Rapid Drug Release Research Articles

Fabrication of a composite 3D-printed titanium alloy combined with controlled in situ drug release to prevent osteosarcoma recurrence

Osteosarcoma is a malignant bone tumor occurring in adolescents. Surgery combined with adjuvant or neoadjuvant chemotherapy is the standard treatment. However, systemic chemotherapy is associated with serious side effects and a high risk of postoperative tumor recurrence, leading to a high amputation rate and mortality in cancer patients. Implant materials that can simultaneously repair large bone defects and prevent osteosarcoma recurrence are in urgent need. Herein, an intelligent system comprising 3D-printed titanium scaffold (TS) and pH-responsive PEGylated paclitaxel prodrugs was fabricated for bone defect reconstruction and recurrence prevention following osteosarcoma surgery. The drug-loaded implants exhibited excellent stability and biocompatibility for supporting the activity of bone stem cells under normal body fluid conditions and the rapid release of drugs in response to faintly acidic environments. An in vitro study demonstrated that five human osteosarcoma cell lines could be efficiently eradicated by paclitaxel released in an acidic microenvironment. Using mice models, we demonstrated that the drug-loaded TS can enable a pH-responsive treatment of postoperative tumors and effectively prevent osteosarcoma recurrence. Therefore, local implantation of this composite scaffold may be a promising topical therapeutic method to prevent osteosarcoma recurrence.

Bioengineered nanogenerator with sustainable reactive oxygen species storm for self-reinforcing sono-chemodynamic oncotherapy

Oxidative stress-based antitumor modalities derived from reactive oxygen species (ROS) storms have attracted increasing attention. Nevertheless, low delivery efficiency, poor selectivity, hypoxia and overexpressed glutathione (GSH) have severely restricted the sustainable generation of the ROS storm in tumor cells. Herein, we design a bioengineered nanogenerator by coordination-driven co-assembly of sonosensitizer indocyanine green (ICG), Fenton-like agent copper ion (CuⅡ) and mitochondrial respiratory inhibitor metformin (MET), which is then camouflaged by a cancer cytomembrane to induce a sustainable intracellular ROS storm for on-demand self-reinforcing sono-chemodynamic oncotherapy. Such a nanogenerator with a core–shell structure, suitable diameter and outstanding stability can efficiently accumulate in tumor regions and then internalize into tumor cells through the camouflaging and homologous targeting strategy of the cancer cytomembrane. The nanogenerator shows an exceptional instability under the triple stimulations of acidic lysosomes, overexpressed GSH and ultrasound (US) radiation, thereby resulting in the rapid disassembly and burst drug release. Interestingly, the released MET significantly enhances the sonodynamic therapy (SDT) efficacy of the released ICG by inhibiting mitochondrial respiration and meanwhile the released CuⅡ obviously reduces ROS elimination by downregulating overexpressed GSH for self-amplifying and self-protecting the intracellular ROS storm. Moreover, such a nanogenerator almost completely achieves the tumor ablation in vivo in a single therapy cycle. Taken together, our bioengineered nanogenerator with a sustainable ROS storm can provide a promising strategy for ROS storm-based oncotherapy.

Bio-Responsive Macromolecular Drug and Small-Molecular Drug Conjugates: Nanoparticulate Prodrugs for Tumor Microenvironment Heterogeneity Management and Therapeutic Response Enhancement.

How to break through the poor response of current drug therapy, which often resulted from tumor microenvironment heterogeneity (TMH), remains an enormous challenge in the treatment of critical diseases. In this work, a practical solution on bio-responsive dual-drug conjugates for overcoming TMH and improving antitumor treatment, which integrates the advantages of macromolecular drugs and small-molecular drugs, is proposed. Nanoparticulate prodrugs based on small-molecular drug and macromolecular drug conjugates are designed as a robust weapon for programmable multidrug delivery at tumor-specific sites: the tumor microenvironment acid condition triggers delivery of macromolecular aptamer drugs (AX102) to manage TMH (including tumor stroma matrix, interstitial fluid pressure, vasculature network, blood perfusion, and oxygen distribution), and intracellular lysosomal acid condition activates rapid release of small-molecular drugs (doxorubicin and dactolisib) to enhance curative effects. As compared with doxorubicin chemotherapy, the tumor growth inhibition rate is enhanced by 47.94% after multiple tumor heterogeneity management. This work verifies that the nanoparticulate prodrugs facilitate TMH management and therapeutic response enhancements, as well as elucidates synergetic mechanisms for drug resistance reversal and metastasis inhibition. It is hoped that the nanoparticulate prodrugs will be an excellent demonstration of the co-delivery of small-molecular drugs and macromolecular drugs.

