hair cells. Overall, the use of a dual vehicle for intratympanic D and IGF1 delivery may maximize the effect of drug delivery to the target organ because the residence time of the vehicle is prolonged.

The kinetics and release behaviour of curcumin loaded pH-responsive PLGA/chitosan fibers with antitumor activity against HT-29 cells.

The bioavailability and clinical effect of curcumin (Cur) are greatly restricted due to its physicochemical instability and high hydrophobicity. To overcome the disadvantages, the nanofibers of poly(lactide-glycolide)/chitosan loaded with Cur (PLGA/CS/Cur) was developed here by electrospinning technique for controlled Cur delivery. The incorporated Cur was well-dispersed and maintained crystalline form in PLGA/CS fiber matrix by hydrogen bonding. The incorporation of Cur had no obvious influence on the fiber size and morphology but exerted impacts on thermal stability. At pH 7.4, the release followed Fickian diffusion mechanism; while at pH 2.0, the release followed the coexistence of diffusion and erosion mechanisms. In addition, the amount of Cur released at pH 2.0 was much higher than that at pH 7.4. As a result, the nanofibers demonstrated higher anticancer activity at acidic environment. Therefore, the PLGA/CS/Cur nanofibers may be served as a potential pH responsive vehicle for the controlled drug delivery.

Biological compatibility, thermal and in vitro simulated degradation for poly(p-dioxanone)/poly(lactide-co-glycolide)/poly(ethylene succinate-co-glycolide).

Bio-absorbable polymers are widely desired to be applied and used as biomaterials for surgery hemostatic and medical tissue engineering devices. Ring-opening copolymerization reaction was applied to synthesize poly(ethylene succinate-co-glycolide) (PES-b-PGA). Stannous octoate was used as a catalyst whereas poly(ethylene succinate) was used as a macro-initiator to react with glycolide. PES-b-PGA was then used as a compatibilizer to prepare the blend biomaterial of PPDO/PLGA/PES-b-PGA by melt blending poly(p-dioxanone) (PPDO) with poly(lactide-co-glycolide) (PLGA). This would enhance the interactions of the inter-molecular chains and intra-molecular segments thus improving the compatibility. To obtain the biomaterial of PPDO/PLGA/PES-b-PGA with a regulated and controlled degradation and/or hydrolysis period, various ratios of PPDO, PLGA, and PES-b-PGA was blended. Behaviors of the thermal and in vitro simulated degradation, biological compatibility, cytotoxicity and subcutaneous implantation of PPDO/PLGA/PES-b-PGA were investigated. The results show that the in vitro hydrolytic degradation cycle is consistent with the wound healing time and that the biomaterial has slight cytotoxicity and it will do good to the cell proliferation, with 1 grade of cytotoxicity and the relative growth rate being the range from 92.5% to 96.2%. The implantation of the biomaterial into the rabbits' ears will not adversely affect the wound healing and the tissues surrounding the implanted sites. Therefore, the biomaterial has good biocompatibility and potential applications in medical tissue engineering devices.

Sustained intrathecal delivery of amphotericin B using an injectable and biodegradable thermogel.

Cryptococcal meningitis is a fungal infectious disease with a poor prognosis and high mortality. Amphotericin B (AMB) is the first choice for the treatment of cryptococcal meninges. The blood-brain barrier (BBB) is the major barrier for the effective delivery of drugs to the brain. In this study, AMB was incorporated in a thermosensitive gel for intrathecal injection. We first synthesized AMB-loaded thermogel, investigated its in vitro cumulative release, and in vivo neurotoxicity, and therapeutic effect. The thermosensitive gel was comprised of 25 wt% poly (lactic acid-co-glycolic acid)-poly (ethylene glycol)-poly (lactic acid-co-glycolic acid) (PLGA-PEG-PLGA) triblock polymer aqueous solution. The AMB loaded in the thermosensitive gel (AMB in gel) had low viscosity at low temperature and resulted in the formation of a non-flowing gel at 37 °C (physiological temperature). AMB loading in gel sustained its release for 36 days and the in vitro cumulative release rate was satisfactory. Compared with the AMB solution, intrathecal administration of AMB in gel could reduce the neurovirulence of AMB and get a better treatment effect. The findings of the current study show that the injectable PLGA-PEG-PLGA thermogel is a biocompatible carrier for the delivery of drugs into the intrathecal.

