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Recent advances in nanoscale metal organic frameworks for cancer chemodynamic therapy.

Copper diethyldithiocarbamate (Cu(DDC)2) has been demonstrated to possess excellent antitumor activity. However, the extremely poor water solubility of Cu(DDC)2 bring difficulty for its formulation research. In this study, we aim to develop a novel nanocarrier for Cu(DDC)2 delivery to overcome this obstacle and enhance antitumor activity. The SP94 modified asymmetrical bilayer lipid-encapsulated Cu(DDC)2 nanoparticles (DCDP) was established by combining the method of inverse microemulsion aggregation and thin-film dispersion. In vitro cellular assays and in vivo tumor-xenograft experiments were conducted to evaluate the tumor chemotherapeutic effect of DCDP. And the vital role of copper ions played in DSF or DDC (DSF/DDC)-based cancer chemotherapy was also explored. DCDP with an encapsulation efficiency (EE%) of 74.0% were successfully prepared. SP94 modification facilitated cellular intake for DCDP, and promoted apoptosis to repress tumor cell proliferation (IC50, 200 nM). And DCDP effectively inhibited tumor growth with a high tumor inhibition rate of 74.84%. Furthermore, Cu(DDC)2 was found to facilitate the copper ion accumulation in tumor tissues, which is beneficial to therapy with high potency. DCDP exhibited high-efficient tumor chemotherapeutic efficacy and provided a novel strategy for investigating the anticancer mechanism of Cu(DDC)2.

This study aims to fabricate core-shell clarithromycin (CAM) microcapsules to cover up the bitter taste of CAM by spray drying with aqueous polymer dispersion. Water dispersion of Eudragit EPO and Surelease

The intention of the study was to co-delivery gemcitabine and cisplatin with totally different nature by prodrug and micelle strategy to improve its in vivo stability and antitumor effect.A prodrug of gemcitabine (mPEG-PLG-GEM) was synthesized through the covalent conjugation between the primary amino group of gemcitabine and the carboxylic group of poly (L-glutamic acid)-g-methoxy poly (ethylene glycol) (mPEG-PLG). It was prepared into micelles by a solvent diffusion method, and then combined with cisplatin through chelation to prepare gemcitabine and cisplatin co-loaded mPEG-PLG micelles (mPEG-PLG-GEM@CDDP micelles).Gemcitabine and cisplatin in each micelle group were released more slowly than in solutions. In addition, pharmacokinetics behaviors of them were improved after encapsulated in prodrug micelles. TBy prodrug strategy, gemcitabine and cisplatin with totally different nature were prepared into micelles and obtained a better pharmacokinetic behavior. And the dual drug delivery system performed a better in vivo stability and antitumor effect compared with each single drug delivery system in the experiment. Scheme. Schematic of mPEG-PLG-GEM@CDDP micelles' formation and action process.

The objective of the present study was to prepare stable and high bioavailability ocular atropine loaded films (ATR-films) as potential ocular drug delivery systems for the treatment of myopia. ATR-films were prepared by the solvent casting method and the physical properties of films were evaluated including thickness, water content, light transparency, disintegration time, and mechanical properties. FT-IR, DSC, XRD, TGA, AFM, and Raman spectroscopy were performed to characterize the film. The stability test was conducted under different conditions, such as high humidity, high temperature, and strong light. The pharmacokinetic study and irritation assessment were conducted in rabbits. The efficacy of ATR-films was evaluated by refraction and ocular biometry in myopia guinea pigs. After optimizing the formulation, the resulting ATR-film was flexible and transparent with lower water content (8.43% ± 1.25). As expected, the ATR-film was stable and hydrolysate was not detected, while the content of hydrolysate in ATR eye drops can reach up to 8.1867% (limit

Nano drug delivery systems have attracted researchers' growing attention and are gradually emerging into the public views. More and more nano-formulations are being approved for marketing or clinical use, representing the field's booming development. Copolymer self-assembly systems such as micelles, nanoparticles, polymersomes occupy a prominent position in the field of nano-drug delivery carriers. Among them, polymersomes, unlike micelles or nanoparticles, resemble liposomes' structure and possess large internal hollow hydrophilic reservoirs, allowing them to carry hydrophilic drugs. Nevertheless, their insufficient drug loading efficiency and unruly self-assembly morphology have somewhat constrained their applications. Especially for the delivery of biomacromolecule such as peptides, the encapsulation efficiency is always considered to be a formidable obstacle, even if the enormous hydrophilic core would render the polymersomes to have considerable potential in this regard. Reassuringly, the emergence of asymmetric polymersomes holds the prospect of solving this problem. With the development of synthetic technology and a deeper understanding of the self-assembly process, the asymmetric polymersomes which are with different inner and outer shell composition have been gradually recognized by researchers. It has made possible elevated drug loading, more controllable assembly processes and release performance. The internal hydrophilic blocks different from the outer shell could be engineered to have a more remarkable affinity to the cargos or could contain a non-watery aqueous phase to enable the thermodynamically preferred encapsulation of cargos, which would allow for a substantial improvement in drug encapsulation efficiency compared to the conventional approach. In this paper, we aim to deepen the understanding to asymmetric polymersomes and lay the foundation for the development of this field by describing four main elements: the mechanism of their preparation and asymmetric membrane formation process, the characterization of asymmetric membranes, the efficient drug loading, and the special stimulus-responsive release mechanism.