Delivery of quercetin for breast cancer and targeting potentiation via hyaluronic nano-micelles

Quercetin (QT) is a very effective anticancer drug in combating breast cancer. However, it has several disadvantages such as poor water solubility, low bioavailability and low targeting, which seriously restrict its clinical application. In this work, amphiphilic hyaluronic acid polymers (dHAD) were synthesized by grafting dodecylamine to hyaluronic acid (HA). The dHAD self-assembles with QT to form drug-carrying micelles (dHAD-QT). The dHAD-QT micelles possessed excellent drug-loading capacities (75.9 %) for QT and showed significantly improved CD44 targeting compared with unmodified HA. dHAD-QT micelles exhibited high cytotoxicity and apoptosis-inducing abilities, which were ascribed to the pH-sensitive dHAD-QT micelles accomplishing rapid drug release of QT under low pH condition. Importantly, in vivo experiments showed that dHAD-QT effectively inhibited tumor growth in tumor-bearing mice, with a tumor inhibition rate of 91.8 %. Furthermore, dHAD-QT prolonged the survival time of tumor-bearing mice and reduced the toxicity of the drug to normal tissues. These findings indicate that the designed dHAD-QT micelles have promising potential as efficient nano-drugs for breast cancer treatment.

Discovery of novel antibody-drug conjugates bearing tissue protease specific linker with both anti-angiogenic and strong cytotoxic effects

Bevacizumab is an FDA-approved class of monoclonal antibodies used to inhibit angiogenesis and promote normalization of blood vessels. It is usually combined with chemotherapeutic agents to treat a variety of solid tumors. However, the whole-body toxicities and toxicity associated with chemotherapy greatly limit the clinical use of this combination therapy. Antibody-drug conjugates (ADCs) couple monoclonal antibodies to cytotoxic molecules via a linker, utilizing the high specificity of monoclonal antibodies to tumor surface antigens to act as a “biological missile” to deliver chemotherapeutic drugs to the tumor site. Herein, we designed a bevacizumab-based ADC, Bevacizumab Vedotin, conjugating bevacizumab to the microtubulin inhibitor MMAE via a tissue protease-specific linker. Biological studies showed strong stability and good tumor cell targeting of our constructed ADCs; rapid drug release was achieved in the presence of exogenous histone protease B. In addition, Bevacizumab Vedotin exhibited good anti-proliferative, apoptosis-promoting and cell cycle-stalling effects on glioma (U87), hepatocellular carcinoma (HepG2), and breast cancer (MCF-7) cell lines. Further in vitro assays demonstrated the enhanced anti-migration activity against MCF-7, potent anti-angiogenic effects, and blockade of the VEGF/VEGFR pathway of Bevacizumab Vedotin.

Mesoporous Silica-Encapsulated Gold Nanorods for Drug Delivery/Release and Two-Photon Excitation Fluorescence Imaging to Guide Synergistic Phototherapy and Chemotherapy.

Photothermal therapy is a promising light-based medical treatment that relies on light absorption agents converting light irradiation into localized heat to destroy cancer cells or other diseased tissues. It is critical to enhance the therapeutic effects of cancer cell ablation for their practical applications. This study reports a high-performance combinational therapy for ablating cancer cells, including both photothermal therapy and chemotherapy to improve therapeutic efficiency. The prepared AuNR@mSiO2 loading molecular Doxorubicin (Dox) assemblies were highlighted by merits of facile acquisition, great stability, easy endocytosis, and rapid drug release in addition to improved anticancer capability upon irradiation with a femtosecond pulsed near-infrared (NIR) laser, where AuNR@mSiO2 nanoparticles afforded a high photothermal conversion efficiency of 31.7%. Two-photon excitation fluorescence imaging was introduced into confocal laser scanning microscope multichannel imaging to track the drug location and cell position in real time for monitoring the process of drug delivery in killing human cervical cancer HeLa cells and then to realize imaging-guiding cancer treatment. These nanoparticles exhibit widespread potential in photoresponsive utilizations including photothermal therapy, chemotherapy, one- and two-photon excited fluorescence imaging, and 3D fluorescence imaging and cancer treatment.