Key Factor Study for Generic Long-Acting PLGA Microspheres Based on a Reverse Engineering of Vivitrol®.

The FDA (U.S. Food and Drug Administration) has approved only a negligible number of poly(lactide-co-glycolide) (PLGA)-based microsphere formulations, indicating the difficulty in developing a PLGA microsphere. A thorough understanding of microsphere formulations is essential to meet the challenge of developing innovative or generic microspheres. In this study, the key factors, especially the key process factors of the marketed PLGA microspheres, were revealed for the first time via a reverse engineering study on Vivitrol® and verified by the development of a generic naltrexone-loaded microsphere (GNM). Qualitative and quantitative similarity with Vivitrol®, in terms of inactive ingredients, was accomplished by the determination of PLGA. Physicochemical characterization of Vivitrol® helped to identify the critical process parameters in each manufacturing step. After being prepared according to the process parameters revealed by reverse engineering, the GNM demonstrated similarity to Vivitrol® in terms of quality attributes and in vitro release (f2 = 65.3). The research on the development of bioequivalent microspheres based on the similar technology of Vivitrol® will benefit the development of other generic or innovative microspheres.

Glutamate-urea-based PSMA-targeted PLGA nanoparticles for prostate cancer delivery of docetaxel.

Targeted drug delivery is a tool to make treatment more specific, selective, and effective and to prevent unwanted complications. Prostate specific membrane antigen (PSMA) is a useful biomarker in order to monitor and control prostate cancer. Glutamate-Urea-R (Glu-Urea-R) is a PSMA enzyme inhibitor capable of binding to this surface marker of prostate cancer cell in an efficient and special manner. The aim of this project was to develop a docetaxel-loaded nanoparticle of poly (lactic-co-glycolic acid) polyethylene glycol which is cojugated to a urea-based anti-PSMA ligand named glutamate-urea-lysine (glu-urea-lys) for targeted delivery of docetaxel in prostate cancer. The obtained nanoparticles, prepared by nanoprecipitation method, were spheres with a particle size of around 150 nm and zeta potential of -7.08 mV. Uptake studies on the PC3 (as PSMA negative) and LNCaP (as PSMA positive) cells demonstrated that drug uptake was efficient by the PSMA positive cells. IC50 of targeted NPs on LNCaP cell line compared to non-targeted ones was reduced by more than 70% in three different incubation times of 24, 48, and 72 h. In conclusion, the nanoparticles are expected to specifically transport docetaxel to PSMA-positive prostate cancer cells and consequently, enhance the antitumor efficacy of docetaxel on these cells.

Poly(lactide-co-glycolide) Nanoparticles Mediate Sustained Gene Silencing and Improved Biocompatibility of siRNA Delivery Systems in Mouse Lungs after Pulmonary Administration.

Pulmonary delivery of small interfering RNA (siRNA)-based drugs is promising in treating severe lung disorders characterized by the upregulated expression of disease-causing genes. Previous studies have shown that the sustained siRNA release in vitro can be achieved from polymeric matrix nanoparticles based on poly(lactide-co-glycolide) (PLGA) loaded with lipoplexes (LPXs) composed of cationic lipid and anionic siRNA (lipid-polymer hybrid nanoparticles, LPNs). Yet, the in vivo efficacy, potential for prolonging the pharmacological effect, disposition, and safety of LPNs after pulmonary administration have not been investigated. In this study, siRNA against enhanced green fluorescent protein (EGFP-siRNA) was either assembled with 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) to form LPX or co-entrapped with DOTAP in PLGA nanoparticles to form LPNs. The disposition and clearance of LPXs and LPNs in mouse lungs were studied after intratracheal administration by using single-photon emission computed tomography/computed tomography (SPECT/CT) and gamma counting. Fluorescence spectroscopy, Western blot, and confocal laser scanning microscopy were used to evaluate the silencing of the EGFP expression mediated by the LPXs and LPNs after intratracheal administration to transgenic mice expressing the EGFP gene. The in vivo biocompatibility of LPXs and LPNs was investigated by measuring the cytokine level, total cell counts in bronchoalveolar lavage fluid, and observing the lung tissue histology section. The results showed that the silencing of the EGFP expression mediated by LPNs after pulmonary administration was both prolonged and enhanced as compared to LPXs. This may be attributed to the sustained release characteristics of PLGA, and the prolonged retention in the lung tissue of the colloidally more stable LPNs in comparison to LPXs, as indicated by SPECT/CT. The presence of PLGA effectively alleviated the acute inflammatory effect of cationic lipids to the lungs. This study suggests that PLGA-based LPNs may present an effective formulation strategy to mediate sustained gene silencing effects in the lung via pulmonary administration.