Long-term daily injection of progesterone for the treatment of threatened abortion can be a source of considerable pain to patients. To reduce the frequency of injections and improve patient compliance, a novel injectable phospholipid-based phase separation gel (PPSG) was prepared using small molecular materials such as phospholipids, medium-chain triglycerides (MCTs), and ethanol. Progesterone was loaded into PPSGs to promote rapid gel formation in situ via a sol-gel transformation mechanism, thereby achieving a sustained controlled release. Furthermore, progesterone was distributed in the oil-water interface layer and within the oil phase. Solvent exchange drives phase transitions, and phospholipid vesicle formation and rupture are likely to promote drug release and gel degradation. At a drug loading of 140 mg/mL, a progesterone release of up to 60% could be reached within 9 days according to the release curve in vitro. Pharmacokinetic studies demonstrated that the progesterone-loaded PPSGs released the drug continuously for over 7 days, the half-life was eight times higher than that of progesterone oil solution, and relative bioavailability of up to 184.90% was obtained. Collectively, the sustained release properties for hydrophobic cargos would effectively enhance patient compliance. Moreover, PPSGs are promising drug delivery systems that have high market value and biosafety given the readily accessible and safe excipients.

PD-1/L1 checkpoint blockade has gained approval in terms of treating patients suffering from hepatocellular carcinoma (HCC). It should be noted that the PD-1/L1 inhibitor (α-PD-1/L1) has a low overall response rate when used as a single agent. Accordingly, the combination of α-PD-1/L1 and a series of therapies to further increase the response rate has become a major research direction. In our previous study, we developed a novel norcantharidin (NCTD) liposome emulsion hybrid delivery system (NE) with enhanced anticancer activity and reduced toxicity. In this study, NE was combined with α-PD-1/L1 for treating HCC. The combination therapy exhibited an enhanced antitumor activity, which led to the up-regulated expression levels of white blood cells, interleukin 12 (IL-12), interferon γ (IFN-γ), PD-L1, as well as CD8. Furthermore, the combination of NE and α-PD-1 achieved the optimal efficiency. NCTD-based chemotherapy is capable of synergizing with α-PD-1/L1 while enhancing checkpoint immunotherapy. It follows a mechanism that NCTD agonizes the non-canonical NF-κB pathway of dendritic cells for better activating CD8

The intramuscular administration of long-acting injectable microparticles elicits a local macrophage uptake resulting in decreased bioavailability. Herein, we developed a ginkgolide B (GB) loaded Solid/Oil/Water (S/O/W) solid lipid microparticles (SLMs) which were modified by hydroxyethyl starch (HES) or poly(ethylene glycol) (PEG) with different surface densities to investigate the influence of surface properties on the cellular uptake and systemic drug exposure. The spherical SLMs with a mean particle size of 10 µm were prepared by melt emulsification and post-insertion method, showing controlled release profile with less than 10 % of GB released in first 2 h. HES-SLMs resulted in lowest degree of RAW264.7 macrophage uptake in vitro and a higher systemic drug exposure in rats than PEG coating SLMs, indicting the capability of thick HES layer of SLMs in evading cellular uptake and sustained GB release. Overall, HES modified SLMs possess a great potential as intramuscular injected drug delivery system to improved bioavailability.

Periodontitis is a chronic inflammation of the soft tissue surrounding and supporting the teeth, which causes periodontal structural damage, alveolar bone resorption, and even tooth loss. Its prevalence is very high, with nearly 60% of the global population affected. Hence, periodontitis is an important public health concern, and the development of effective healing treatments for oral diseases is a major target of the health sciences. Currently, the application of local drug delivery systems (LDDS) as an adjunctive therapy to scaling and root planning (SRP) in periodontitis is a promising strategy, giving higher efficacy and fewer side effects by controlling drug release. The cornerstone of successful periodontitis therapy is to select an appropriate bioactive agent and route of administration. In this context, this review highlights applications of LDDS with different properties in the treatment of periodontitis with or without systemic diseases, in order to reveal existing challenges and future research directions.

Oral absorption of BCS IV drug benefits little from improved dissolution. Therefore, the absorption of BCS IV drug nanocrystals 'as a whole' strategy is preferred, and structural modification of nanocrystals is required. Surface modification helps the nanocrystals maintain particle structure before drug dissolution is needed, thus enhancing the oral absorption of BCS IV drugs and promoting therapeutic effect. Here, the main challenges and solutions of oral BCS IV drug nanocrystals delivery are discussed. Moreover, strategies for nanocrystal surface modification that facilitates oral bioavailability of BCS IV drugs are highlighted, and provide insights for the innovation in oral drug delivery.Promising size, shape, and surface modification of nanocrystals have gained interests for application in oral BCS IV drugs.Nanocrystal surface modification is a feasible method to maintain the structural integrity of nanocrystals, and the introduced materials can also be modified to integrate additional functions to further facilitate the absorption of nanocrystals. It is expected that the absorption 'as a whole' strategy of nanocrystals will provide different choices for the oral BCS IV drugs.