Sono-promoted drug penetration and extracellular matrix modulation potentiate sonodynamic therapy of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) exhibits difficult penetration of most drugs, leading to a very poor therapeutic outcome with a quite low five-year survival rate. The foremost reason is the highly-dense extracellular matrix (ECM) with abundant collagen and fibronectin secreted by the activated pancreatic stellate cells (PSCs). Here, we constructed a sono-responsive polymeric perfluorohexane (PFH) nanodroplet to elicit a deep drug penetration in PDAC via the combination of exogenous ultrasonic (US) exposure and endogenous ECM modulation for potent sonodynamic therapy (SDT) of PDAC. Under US exposure, the rapid drug release and deep penetration in PDAC tissues were realized. The released and well penetrated all-trans retinoic acid (ATRA) as an inhibitor of activated PSCs successfully reduced the secretion of ECM components to form a non-dense matrix conducive to drug diffusion. Meanwhile, the sonosensitizer, manganese porphyrin (MnPpIX), was triggered to produce robust reactive oxygen species (ROS) to exert the SDT effect under US exposure. Furthermore, oxygen (O2) delivered by PFH nanodroplets alleviated tumor hypoxia and enhanced the eradication of cancer cells. Overall, the sono-responsive polymeric PFH nanodroplets were successfully developed as an efficient strategy for PDAC therapy. STATEMENT OF SIGNIFICANCE: Pancreatic ductal adenocarcinoma (PDAC) is a representative refractory cancer with a highly dense extracellular matrix (ECM), making it difficult for most drugs to penetrate the nearly impenetrable desmoplastic stroma. Seeking methods for deep drug penetration is an extremely pressing matter for the treatment of PDAC and many other solid tumors. Herein, we designed a fluoroalkane-modified polymer to prepare a sono-responsive polymeric perfluorohexane (PFH) nanodroplet for loading sonosensitizers, and inhibitors of activated PSCs and O2. Under ultrasonic exposure, the nanodroplet elicited deep drug penetration in PDAC via ultrasonic disturbance and stromal remodeling, inducing potent sonodynamic therapy (SDT) of PDAC. By combining exogenous ultrasonic exposure and endogenous ECM modulation, this work successfully alleviated the severe physiological barrier of PDAC and achieved a favourable treatment effect.

Complete in vitro Dissolution of Valbenazine as Either Whole Capsules or Crushed Capsule Contents

AbstractIntroductionTardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with exposure to antipsychotics and other dopamine receptor blocking agents. Three valbenazine capsule strengths (40 mg, 60 mg, 80 mg) are approved for the once-daily treatment of TD. However, some patients with TD, especially in elderly populations, have trouble swallowing due to orolingual movements. This study was conducted to evaluate two different dissolution methods for valbenazine: whole intact capsules versus crushed capsule contents.MethodsSamples were prepared using two commercial lots (Lot-A, Lot-B) for two doses (40 mg, 80 mg), with six replicate samples per lot and dose. The whole capsules were weighed, put into a sinker, and added to a dissolution bath containing 900 mL of 0.1N HCl at 37±0.5° Celsius. Testing on the crushed capsule contents commenced after opening the capsules, weighing and crushing the contents, and transferring the contents to the dissolution bath. Samples were collected (at 10, 15, 20, 30, 45, and 60 min) with a paddle speed of 50 rpm and analyzed using high performance liquid chromatography. Standards were prepared at nominal concentrations of 0.044 mg/mL (for 40 mg) and 0.089 mg/mL (for 80 mg).ResultsCapsules were opened easily by manual manipulation, and contents were crushed easily between spoons. Very rapid (>85% in 15 min) and complete drug release was observed in all samples, independent of capsule strength (40 mg, 80 mg) or preparation (whole intact capsule or crushed capsule contents). For 40-mg capsules, average percent release at first and last collection timepoints were as follows (whole vs crushed): 10 min (98.4% vs 98.6% [A], 93.7% vs 97.6% [B]); 60 min (102.3% vs 100.5% [A], 100.9% vs 100.6% [B]). Results for 80-mg capsules were as follows: 10 min (98.2% vs 99.6% [A], 99.4% vs 97.9% [B]); 60 min (102.0% vs 101.6% [A], 103.2% vs 100.9% [B]).ConclusionsCrushing the capsule contents did not impact the in vitro dissolution performance of valbenazine. Many patients with TD, particularly elderly patients, have difficulty swallowing and may benefit from alternative delivery methods for valbenazine, especially if other TD medications cannot be crushed. More research is needed to better understand if and how crushing the capsule contents of valbenazine affects their stability when mixed with food or delivered through a feeding tube.FundingNeurocrine Biosciences, Inc.