pH-Triggered Poly(ethylene glycol)-Poly(lactic acid/glycolic acid)/Croconaine Nanoparticles-Assisted Multiplexed Photoacoustic Imaging and Enhanced Photothermal Cancer Therapy.

The most advantageous and attractive property of photoacoustic imaging is its capability to visualize and differentiate multiple species according to their unique absorbance profiles simultaneously in a single mixture. We here report the pH-sensitive near-infrared (NIR) croconaine (Croc) dyes-loaded copolymeric PEG-PLGA nanoparticles (NPs) for in vivo multiplexed PA imaging and pH-responsive photothermal therapy (PTT) in an orthotopic xenograft model. PEG chains on the polymeric NPs shell were conjugated with iRGD in another set of NPs to realize efficient tumor targeting. The distribution and the intensity of two sets of iRGD-targeted and nontargeted NPs inside tumors are simultaneously imaged and monitored in vivo. Meanwhile, the utilization of iRGD-targeted PPC815 NPs as a pH-active photothermal agent with promising tumor-inhibition efficacy was demonstrated. As a result, this nanoplatform is capable of assisting multiwavelength unmixing of PA imaging as well as providing remarkable photothermal ablation for anticancer treatment.

Hemoglobin-Based Oxygen Carriers Incorporating Nanozymes for the Depletion of Reactive Oxygen Species.

While transfusion of donor blood is a reasonably safe and well-established procedure, artificial oxygen carriers offer several advantages over blood transfusions. These benefits include compatibility with all blood types, thus avoiding the need for cross matching, availability, lack of infection, and long-term storage. Hemoglobin (Hb)-based oxygen carriers (HBOCs) are being explored as an "oxygen bridge" to replace or complement standard blood transfusions in extreme, life-threatening situations such as trauma in remote locations or austere battlefield or when blood is not an option due to compatibility issues or patient refusal due to religious objections. Herein, a novel HBOC was prepared using the layer-by-layer technique. A poly(lactide-co-glycolide) core was fabricated and subsequently decorated with Hb and nanozymes. The Hb was coated with poly(dopamine), and preservation of the protein structure and functionality was demonstrated. Next, cerium oxide nanoparticles were incorporated as nanozymes, and their ability to deplete reactive oxygen species (ROS) was shown. Finally, decorating the nanocarrier surface with poly(ethylene glycol) decreased protein adsorption and cell association/uptake. The as-prepared Hb-based oxygen nanocarriers were shown to be hemo- and bio-compatible. Their catalytic potential was furthermore demonstrated in terms of superoxide radical- and peroxide-scavenging abilities, which were retained over multiple cycles. Overall, these results demonstrate that the reported nanocarriers show potential as novel oxygen delivery systems with prolonged catalytic activity against ROS.

A Simultaneous Differential Scanning Calorimetry-X-ray Diffraction Study of Olanzapine Crystallization from Amorphous Solid Dispersions.