Currently, reducing particle size or preparing drugs into amorphous forms are widely used methods to improve the solubility and dissolution rate of insoluble drugs. The purpose of this study was to prepare nimodipine amorphous nanopowder (NMD-NAP) using nimodipine (NMD) as a model drug to increase the solubility and dissolution rate of insoluble drugs by the combined effect of reducing the particle size and preparing the drug into an amorphous form. The NMD-NAP was successfully prepared by quenching cooling combined with wet milling and spray drying. The prepared NMD-NAP was shown to have good redispersibility by particle size analysis. The shapeof NMD-NAP was characterized by SEM and AFM, showing a spherical or spheroidal structure. The results of PLM, DSC, XRD, and FT-IR indicated that the drug existed in an amorphous form. The dissolution study showed that the dissolution rate of NMD in NMD-NAP was improved about 5 times that of pure NMD and 3 times that of nimodipine nanocrystalline (NMD-NC), indicating the combination of nano size and amorphous form produced a synergistic effect that could significantly increase the dissolution rate of NMD. Due to the significantly improved solubility and good industrial feasibility of the prepared NMD-NAP, the preparation of insoluble drugs into amorphous nanopowders is an effective method to improve the solubility of insoluble drugs and has good application prospects.

The influence of circadian rhythms is an important content in oral dosage form study which is shown as different pH conditions and gastrointestinal dynamics in the gastrointestinal tract. The purpose of this study was to alleviate the influence of circadian rhythms and drug properties to the release of gel matrix tablets in vitro and in vivo. In this study, the compression coating technology and microenvironment shaping were utilized to achieve the alleviation of the influence of circadian rhythms and drug properties. The compression coating technology was used to alleviate the influence of gastrointestinal dynamics, and microenvironment shaping was used to alleviate the interference of different pH condition variations. The self-made compression coating tablet could maintain a consistent release rate in different pH conditions and different dynamic environments in vitro for 24 h. In vivo, the pharmacokinetic parameters C

Norcantharidin (NCTD) has a certain degree of hydrophilicity and poor lipophilicity, and has some side-effects, including short tPhospholipid complexes methods were used for increasing the lipophilicity of norcantharidin (NCTD), then NCTD phospholipid complexes were not only loaded in the oil phase and oil-water interface surface, but also encapsulated in phospholipid bilayers to obtain NCTD liposome-emulsion hybrid (NLEH) delivery system. TheNLEH exhibited an improved encapsulation efficiency (89.3%) and a better sterilization stability, compared to NCTD liposomes and NCTD emulsions. NLEH can achieve a better antitumor activity by promoting absorption (1.93-fold), prolonging blood circulation (2.08-fold), enhancing tumor-targeting accumulation (1.19 times), improving tumor penetration, and increasing antitumor immunity.The liposome-emulsion hybrid (LEH) delivery system was potential carrier for NCTD delivery, and LEH could open opportunities for delivery of poorly soluble anticancer drugs, especially drugs that are more hydrophilicity than lipophilicity.

In recent years, the oral administration of vinorelbine has gradually replaced intravenous administration in the treatment of several types of tumors. Even though the risk of phlebitis is avoided with oral administration, oral vinorelbine is still not a highly patient-compliant route due to the severe gastrointestinal toxicity. Vinorelbine-loaded liposomes with high encapsulation efficiency and suitable particle size were prepared using the ammonium sulfate gradient method. Chitosan-coated liposomes showed the slowest in vitro release compared to uncoated liposomes and vinorelbine solution. No damage was observed in the intestinal epithelial cells of mice orally administered with coated vinorelbine liposomes due to the low presence of the free drug in the gastrointestinal tract and the LD

High oil ratio fat emulsion injections are prone to poor emulsification, rapid creaming, and other quality problems; therefore, the selection of emulsifiers with high emulsifying ability is crucial for the production of fat emulsions. The existing methods used to evaluate the emulsifying ability of emulsifier are to evaluate the emulsifying ability from the emulsifier itself. In the study, Langmuir monolayer selected the most miscible phospholipid with oil phase from the alternative three phospholipids by studying the molecular interaction between oil phase and phospholipid at the air/water interface. The miscibility and thermodynamic stability analyses of the different oil phase/phospholipid mixed monolayers were performed, and the data from [Formula: see text] and [Formula: see text] concluded that all three oil phases had the strongest molecular interaction with E80 and the best miscibility. The emulsions were then prepared and analyzed by the results of particle size, ζ-potential, and stability of the emulsions, where the surface free energy in the stability test echoed the results reflected by the [Formula: see text] values in the thermodynamic stability test. These results indicate that Langmuir monolayers can be used to study the interaction between oil phase and emulsifier, thus providing new ideas for evaluating the emulsifying ability of phospholipids.