FABRICATION AND EVALUATION OF MOUTH-DISSOLVING FILMS OF DOMPERIDONE

Objective: The objective of present research work was to fabricate and evaluate mouth-dissolving films of domperidone by solvent casting method using hydroxypropyl methyl cellulose as polymer for rapid release of drug.
 Methods: Domperidone (DMP) is specific blocker of dopamine receptors (D2 and D3) and is widely used to treat emesis. Since domperidone solubility is less, domperidone solid dispersion (DMP SD’s) were prepared with β-cyclodextrine inclusion complexes in different ratio (1:1, 1:2, 1:3 and 1:4) by kneading method to increase the solubility. The DMP mouth dissolving films (MDF) were developed using DMP SD’s by solvent casting method. Hydroxypropyl methyl cellulose (HPMC) was used as film forming agent and glycerine was used as plasticizer. Nine formulations were fabricated and were evaluated for their various physico-mechanical properties, in vitro disintegration time and in vitro dissolution characteristics.
 Results: The solid dispersion SD3 increased the solubility of drug compared to pure drug. FTIR studies revealed the integrity of the drug in its pure form in both drug-βcyclodextrine complex and finished MDF. The thickness uniformity, weight uniformity, folding endurance, surface pH and drug content of mouth dissolving films were uniform and reproducible. Formulation F1 released highest percentage of drug i.e., 100% of drug in 16 min compared to other formulations in in vitro release studies and disintegrated within 2.5 min and hence was considered as optimized formulation. The mechanism of drug release of prepared mouth dissolving films was Non-Fickian diffusion controlled kinetics.
 Conclusion: Complexation by Kneading technique was found satisfactory for solid dispersion of domperidone. Solvent casting method was successfully used to obtain uniform mouth dissolving films containing drug-β cyclodextrine solid dispersion. Mouth dissolving films containing domperidone could be successfully developed and optimised.

Effect of cold plasma treatment on polylactic acid and polylactic acid/poly (ethylene glycol) films developed as a drug delivery system for streptomycin sulfate

Polylactic acid (PLA) being a renewable polyester have extensively researched in the biomedical field due to its non-toxicity, high biocompatibility, and easy processing properties. However, low functionalization ability and hydrophobicity limit its applications and hence demands physical and chemical modifications to overcome these limitations. Cold plasma treatment (CPT) is frequently used to improve the hydrophilic properties of PLA-based biomaterials. This provides an advantage to obtain a controlled drug release profile in drug delivery systems. The rapid drug release profile may be advantageous in some applications such as wound application. The main objective of this study is to determine the effects of CPT on PLA or PLA@polyethylene glycol (PLA@PEG) porous films fabricated by solution casting method for use as a drug delivery system with a rapid release profile. The physical, chemical, morphological and drug release properties of PLA and PLA@PEG films, such as surface topography, thickness, porosity, water contact angle (WCA), chemical structure, and streptomycin sulfate release properties, after CPT were systematically investigated. XRD, XPS and FTIR results showed that oxygen-containing functional groups were formed on the film surface with CPT without changing the bulk properties. Along with the changes in the surface morphology such as surface roughness and porosity, the new functional groups provide the films hydrophilic properties by reducing the water contact angle. The improved surface properties enabled the selected model drug, streptomycin sulfate, to exhibit a faster release profile with drug-released mechanism fitted by first order kinetic model. Considering all the results, the prepared films showed an enormous potential for future drug delivery applications, especially in wound application where rapid drug release profile is an advantage.