Amorphous solid dispersions (ASDs) of class II and IV biopharmaceutics classification system drugs in water-miscible polymers are a well-recognized means of enhancing dissolution, while such dispersions in hydrophobic polymers form the basis of micro- and nanoparticulate technologies. However, drug recrystallization presents significant problems for product development, and the mechanisms and pathways involved are poorly understood. Here, we outline the use of combined differential scanning calorimetry (DSC)-synchrotron X-ray diffraction to monitor the sequential appearance of polymorphs of olanzapine (OLZ) when dispersed in a range of polymers. In a recent study (Cryst. Growth Des.2019,19, 2751-2757), we reported a new polymorph (form IV) of OLZ which crystallized from a spray-dried dispersion of OLZ in polyvinylpyrrolidone. Here, we extend our earlier study to explore OLZ dispersions in poly(lactide-co-glycolide) (PLGA), polylactide (PLA), and hydroxypropyl methyl cellulose acetate succinate (HPMCAS), with a view to identifying the sequence of form generation on heating each dispersion. While spray-dried OLZ results in the formation of crystalline form I, the spray-dried material with HPMCAS comprises an ASD, and forms I and IV are generated upon heating. PLGA and PLA result in a product which contains both amorphous OLZ and the dichloromethane solvate; upon heating, the amorphous material converts to forms I, II, and IV and the solvate to forms I and II. Our data show that it is possible to quantitatively assess not only the polymorph generation sequence but also the relative proportions as a function of temperature. Of particular note is that the sequence of form generation is significantly more complex than may be indicated by DSC data alone, with coincident generation of different polymorphs and complex interconversions as the material is heated. We argue that this may have implications not only for the mechanistic understanding of polymorph generation but also as an aid to identifying the range of polymorphic forms that may be produced by a single-drug molecule.

Surface-Modified Poly(l-lactide-co-glycolide) Scaffolds for the Treatment of Osteochondral Critical Size Defects-In Vivo Studies on Rabbits.

Poly(l-lactide-co-glycolide) (PLGA) porous scaffolds were modified with collagen type I (PLGA/coll) or hydroxyapatite (PLGA/HAp) and implanted in rabbits osteochondral defects to check their biocompatibility and bone tissue regeneration potential. The scaffolds were fabricated using solvent casting/particulate leaching method. Their total porosity was 85% and the pore size was in the range of 250-320 µm. The physico-chemical properties of the scaffolds were evaluated using scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), X-ray diffractometry (XRD), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR), sessile drop, and compression tests. Three types of the scaffolds (unmodified PLGA, PLGA/coll, and PLGA/HAp) were implanted into the defects created in New Zealand rabbit femoral trochlears; empty defect acted as control. Samples were extracted after 1, 4, 12, and 26 weeks from the implantation, evaluated using micro-computed tomography (µCT), and stained by Masson-Goldner and hematoxylin-eosin. The results showed that the proposed method is suitable for fabrication of highly porous PLGA scaffolds. Effective deposition of both coll and HAp was confirmed on all surfaces of the pores through the entire scaffold volume. In the in vivo model, PLGA and PLGA/HAp scaffolds enhanced tissue ingrowth as shown by histological and morphometric analyses. Bone formation was the highest for PLGA/HAp scaffolds as evidenced by µCT. Neo-tissue formation in the defect site was well correlated with degradation kinetics of the scaffold material. Interestingly, around PLGA/coll extensive inflammation and inhibited tissue healing were detected, presumably due to immunological response of the host towards collagen of bovine origin. To summarize, PLGA scaffolds modified with HAp are the most promising materials for bone tissue regeneration.

In vivo biocompatibility and efficacy of dexamethasone-loaded PLGA-PEG-PLGA thermogel in an alkali-burn induced corneal neovascularization disease model.

Challenges of ophthalmic drug delivery arise not only from the limited solubility of hydrophobic therapeutics, but also the restricted permeability and fast clearance of drugs due to the complex anatomy and physiology of eyes. Excellent biocompatibility of a thermosensitive polymer, PLGA-PEG-PLGA (1800-1500-1800, LA:GA ratio = 3:1), as an ophthalmic delivery system was demonstrated in our previous work. In this study, delivery of dexamethasone using this thermogel via a single subconjunctival injection for prolonged treatment was evaluated with corneal neovascularization using an alkali-burn diseased model in rat. Solubility of dexamethasone in the polymeric solution was increased by 5.2-fold and the resulting drug-loaded solution formed in situ rigid gel at body temperature. Prolonged in vitro release of dexamethasone from the gel structure was noted. Dexamethasone gel formulation was demonstrated to be more effective in reducing the burn stimulus and neovascularization in the rat diseased model. The findings suggest the PLGA-PEG-PLGA in situ gelling system can be applied for ophthalmic drug delivery to achieve sustained drug release and improved efficacy.