Curcumin (CUR), a polyphenol derived from turmeric, exhibits anticancer and anti-inflammatory properties. However, it has poor water solubility, stability, and oral bioavailability. To overcome these limitations, lipid-polyester mixed nanoparticles (NPs) embedded in enteric polymer-EudragitL100-55(Eu) were formulated (CUR-NPs-Eu). NPs composed of mPEG-b-PCL have a hybrid core made up of middle chain triglyceride (MCT) and poly(e-caprolactone) (PCL) for enhancing drug loading. The CUR-NPs with MCT content of 10% had a particle size of 121.2 ± 16.8 nm, ζ potential of -16.25 ± 1.38 mV, drug loading of 9.8%, and encapsulation efficiency of 87.4%. The transport of the CUR-NPs-Eu across Caco-2 monolayers is enhanced compared with CUR alone (1.98 ± 0.94 × 10-6 of curcumin versus 55.43 ± 6.06 × 10-6 cm/s of curcumin-loaded NPs) because of the non-disassociated nanostructure during absorption. The absolute bioavailability of CUR-NPs-Eu was 7.14%, which was drastically improved from 1.08% of the CUR suspension (CUR-Sus). Therefore, in the xenograft 4T1 tumor-bearing mice, increased drug accumulation in heart and tumor was noticed because of enhanced oral bioavailability of CUR. The chemosensitizing effect of CUR was attributed to its NF-κB reduction effect (148 ± 11.83 of DOX alone versus 104 ± 8.71 of combined therapy, ng/g tissue). The cardioprotective effect of CUR was associated with maintenance of cardiac antioxidant enzyme activity and down-regulation of NF-κB. This study provided a partial illustration of the mechanisms of chemosensitizing and cardioprotective effects of CUR utilizing the oral availability promotion effect brought by the NPs-Eu formulation. And these results further demonstrated that the capability of this NPs-Eu system in oral delivery of poorly soluble and poorly permeable drugs.

Panax quinquefolium saponin (PQS) composed of 45% pseudo-ginsenoside F11 (PF11), is a natural mixture of sterol compounds obtained from the American ginseng plant, having numerous promising benefit...

The oral delivery of macromolecules using nanoparticles is limited by secreted mucus, resulting in low contact or internalization via intestinal cells and, thus, both mucus trapping and further low cellular uptake need to be overcome. Here, hydrophilic and electroneutral nanoparticles were developed to overcome mucus trapping and enhance the oral delivery of macromolecules. Mesoporous silica nanoparticles (MSNs) were synthesized and modified with a hydrophilic block polymer (poly(lactic acid)-methoxy poly(ethylene glycol), PLA-PEG), and then an overall electroneutrality and promoted cellular uptake were achieved by sequential modification with cell-penetrating peptides (CPPs). Reduced hydrophobic and electrostatic interactions of MSN@PLA-PEG-CPP with mucus decreased mucus trapping by 36.0%, increased the cellular uptake of MSN@PLA-PEG-CPP by 2.3-folds in mucous conditions via active heparan sulfate proteoglycan receptor (HSPG)-mediated and caveolae-mediated endocytosis and electrostatic interactions. Furthermore, insulin, a model macromolecular drug, was successfully loaded into the nanoparticles (INS@MSN@PLA-PEG-CPP). Compared with insulin solution, in vitro cellular uptake in mucous conditions and in vivo pharmacodynamic effects were significantly increased by 9.1- and 14.2-folds, respectively. As well, all nanoparticles with or without insulin loading presented negligible in vitro and in vivo toxicity. Herein, hydrophilic and electroneutral nanoparticles with sequential PEG and CPP modification could promote cellular uptake against mucus trapping and finally show good prospects for oral insulin delivery.