Preparation and characterization of fast-release oral film formulation containing ondansetron hydrochloride solid dispersion

Ondansetron has been widely applied as an antiemetic drug in the treatment or prevention of nausea and vomiting caused by emetic cancer chemotherapy . Fast-release films have the advantages of rapid drug release and improved patients’compliance, especially for the disabled bedridden, the elderly or pediatric patients.The basic film-forming materials were studied through single factor tests and the crystal inhibitors were optimized using solid dispersion technique. The ratio of drug and polymers were optimized by X-ray diffraction (XRD) and Differential Scanning Calorimetry (DSC) which revealed there was no presence of crystal in the optimized solid dispersion. The final film was white thin films and was smooth in surface without obvious bubbles or cracks. Mean weight of each film was 40~50mg. Mean thichness was 60~70μm. Surface pH was 6.4~6.6. The films could release 85% of drug with 1.5min in 0.1mol/L HCl and within 30min in pH6.8PBS. Pharmacolinetic experiment of Ondansetron Hydrochloric solution, marketed films Zuplenz® and the preparation were carried out in rats. As a result, the films of Ondansetron Hydrochloric containing ondansetron solid dispersion had the advantages of fast drug release, improved patient compliance, higher bioavalibility compared to oral solution and the marketed films.

Carboxylated paclitaxel prodrug nanofibers for enhanced chemotherapy.

The facile availability of nanoformulations with enhanced antitumor performance remains a big challenge. Herein, we synthesize paclitaxel prodrugs with amphiphilic structures and robust assembling ability. Carboxylated paclitaxel prodrugs (PSCB) containing disulfide bonds prefer to form exquisite nanofibers, while phenylcarbinol end capped paclitaxel prodrugs (PSP) assemble into spherical nanoparticles. The transformation of morphology from nanofibers to nanorods can be realized via tuning the content of paclitaxel. Hydrophilic domains of PSCB nanofibers accelerate the cleavage of disulfide bond for rapid drug release in tumor cells, thus exhibiting the enhanced cytotoxicity and antitumor activity. This study provides a crucial insight into the functional design of hydrophobic drugs to improve chemotherapy.

Self-Assembled Redox-Sensitive Polymeric Nanostructures Facilitate the Intracellular Delivery of Paclitaxel for Improved Breast Cancer Therapy.

A two-tier approach has been proposed for targeted and synergistic combination therapy against metastatic breast cancer. First, it comprises the development of a paclitaxel (PX)-loaded redox-sensitive self-assembled micellar system using betulinic acid-disulfide-d-α-tocopheryl poly(ethylene glycol) succinate (BA-Cys-T) through carbonyl diimidazole (CDI) coupling chemistry. Second, hyaluronic acid is anchored to TPGS (HA-Cys-T) chemically through a cystamine spacer to achieve CD44 receptor-mediated targeting. We have established that there is significant synergy between PX and BA with a combination index of 0.27 at a molar ratio of 1:5. An integrated system comprising both BA-Cys-T and HA-Cys-T (PX/BA-Cys-T-HA) exhibited significantly higher uptake than PX/BA-Cys-T, indicating preferential CD44-mediated uptake along with the rapid release of drugs in response to higher glutathione concentrations. Significantly higher apoptosis (42.89%) was observed with PX/BA-Cys-T-HA than those with BA-Cys-T (12.78%) and PX/BA-Cys-T (33.38%). In addition, PX/BA-Cys-T-HA showed remarkable enhancement in the cell cycle arrest, improved depolarization of the mitochondrial membrane potential, and induced excessive generation of ROS when tested in the MDA-MB-231 cell line. An in vivo administration of targeted micelles showed improved pharmacokinetic parameters and significant tumor growth inhibition in 4T1-induced tumor-bearing BALB/c mice. Overall, the study indicates a potential role of PX/BA-Cys-T-HA in achieving both temporal and spatial targeting against metastatic breast cancer.

Autocatalytic strategy for tuning drug release from peptide-drug supramolecular hydrogel

Peptide-drug conjugates (PDCs) composed of peptide, spacer and drug have gained extensive attention in the field of drug delivery owing to its precise control over the drug payload and architecture. However, the achievement of controllable and rapid drug release at targeted site by PDCs is still a great challenge for pharmaceutist. Herein, we introduced the histidine residue into PDCs to generate a supramolecular hydrogel via a pH-trigger strategy, which exhibited an autocatalytic effect to precisely tune drug release from PDCs hydrogel. Using indomethacin (Idm) as model drug, various PDCs (Y(Idm)EEH, Y(Idm)EEK and Y(Idm)EER) were synthesized and their self-assembling properties were investigated in terms of critical aggregation concentration (CAC), transmission electron microscopy (TEM) and rheometer. Introduction of histidine residue into PDCs presented a robust catalytic activity on the ester hydrolysis of p-nitrophenyl acetate in aqueous solution, as well conferred the autocatalytic capacity to hydrolyze the PDCs into active parent drug (Idm). Overall, we reported an autocatalytic activity of histidine residue to precisely tune drug release from PDCs hydrogels.

