Controlled release of Lactiplantibacillus plantarum by colon-targeted adhesive pectin microspheres: Effects of pectin methyl esterification degrees.

The aim of this study is to report the preparation of pectin microspheres by varying degrees of methyl esterification (DM) cross-linked with divalent cationic calcium to encapsulate Lactiplantibacillus plantarum STB1 and L. plantarum LJ1, respectively. Scanning electron microscopy revealed the compact and smooth surface of pectin of DM 28 %, and the stochastic distribution of L. plantarum throughout the gel reticulation. And the pectin of DM 28 % considerably increased probiotics tolerance after continuous exposure to stimulated gastrointestinal tract conditions, with viable counts exceeding 109 CFU/mL. This data indicated that low methoxy-esterification pectin was more efficient to improve the targeted delivery of probiotics in GIT. Additionally, the controlled release of microspheres was dependent on various pH levels. At pH 7.4, the release rates of L. plantarum STB1 and L. plantarum LJ1 reached up to 97.63 % and 95.33 %, respectively. Finally, the Caco-2 cell adhesion model was used to evaluate the cell adhesion rate after encapsulation, which exhibited better adhesion at DM of 60 %.

Improving the in vitro and in vivo bioavailability of pterostilbene using Yesso scallop gonad protein isolates-epigallocatechin gallate (EGCG) conjugate-based emulsions: effects of carrier oil.

This study investigated the influence of carrier oils on the in vitro and in vivo bioavailability of PTE encapsulated in scallop gonad protein isolates (SGPIs)-epigallocatechin gallate (EGCG) conjugate stabilized emulsions. The SGPIs-EGCG stabilized emulsions were subjected to an in vitro simulated digestion, and the resulting corn oil and MCT micelles were used to evaluate the PTE transportation using the Caco-2 cell model. Both emulsions remarkably improved the bioaccessibility of PTE in the micelle phase. Nevertheless, corn oil emulsions increased trans-enterocyte transportation of PTE more efficiently than MCT emulsions. Furthermore, the maximum plasma concentrations of PTE and its metabolites in mice fed with PTE emulsions were prominently higher than those in mice fed with PTE solution, while the in vivo metabolic patterns of PTE in different oil-stabilized emulsions were different. Therefore, SGPIs-EGCG stabilized emulsions could enhance the bioavailability of PTE through controlled release, in which corn oil is more suitable than MCT.

A Novel Technique to Improve Drug Loading Capacity of Fast/Extended Release Orally Dissolving Films with Potential for Paediatric and Geriatric Drug Delivery.

Orally dissolving films (ODFs) have received much attention as potential oral drug delivery systems for paediatric and geriatric patients, particularly those suffering from dysphagia. With their unique properties and advantages, the technology offers improved patient compliance and wider acceptability, eliminates the fear of choking, enables ease of administration and offers dosing convenience, without the requirement of water. However, adequate drug loading remains a challenge. The aim of this study was to mechanistically design and evaluate fast and extended release ODF formulations with high drug loading capacity, displaying good physicochemical and mechanical properties, as a potential dosage form for paediatric and geriatric use employing a slightly soluble model drug-ibuprofen. Different polymers (0.6-10% HPMC, 0.6-1.5% guar gum), plasticisers (0.1-0.5% glycerine, 0.1% sorbitol) and processing conditions (40-60°C drying temperatures, 8-16 h drying times) were investigated to produce films using the solvent casting method. Molecular compatibility was assessed using TGA, XRD and FTIR whereas film topography was assessed using SEM. Maximum ibuprofen load in single films was 20.7 mg/film (54.4%) and released 100% drug content in 5 min, while triple layered ibuprofen-loaded films contained 62.2 mg/film and released 100% drug release in 1 h. The ODFs demonstrated good disintegration time using low volume artificial saliva media and high dosage from uniformity. This study provides a mechanistic insight to the design and evaluation of fast and extended release ODFs with high drug loading, suitable for administration to paediatric and geriatric patients.

Bioresponsive nanostructured systems for sustained naltrexone release and treatment of alcohol use disorder: Development and biological evaluation.