Background: Lutein is the primary macular pigment with an favorable effect on the treatment of age-related macular degeneration (AMD). However, the poor water solubility of lutein hinders its absorption and delivery. In this study, a penetratin-modified lutein nanoemulsion in-situ gel (GEL) was prepared for the treatment of AMD.Methods: A nanoemulsion (NE) was prepared and modified with penetratin (P-NE) to improve the penetration. The effect of penetratin was evaluated by cell uptake and intraocular distribution assays. A dry AMD model was induced using NaIO3, and the therapeutic effect was evaluated by electroretinography, the number of apoptosis cells and the reactive oxygen species (ROS) level.Results: Lutein showed a good ability to protect ARPE-19 from the damage of H2O2 and the uptake rate of P-NE was significantly higher than NE. In the efficacy experiments, the structure of retina was significantly improved after treatment, the apoptosis rate decreased from 31.98% to 2.05%, and the level of ROS was significantly decreased (p < 0.0001).Conclusions: With the aid of penetratin, lutein could be delivered to the retina effectively. The P-NE GEL could evidently inhibit the apoptosis and ROS, demonstrating that the P-NE GEL has a good application prospect in the treatment of AMD.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers due to its long incubation period and low cure rate. Layered double hydroxide (LDH) nanoparticles have attracted considerable research interest in the field of nanomedicine owing to their surface effects and good biocompatibility. In this research, we synthesized a hexagonal nanoparticle by the co-precipitation method, referred to as Cu-Al LDH. As an alternative to traditional drug-loading methods, sodium diethyldithiocarbamate (DDC) was introduced and combined with Cu2+ in LDHs to form a diethyldithiocarbamate-copper complex (Cu(DDC)2), which was not only the composition of carrier materials but also an effective component for cancer therapy. Doxorubicin (DOX) was also encapsulated into LDHs due to the clinical relevance of DOX treatment for HCC. Formulations of the Cu(DDC)2 and DOX co-loaded nanoparticles were optimized to precisely control the Cu(DDC)2/DOX ratio. The nanoparticles were coated with polyethylene glycol-graft-polyglutamic acid (PEG-PLG) through electrostatic adsorption to improve the stability of the nanoparticles. The outer layer was decorated with hyaluronic acid (HA) to achieve specific targeting of tumors. Compared with non-HA coated nanoparticles, HA coated nanoparticles showed greater cellular uptake in Hep G2 cells, which could cause higher cytotoxicity. In addition, targeted nanoparticles effectively inhibited tumor growth in mouse models of ectopic hepatocellular carcinoma. It can be concluded that there is a great potential for synergistic cancer therapy using the novel DOX intercalated Cu(DDC)2 functionalized layered double hydroxide hybrid nanoparticles.

The old alcohol-aversion drug disulfiram (DSF) has aroused wide attention as a drug repurposing strategy in terms of cancer therapy because of the high antitumor efficacy in combination with copper ion. However, numerous defects of DSF (e.g., the short half-life and acid instability) have limited the application in cancer treatment. Cu (DDC)

This study aims to investigate the effect of poly(D, L-lactic acid)The incorporation ratios of PDLLAAfter the incorporation of 5 wt% PDLLAPDLLA

This study systematically compared enzalutamide (ENZ) nanocrystals and amorphous formulation (Xtandi® Tablets) and proposed an effective method for predicting pharmacokinetic behavior. ENZ nanosuspensions were prepared by anti-solvent precipitation (ENZ/NS-AS) and wet milling (ENZ/NS-WM) under optimal conditions and were solidified by spray drying and further tableting. Spray dried ENZ/NS-WM was confirmed to exist in crystalline state by DSC and PXRD, while spray dried ENZ/NS-AS was amorphous form. The dissolution testing revealed that ENZ/NS-WM tablets exhibited significantly faster dissolution rate than the physical mixture of untreated ENZ and HPMCAS-HG (1:1) prepared by gently grinding with a mortar and pestle for 2 min and were comparable to Xtandi® Tablets. However, the pharmacokinetic study in beagle dogs indicated that ENZ/NS-WM tablets displayed 0.43-fold lower C

Various studies were performed on the intermolecular interactions of daunorubicin (DNR) and cytarabine (Ara-C) co-loaded liposome to predict and elucidate its stability and in vitro drug release behavior. Langmuir monolayer and spectroscopy studies showed interactions between its components. The Langmuir monolayer study and blank liposomes stability study illustrated that interactions between lipids could affect their stability, and the DSPC/DSPG/Chol (7/2/1, mol%) mixed system tended to be thermodynamically and physicochemically stable. The interactions between daunorubicin and copper ions were then investigated by ultraviolet-visible (UV-vis) electronic absorption spectroscopy and circular dichroism (CD) spectroscopy, which revealed that the DNR-Cu complex was composed of daunorubicin and copper ions at a molar ratio of 1:1 or 1:2, and its solubility was related to the acidity of the solution. In vitro release experiment of liposomes with different copper gluconate contents illustrated that the interactions between drugs and copper ions were conducive to the retention and synergetic release of drugs. The stability and release studies of the DSPC/DSPG/Chol (7/2/1, mol%) co-loaded liposome illustrated that it had good storage and plasma stability, and the release behaviors of drugs were pH-related, i.e., drugs could be released faster under acidic condition. These studies indicated that intermolecular interactions could affect the stability and release behavior of the liposome, and a certain ratio of components could be conducive to its stability and synergistic release of drugs.

Microcrystalline cellulose (MCC) is a diluent for oral solid dosage forms. The wet granulation process was selected to prepare losartan potassium tablets using MCC as a model for a predictive study. It was found that the hardness of the tablets could not satisfy the quality standards. In this study, the effect of the high-shear granulation process on the compressibility of MCC was characterized by plotting the compression characteristics curve, as well as the mechanism of the effect from the perspectives of mechanical properties, powder properties. The solid-state properties were also analyzed. Combined with the Heckel equation, the Ryshkewitch-Duckworth equation, the energy method, PXRD, SEM, and other evaluation methods, the results suggest that the high-shear granulation process reduced the compressibility of MCC, which may be caused by the reduced plastic deformation capacity of MCC and the change of the particle morphology structure. The method applied in this study can also be applied to other excipients, which is an important guideline for solving possible problems and process selections during the preparation stage of solid formulations.