Flexible Transient Bioelectronic System Enables Multifunctional Active‐Controlled Drug Delivery

AbstractOn‐demand drug delivery systems (DDSs) have tremendous promise for clinical in vivo personalized drug delivery. However, the current DDSs are monofunctional and unable to meet the individualized needs of patients. Herein, a biodegradable multifunctional active‐controlled drug delivery system (ADDS) is reported. The device can be implanted in various tissues with valves controlled by the deactivation of magnesium (Mg) for rapid drug release from drug reservoirs and long‐term drug delivery with the biodegradation of the ADDS. Multiple chambers are constructed by designing a structure with tandem Mg valves and aligning them in the z‐axis direction, allowing the system to deliver drugs in a pulsatile or sequential manner. The biodegradability of the entire system minimizes the potential side effects of the ADDS. The application of the device for drug delivery in rats confirmed its ability to perform pulsatile delivery in vivo. The excellent biocompatibility and dual timeline drug delivery capability of this system are demonstrated with cellular and in vitro vascular bioreactors. This multifunctional ADDS will play an important role in precise drug delivery in the treatment of chronic diseases and diseases with complications.

3D-Printed Fast-Dissolving Oral Dosage Forms via Fused Deposition Modeling Based on Sugar Alcohol and Poly(Vinyl Alcohol)—Preparation, Drug Release Studies and In Vivo Oral Absorption

Three-dimensional printing technology holds marked promise for the pharmaceutical industry and is now under intense investigation. Most research is aimed at a greater efficiency in printing oral dosage forms using powder bed printing or fused deposition modeling (FDM). Oral dosage forms printed by FDM tend to be hard objects, which reduce the risk of cracking and chipping. However, one challenge in printing oral dosage forms via FDM is achieving rapid drug release, because the materials for FDM are basically thermoplastic polymers with slow drug release properties. In this study, we investigated printing a fast-dissolving oral dosage form by adding sugar alcohol to a poly(vinyl alcohol)-based formulation for FDM. Filaments which contain sugar alcohol were successfully prepared, and objects were printed with them as oral dosage forms by FDM. On drug release testing, a printed oral dosage form in a ring shape which contained 55% maltitol showed a more than 85% drug release in 15 min. In vivo oral absorption of this printed oral dosage form in dogs was comparable to that of a conventional fast-dissolving tablet. Of particular interest, the drug release profile and drug amount of the oral dosage forms can be easily controlled by a change in shape using 3D Computer Aided Design. These characteristics will encourage the prevalence of FDM by the pharmaceutical industry, and contribute to the promotion of personalized medicine.

Design of an Antibiotic-Releasing Polymer: Physicochemical Characterization and Drug Release Patterns.

Conventional drug delivery has its share of shortcomings, especially its rapid drug release with a relatively short duration of therapeutic drug concentrations, even in topical applications. Prolonged drug release can be effectively achieved by modifying the carrier in a drug delivery system. Among the several candidates for carriers studied over the years, poly (ether ether ketone), a biocompatible thermoplastic, was chosen as a suitable carrier. Its inherent hydrophobicity was overcome by controlled sulfonation, which introduced polar sulfonate groups onto the polymer backbone. Optimization of the sulfonation process was completed by the variation of the duration, temperature of the sulfonation, and concentration of sulfuric acid. The sulfonation was confirmed by EDS and the degree of sulfonation was determined by an NMR analysis (61.6% and 98.9%). Various physical properties such as morphology, mechanical strength, and thermal stability were studied using scanning electron microscopy, tensile testing, and thermogravimetric analysis. Cytotoxicity tests were performed on the SPEEK samples to study the variation in biocompatibility against a Vero cell line. The drug release kinetics of ciprofloxacin (CP) and nalidixic acid sodium salt (NA)-loaded membranes were studied in deionized water as well as SBF and compared against the absorbance of standardized solutions of the drug. The data were then used to determine the diffusion, distribution, and permeability coefficients. Various mathematical models were used to fit the obtained data to establish the order and mechanism of drug release. Studies revealed that drug release occurs by diffusion and follows zero-order kinetics.