In this study, microemulsions capable of transforming into nanostructured hexagonal phase gels in vivo upon uptake of biological fluids for naltrexone prolonged release were investigated as a strategy for management of alcohol use disorder (AUD). Microemulsions were prepared using monoolein, tricaprylin, water and propylene glycol; after preliminary characterization, one formulation was selected, which contained 55% of monoolein-tricaprylin (M-55). This microemulsion displayed size below 200 nm and Newtonian rheological behavior. Liquid crystalline gels formed in vitro upon 8 h of contact with water following a second order kinetics. After 120 h, <50% of naltrexone was released in vitro independently on drug loading (5 or 10%). In vivo, gels formed within 24 h of M-55 subcutaneous administration, and persisted locally for over 30 days providing slow release of the fluorescent marker Alexa fluor compared to a solution. Using the conditioned place preference paradigm, a test used to measure drug's rewarding effects, a single dose of M-55 containing 5% naltrexone reduced the time spent in the ethanol-paired compartment by 1.8-fold compared to saline; this effect was similar to that obtained with daily naltrexone injections, demonstrating the formulation efficacy and its ability to reduce dosing frequency. A more robust effect was observed following administration of M-55 containing 10% of naltrexone, which was compatible with aversion. These results support M-55 as a platform for sustained release of drugs that can be further explored for management of AUD to reduce dosing frequency and aid treatment adherence.

pH-Responsive Emulsions with ß-Cyclodextrin/Vitamin E Assembled Shells for Controlled Delivery of Polyunsaturated Fatty Acids.

Lipid-based delivery systems (LBDSs) are widely applied in pharmaceuticals and health care because of the increased bioavailability of lipophilic components when they are coadministered with high-fat meals. However, how to accurately control their in vivo release and stability is still challenging. Here, after introducing the simple esterification and coprecipitation, we created the dual-functional composite ODS-ß-CD-VE by the coassembly of ß-cyclodextrin (ß-CD), octadecenyl succinic anhydride (ODSA), and vitamin E (VE). The resulting dual-functional particle presented a uniform sheetlike shape and nanometer size. In addition, its chemical structure was clarified in detail via nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD). Benefiting from the antioxygenation of VE, lipid oxidation in the ODS-ß-CD-VE-stabilized Pickering emulsion was effectively inhibited. Meanwhile, pH-induced protonation/deprotonation of carboxyl groups guaranteed that the emulsions kept steady at pH ≤4 but were unsteady under neutral conditions. In this way, the lipids contained in the emulsion were protected from gastric juice and then digested and accurately released as n-3 polyunsaturated fatty acids (PUFA) in the simulated intestine environment. This strategy sheds some light on the rational and efficient construction of LBDSs for nutrient supplements and even pharmaceuticals in a living digestive tract.

Carboxymethylpachymaran entrapped plant-based hollow microcapsules for delivery and stabilization of ß-galactosidase.

ß-Galactosidase (ß-Gal) as a dietary supplement can alleviate symptoms of lactose intolerance. However, ß-Gal is deactivated due to the highly acidic conditions and proteases in the digestive tract. In this work, ß-Gal was encapsulated into L. clavatum sporopollenin exine capsules (SECs) to fabricate an oral-controlled release system and increase the stability of ß-Gal in the digestive tract. The SEC extraction process was optimized. A 3-hour vacuum loading was determined as the optimal loading time. Five different initial ratios of SECs : ß-Gal were optimized with the maximum enzyme retention rate reaching 79.40 ± 1.96%. Furthermore, ß-Gal-loaded SECs entrapped in carboxymethylpachymaran (CMP) could control the release of ß-Gal under simulated gastrointestinal conditions (SGC). The optimal enzyme retention rate reached 65.33 ± 1.46% within 24 h under SGC. Collectively, these results indicated that the entrapped SECs could be used as an effective oral delivery vehicle of ß-Gal to improve its performance as a dietary supplement in the digestion of lactose.

Development of Valsartan Floating Matrix Tablets Using Low Density Polypropylene Foam Powder: In vitro and In vivo Evaluation.

The main purpose of the study was to develop valsartan floating tablets (VFT) via non-effervescent technique using low density polypropylene foam powder, carbopol, and xanthan gum by direct compression. Before compression, the particulate powdered mixture was evaluated for pre-compression parameters. The prepared valsartan tablets were evaluated for post-compression parameters, swelling index, floating lag time, in vitro buoyancy studies, and in vitro and in vivo X-ray imaging studies in albino rabbits. The result of all formulations for pre- and post-compression parameters were within the limits of USP. FTIR and DSC studies revealed no interaction between the drug and polymers used. The prepared floating tablets had good swelling and floating capabilities for more than 12 h with zero floating lag time. The release of valsartan from optimized formulation NF-2 showed sustained release up to 12 h; which was found to be non-Fickian release. Moreover, the X-ray imaging of optimized formulation (NF-2) revealed that tablet was constantly floating in the stomach region of the rabbit, thereby indicating improved gastric retention time for more than 12 h. Consequently, all the findings and outcomes have showed that developed valsartan matrix tablets could be effectively used for floating drug delivery system.