This study aims to explore the influence of wet milling and jet pulverization on the aripiprazole microcrystalline long-acting injection. Crystal form and particle size distribution were taken as inspection indicators in vitro, and process parameters were optimized. The formulation prepared by wet milling (AMLAI-WM) was shown to undergo a slight conversion of crystal form by DSC, PXRD, TG, FT-IR and have a wider particle size distribution with D50 and Span values of 2.967 μm and 3.457 compared to the formulation fabricated by jet pulverization (AMLAI-JP) with 2.887 μm and 2.258 respectively. In addition, the in vitro release of AMLAI-WM was faster, whereby the pharmacokinetic data indicated that AMLAI-WM was absorbed more quickly within five days with AUC0-5d of 5243.7 μg·L-1·h and 4818.28 μg·L-1·h, respectively. Furthermore, no statistically significant differences in Cmax, tmax and AUC between AMLAI-JP and the commercial formulation (Abilify Maintena™) were found. The absorption mechanism was studied and showed a 1.4-fold later Tmax after depletion of macrophages and significantly lower Cmax and AUC after inhibiting angiogenesis, indicating inflammatory granuloma could facilitate drug plasma exposure. Overall, we demonstrated that jet pulverization was a good strategy for long-acting microcrystalline injection, and that the absorption behavior was affected by both particle size distribution and inflammatory granuloma.

Cisplatin is a widely used anticancer drug for various solid tumors. However, the serious adverse effects caused by systemic distribution limit its wide use. In this study, we intend to use biocompatible materials polyethyleneimine (PEI) and poly( L -glutamic acid)-g-methoxy poly(ethylene glycol) (PLG-g-PEG) to construct nanoparticles to enhance the efficacy of cisplatin and reduce its side effects. The micelle-like nanoparticles were fabricated by a simple two-step method, with a core consisting of PEI and cisplatin and a PLG-g-mPEG coating layer. The obtained nanoparticles have a small particle size (41.79 nm) and high drug loading (16.43%). The coated nanoparticles (NP-II) strengthened the structure of PEI and cisplatin complex (NP-I) and slowed the drug release for less than 20% at pH 7.4 PBS in 24 h. Therefore, it could effectively inhibit the binding of free drug and plasma proteins to achieve the long circulation, and the bioavailability could be increased to about 600% and 285% of cisplatin solution and NP-I respectively. Besides, the cellular uptake of NP-II was enhanced in the acidic tumor microenvironment due to the detachment of coating layer and the increase of positive zeta potential of nanoparticles, which was benefit to reduce the side effect of cisplatin to normal cells. In vivo pharmacodynamic experiments also showed that NP-II improved the efficacy and reduced side effects compared to the cisplatin solution. In conclusion, the two-step fabricating micelle-like nanoparticles with the improved therapeutic efficiency and reduced side effects show great potential for cancer chemotherapy.

This study aimed to evaluate the performance of cisplatin-loaded polymeric micelles (CDDP-PMs) with different drug/copolymer ratios of 1:1, 1:3 and 1:6 (w/w) prepared by coordinated complexation and self-assembly method. The mass ratio influenced the self-assembly behaviors and the complex degree, where both single- and double- complexation existed in CDDP-PMs. With the increase of CDDP/copolymer ratio, the particle size and drug loading increased, while encapsulation efficiency decreased. The PEG density of CDDP-PM1-6, CDDP-PM1-3 and CDDP-PM1-1 were 0.20, 0.61 and 0.38 PEG/nm2, respectively. CDDP-PM1-3 and CDDP-PM1-6 had similar sustained release behavior, while CDDP-PM1-1 showed burst release. Pharmacokinetics showed the AUC of CDDP-PM1-6, CDDP-PM1-3 and CDDP-PM1-1 was 27.2, 76.6 and 13.0 fold higher than CDDP solution. Tissue distribution presented the platinum concentration of CDDP-PM1-6, CDDP-PM1-3 and CDDP-PM1-1 was 1.03, 0.80 and 0.48 times of CDDP solution in kidney at 10 min, and 17.61, 28.63 and 16.6 times in tumor at 48 h respectively, indicating CDDP-PMs significantly reduced nephrotoxicity and increased tumor-targeting accumulation. In vivo antitumor test showed that CDDP-PMs exhibited an improved antitumor efficacy and lower systemic toxicity compared with CDDP solution. From CDDP-PM1-1 to CDDP-PM1-6, the toxicity decreased with the increase of copolymer ratio, but the tumor inhibition rate also decreased. CDDP-PM1-3 had relative high therapeutic effect and low toxicity compared with other formulations. CDDP-PM1-3 could improve the antitumor efficacy by increasing the dose within systemic tolerability, but CDDP solution cannot. This work provides an effective strategy by modulating drug/copolymer ratio of CDDP-PMs to balance the antitumor efficacy and toxicity for better payoff. Statement of Significance Cancer chemotherapy always exists a contradiction between antitumor efficacy and toxicity. Higher efficacy against tumor often associated with larger toxicity for normal tissues. This work provides an important strategy by modulating the drug/copolymer ratios to balance the antitumor efficacy and toxicity to obtain better payoff. The cisplatin-loaded polymeric micelles (CDDP-PMs) based on the complexation between CDDP and copolymer with different mass ratios make differences in vitro and in vivo because of the single- or double-complexation degree. Most importantly, we found the balance at CDDP/copolymer ratio of 1:3, which has relative high therapeutic effect and low toxicity compared with other formulations. CDDP-PM1-3 could improve the antitumor efficacy by increasing the dose within systemic tolerability, but CDDP solution cannot.