Photochemically-driven highly efficient intracellular delivery and light/hypoxia programmable triggered cancer photo-chemotherapy

BackgroundUsing nanotechnology to improve the efficiency of tumor treatment represents a major research interest in recent years. However, there are paradoxes and obstacles in using a single nanoparticle to fulfill all the requirements of complex tumor treatment.ResultsIn this paper, a programmed-triggered nanoplatform (APP NPs), which is sequentially responsive to light and hypoxia, is rationally integrated for photoacoustic (PA) imaging-guided synergistic cancer photo-chemotherapy. The nanoplatform is constructed by in situ hybridization of dopamine monomer in the skeleton of PCN-224 and loading prodrug banoxantrone (AQ4N). Upon first-stage irradiation with a 660 nm laser, cellular internalization was effectively promoted by a photosensitizer-mediated photochemical effect. Furthermore, under second-stage irradiation, APP NPs exhibit a notably high photothermal conversion efficiency and sufficient reactive oxygen species (ROS) production for photothermal therapy (PTT) and photodynamic therapy (PDT), respectively, which not only triggers rapid intercellular drug release but also consequently aggravates tumor hypoxia levels, and aggravated hypoxia can further active the cytotoxicity of AQ4N for chemotherapy. Both in vitro and in vivo studies confirm that the dual-stage light guided photo-chemotherapy strategy exhibits a greatly enhanced anticancer effects and superior therapeutic safety.ConclusionThis work represents a versatile strategy to construct a dual-stage light induced PDT/PTT and hypoxia-activated chemotherapy nanoplatform and will be promising for the development of multistimuli-responsive nanosystems with programmable functions for precise cancer therapy.

Reduction-Responsive Stearyl Alcohol-Cabazitaxel Prodrug Nanoassemblies for Cancer Chemotherapy.

Cabazitaxel (CTX) has distinct therapeutic merits for advanced and metastatic cancer. However, the present clinical formulation (Jevtana®) has several defects, especially for undesirable tumor-targeting and serious side effects, greatly limiting the therapeutic efficacy. Small-molecule prodrug-based nanoassemblies integrate the advantages of both prodrug strategy and nanotechnology, emerging as a promising treatment modality. Herein, disulfide bonds with different lengths were employed as linkages to elaborately synthesize three redox-sensitive stearyl alcohol (SAT)-CTX prodrug-based nanoassemblies (SAC NPs, SBC NPs and SGC NPs) for seeking optimal chemotherapeutical treatment. All the prodrug-based nanoassemblies exhibited impressive drug-loading efficiency, superior self-assembly capability and excellent colloidal stability. Interestingly, the drug release behaviors of three prodrug-nanoassemblies in the same reductive environment were different owing to tiny changes in the carbon chain length of disulfide bonds, resulting in disparate cytotoxicity effects, pharmacokinetic outcomes and in vivo antitumor efficacies. Among them, SAC NPs displayed rapid drug release, excellent cytotoxicity, long blood circulation and enhanced tumor accumulation, thus showing strong tumor inhibition in the 4T1-bearing mouse model. Our study shed light on the vital role of connecting bonds in designing high-efficiency, low-toxicity prodrug nanoassemblies.

Review of the Delivery Kinetics of Thermosensitive Liposomes.

Thermosensitive liposomes (TSL) are triggered nanoparticles that release the encapsulated drug in response to hyperthermia. Combined with localized hyperthermia, TSL enabled loco-regional drug delivery to tumors with reduced systemic toxicities. More recent TSL formulations are based on intravascular triggered release, where drug release occurs within the microvasculature. Thus, this delivery strategy does not require enhanced permeability and retention (EPR). Compared to traditional nanoparticle drug delivery systems based on EPR with passive or active tumor targeting (typically <5%ID/g tumor), TSL can achieve superior tumor drug uptake (>10%ID/g tumor). Numerous TSL formulations have been combined with various drugs and hyperthermia devices in preclinical and clinical studies over the last four decades. Here, we review how the properties of TSL dictate delivery and discuss the advantages of rapid drug release from TSL. We show the benefits of selecting a drug with rapid extraction by tissue, and with quick cellular uptake. Furthermore, the optimal characteristics of hyperthermia devices are reviewed, and impact of tumor biology and cancer cell characteristics are discussed. Thus, this review provides guidelines on how to improve drug delivery with TSL by optimizing the combination of TSL, drug, and hyperthermia method. Many of the concepts discussed are applicable to a variety of other triggered drug delivery systems.