Optimal Selection of Incoming Materials from the Inventory for Achieving the Target Drug Release Profile of High Drug Load Sustained-Release Matrix Tablet.

In the pharmaceutical process, raw material (including APIs and excipients) variability can be delivered to the final product, and lead to batch-to-batch and lot-to-lot variances in its quality, finally impacting the efficacy of the drug. In this paper, the Panax notoginseng saponins (PNS) sustained-release matrix tablet was taken as the model formulation. Hydroxypropyl methylcellulose with the viscosity of 4000 mPa·s (HPMCK4M) from different vendors and batches were collected and their physical properties were characterized by the SeDeM methodology. The in-vitro dissolution profiles of active pharmaceutical ingredients (APIs) from matrix tablets made up of different batches HPMC K4M displayed significant variations. Multi-block partial least squares (MB-PLS) modeling results further demonstrated that physical properties of excipients played dominant roles in the drug release. In order to achieve the target drug release profile with respect to those far from the criteria, the optimal selection method of incoming materials from the available was established and validated. This study provided novel insights into the control of the input variability of the process and amplified the application of the SeDeM expert system, emphasizing the importance of the physical information of the raw materials in the drug manufacturing process.

All-active antitumor micelles via triggered lipid peroxidation.

Traditional antitumor nanomedicines have been suffering from the poor tumor targeting (ca. 1%) by the enhanced permeability and retention (EPR) effect, and the low drug loading (<5%). It was postulated that engineering all-active nanoplatform could increase the therapeutic efficacy to enable the nanocarrier function as both vehicle and active ingredient. To achieve this, a photosensitizer, Ce6 was encapsulated within polymeric micelles with unsaturated fatty acids as the building blocks. Upon light irradiation, the singlet oxygen produced by Ce6 induced lipid peroxidation, resulting in the generation of both active free radicals and aldehydes. These supplementary radicals could exert cytotoxic effect for direct killing tumor cells. The aldehyde end-products induced significant cell cycle arrest at G2 phase in 4T1 cells. The peroxidation process also facilitated the on-demand disassembly of micelles and rapid release of Ce6 to maximize the therapeutic effect of singlet oxygen. These all-active micelles showed a significantly enhanced cytotoxicity with the half maximal inhibitory concentration (IC50) of 0.6 ±â€¯0.2 µg/mL in contrast to the control micelles at 3.4 ±â€¯0.5 µg/mL. The improved antitumor efficacy of the all-active micelles was also demonstrated in the 4T1 tumor-bearing mice in vivo. The current work provides a facile approach to enhance the antitumor efficacy of PDT nanomedicine using the biocompatible fatty acids, which can be applied to various antitumor drugs and unsaturated lipids.

Chronotherapeutic Drug Delivery of Ketoprofen and Ibuprofen for Improved Treatment of Early Morning Stiffness in Arthritis Using Hot-Melt Extrusion Technology.

This work developed a chronotherapeutic drug delivery system (CTDDS) utilizing a potential continuous hot-melt extrusion (HME) technique. Ketoprofen (KTP) and ibuprofen (IBU) were used as two separate model drugs. Eudragit S100 (ES100) was the matrix-forming agent, and ethyl cellulose (EC) (2.5 and 5%) was the release-retarding agent. A 16-mm extruder was used to develop the CTDDS to pilot scale. The obtained extrudate strands were transparent, indicating that the drugs were homogeneously dispersed in the matrix in an amorphous form, confirmed by both differential scanning calorimetry and powder X-ray diffraction. The strands were pelletized into 1, 2, and 3 mm size pellets. A 100% drug release from 1, 2, and 3 mm pellets with 2.5% EC was observed at 12, 14, and 16 h, whereas the drug release was sustained for 14, 16, and 22 h from 5% EC pellets, respectively, for KTP. The release characteristics of IBU were similar to those of KTP with modest variations in release at lag time. The in vitro drug release study conducted in three-stage dissolution media showed a desired lag time of 6 h. The percent drug release from 1, 2, and 3 mm pellets with 40% drug load showed < 20% release from all formulations at 6 h. The amount of ethyl cellulose and pellet size significantly affected drug release. Formulations of both KTP and IBU were stable for 4 months at accelerated stability conditions of 40°C/75% RH. In summary, HME is a novel technique for developing CTDDS.