This manuscript reported a preliminary study of triacetylated andrographolide solid dispersion (TA-SD) that investigated the influence of preparation method and carrier materials on the physical stability of prepared SDs, and tested the anti-inflammatory effect of TA-SD. SDs were prepared by hot-melt extrusion (HME) or solvent-evaporation (SE) with fixed drug loading of 10% using Kollidon VA64 (VA64-SD) or Soluplus (So-SD) as carriers. The physical stability of the four prepared SDs was studied after a 7-day exposure to heat (30 °C and 60 °C) or moisture (75% and 92.5% relative humidity). All SDs samples, except So-SD prepared by HME (So-HME-SD), were found with drug recrystallization after 7-day exposure to 92.5% RH, as illustrated by DSC analysis. All prepared SDs showed reduced dissolution after storage under stressed conditions, and according to their changes in dissolution profiles, it was found that So-SDs were more sensitive to heat while VA64-SDs were more sensitive to moisture, and SDs prepared by HME could inhibited drug recrystallization more effectively. In anti-inflammatory study, TA solid dispersion prepared by HME using VA64 as carrier material showed comparable therapeutic effect against ulcerative colitis with commercial andrographolide drop pills but significant improved activity over crude TA suspension, indicating the necessity of solid dispersion preparation.

The aim of this study was to investigate the correlation between critical granules characters (including particle size, surface roughness, and apparent porosity) and mechanical properties of press-coated tablets. Granules of a model formulation were prepared through Roll Compaction Granulation (RCG), High Shear Granulation (HSG), and Fluidized Bed Granulation (FBG) to prepare granules with different surface roughness and apparent porosity. The surface roughness and porosity of granules had a significantly greater effect on mechanical properties than the particle size of granules. Whether for brittle or plastic materials, FBG granules with the roughest surface and the greatest apparent porosity exhibited the best compression properties. The elastic recovery test, the interlayer adhesion forces study, the break pattern test, and the X-ray microcomputed tomography investigation suggested that granules with great apparent porosity and rough surfaces could contribute to the production of stable press-coated structures. Moreover, for press-coated tablets prepared using granules, the proper granules in the coat layer could eliminate the side effect of the rigid core on the mechanical strength. The above understandings will be conducive to the selection of compatible and appropriate granules characters, which can enhance mechanical properties and extend the application of press-coated tablets.

Chemotherapy is an effective anti-tumor treatment. Some anticancer chemotherapeutic drugs can not only induce cell death, but can also elicit antitumor immune responses. Here, the stability of cisplatin-loaded polymeric micelles (CDDP-PMs), pharmacokinetic drug-drug interactions of CDDP and anti-PD-L1 antibody (aPD-L1) in vivo and the alteration of the tumor microenvironment by combination of CDDP-PMs and aPD-L1 were evaluated. CDDP-PMs were fabricated by coordinated complexation and self-assembly method for tumor targeting. CDDP-PMs with higher mass ratio of copolymer have higher thermodynamic stability. The pharmacokinetic study showed that the CDDP and aPD-L1 were metabolized and cleared by two different pathways, suggesting that there is almost no risk of potential drug interactions between CDDP and aPD-L1 and the combination of aPD-L1 and CDDP- PMs may not alter the tissue distribution of CDDP. In vivo antitumor test showed that the tumor growth inhibition rates of CDDP-PMs combined with medium-dose aPD-L1 and CDDP-PMs combined with high-dose PD-L1 were 89.41% and 93.16%, respectively and therapeutic efficacy can be further increased by increasing the dose of aPD-L1 in co-administration group. This therapeutic system by combining chemotherapy and immunotherapy further increases the link between them and holds great potential to offer better safety and antitumor efficacy profiles.

Here we report the combination of thermo-sensitive hydrogel systems and nanocomplexes for prolonged subcutaneous delivery of enoxaparin (EX). Thermo-sensitive hydrogels were prepared with enoxaparin solution and dispersion of enoxaparin nanocomplexes. Nanocomplexes (NC) were formed by self-assembly of enoxaparin with cationic polymers. Three polymers namely e-polylysine (Plys), chitosan (CS), polyethylenimine (PEI), were tested. Three nanocomplexes were optimized in terms of different EX/polymer mass ratio, and their size, zeta-potential and morphology were evaluated. Thermo-sensitive hydrogels were examined by gelation temperature, gel dissolution. In vitro EX release study demonstrated that nanocomplexes incorporation into thermo-sensitive hydrogels could prolong the EX release. Overall, nanocomplexes in thermo-sensitive hydrogels is promising delivery systems for prolonged subcutaneous EX delivery.

Poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) have attracted considerable interest in the medical community as a sustained-release drug delivery system for localized treatment. However, it is currently a grand challenge to simultaneously achieve low-dose drugs, stable and prolonged drug release, and long-term retention circumventing uptake by macrophages. Here, we construct a solvent-exchange in-situ depot system by incorporating progesterone (PRG) loaded PLGA NPs into a sucrose acetate isobutyrate (SAIB) and PLGA matrix for the long term treatment of Assisted Reproductive Technology (ART). The results showed that different solvent and PLGA contents could affect the drug release rate of PRG NPs-SAIB-PLGA in-situ depot system (PSPIDS). When DMSO was used as solvent with the addition of 8% PLGA to the depot, PSPIDS could achieve a constant drug release with no burst for 2 weeks in vitro. After a single intramuscular injection, such PSPIDS showed higher drug concentration and AUC (6773.0 ± 348.8 μg/L·h) over the entire 7-day testing period compared with the commercial multiple-day-dosing intramuscular PRG-oil solution (1914.5 ± 180.7 μg/L·h) in vivo. Importantly, PSPIDS could be administered at a dose of 3.65 mg/kg, which was one fourth of dose required for PRG-oil solution. The results demonstrate that PRG NPs could successfully achieve both reduced administered dosage and burst release, and therefore that PSPIDS is a promising long-acting composite system for hydrophobic drugs.

Shuhang Wang,1 Jingxin Gou,2 Yue Wang,1 Xinyi Tan,2 Linxuan Zhao,1 Xiangqun Jin,1 Xing Tang2 1Department of Pharmaceutics, College of Pharmacy Sciences, Jilin University, Changchun, 130021, Jilin, People’s Republic of China; 2Department of Pharmaceutics Science, Shenyang Pharmaceutical University, Shenyang, 110016, People’s Republic of ChinaCorrespondence: Xiangqun JinDepartment of Pharmaceutics, College of Pharmacy Sciences, Jilin University, Changchun, 130021, Jilin, People’s Republic of ChinaTel +86 431 85619252Fax +86 431 85619662Email jinxq@jlu.edu.cnPurpose: Non-small cell lung cancer (NSCLC) is an aggressive tumor with high mortality and poor prognosis. In this study, we designed a liposome encapsulating polymeric micelles (PMs) loaded with vinorelbine (NVB) and cis-diamminedichloroplatinum (II) (cisplatin or CDDP) for the treatment of NSCLC.Materials and Methods: Sodium poly(α-l-glutamic acid)-graft-methoxy-polyethylene glycol (PLG-G-PEG5K) was used to prepare NVB-loaded NVB-PMs and CDDP-loaded CDDP-PMs that were co-encapsulated into liposomes by a reverse evaporation method, yielding NVB and CDDP co-delivery liposomes (CoNP-lips) composed of egg phosphatidyl lipid-80/cholesterol/DPPG/DSPE-mPEG2000 at a molar ratio of 52:32:14:2. The CoNP-lips were characterized in terms of particle size, zeta potential, drug content, encapsulation efficiency, and structural properties. Drug release by the CoNP-lips as well as their stability and cytotoxicity was evaluated in vitro, and their antitumor efficacy was assessed in a mouse xenograft model of Lewis lung carcinoma cell-derived tumors.Results: CoNP-lips had a spherical shape with uniform size distribution; the average particle size was 162.97± 9.06 nm, and the average zeta potential was − 13.02± 0.22 mV. In vitro cytotoxicity analysis and the combination index demonstrated that the CoNP-lips achieved a synergistic cytotoxic effect at an NVB:CDDP weight ratio of 2:1 in an NSCLC cell line. There was sustained release of both drugs from CoNP-lips. The pharmacokinetic analysis showed that CoNP-lips had a higher plasma half-life than NP solution, with 6.52- and 8.03-fold larger areas under the receiver operating characteristic curves of NVB and CDDP. CoNP-lips showed antitumor efficacy in tumor-bearing C57BL/6 mice and drug accumulation in tumors via the enhanced permeability and retention effect.Conclusion: CoNP-lips are a promising formulation for targeted therapy in NSCLC.Keywords: cisplatin, vinorelbine, co-delivery liposomes, combination therapy, polymeric micelles, non-small cell lung cancer