Design and Evaluation of Hydrophilic Matrix System for pH-Independent Sustained Release of Weakly Acidic Poorly Soluble Drug.

The aim of this research was to design and evaluate a hydrophilic matrix system for sustained release of glipizide, a weakly acidic poor soluble drug. A combination of inclusion complexation and microenvironmental pH modification techniques was utilized to improve the dissolution and pH-independent release of glipizide. Hydroxypropyl-ß-cyclodextrin (HP-ß-CD) was used as the complexation agent while sodium citrate and magnesium oxide (MgO) were used as model pH modifiers. The hydrophilic matrix tablets were prepared by powder direct compression and evaluated by in vitro dissolution study respectively in pH 6.8 and pH 1.2 dissolution media. The formulations containing MgO exhibited increased cumulative drug release from less than 40% in the reference formulation to 90% within 24 h in acidic media (pH 1.2). The release profile in acidic media was similar to the alkaline media (pH 6.8) with a similarity factor (f2) of 55.0, suggesting the weakening of the effect of pH on the dissolution efficiency of glipizide. The release profile fitted well into the Higuchi model and the dominant mechanism of drug release was Fickian diffusion while case II transport/polymer relaxation occurred. In conclusion, combining inclusion complexation agents and pH modifiers had improved the dissolution of glipizide as well as achieved the pH-independent release profile.

Gastroretentive raft liquid delivery system as a new approach to release extension for carrier-mediated drug.

Gabapentin (GBP), an antiepileptic and anti-neuropathic agent, suffers from short half-life (5-7 h), has narrow absorption window, and is absorbed via carrier-mediated mechanism resulting in frequent dosing, poor compliance, and poor bioavailability (<60%). Moreover, GBP is a freely water-soluble drug, thus it is considered a challenging candidate to be formulated as extended release dosage form. In this study, raft forming systems were investigated as a potential drug delivery system for prolonging gastric residence time of GBP. A 23 full factorial design was adopted to study the effect of formulation variables (% gellan gum, % GMO, and % LM-pectin 101), on the percent of GBP released at different time intervals (1, 5, and 8 h) as well as the gel strength, and thus was achieved an optimized formula with zero-order release profile suitable for once-daily administration. In vivo assessment was performed in rats to evaluate gastric residence of the gel formed. In addition, the oral bioavailability of GBP relative to commercially available Neurontin® immediate release oral solution was also investigated. Significant increase was observed for Cmax, AUC(0-t), and AUC(0-∞). The increase in relative bioavailability of GBP from the optimized formula was 1.7 folds.

Telomerase Responsive Delivery of Doxorubicin from Mesoporous Silica Nanoparticles in Multiple Malignancies: Therapeutic Efficacies against Experimental Aggressive Murine Lymphoma.

Mammalian telomerase maintains the length and integrity of telomeres by adding the telomeric repeats to the chromosome end. This work describes the telomerase responsive delivery of doxorubicin against telomerase positive human and murine cancer cells. Wrapping of doxorubicin loaded mesoporous silica nanoparticles with specific oligonucleotide sequence, containing telomeric repeat complementary sequence and a telomerase substrate primer sequence, resulted in slow and sustained release of doxorubicin, contiguous to the tumor cells. The DNA wrapped nanoprobe significantly inhibits the proliferation and enhanced the cytotoxicity in telomerase positive human and mouse tumor cells, and its function is impeded following exposure to specific telomerase inhibitor, AZT. Entrapping of doxorubicin by telomerase specific oligo manifests enhanced apoptosis and significantly higher uptake of the drug in the tumor cells. Treatment of telomerase positive Dalton's lymphoma bearing mice with a novel and newly designed oligo wrapped nanoprobe, specific for mouse telomerase, significantly enhanced the survival and improved the histopathological parameters. In addition, the treatment also induced significant reduction in the number of tumor foci and restored the normal architecture of the vascularized organs, besides preventing metastasis.

Selenomethionine as a Safer Substitute for Barium Selenate in Long-Acting Injectable Se Supplements for Food-Producing Animals.

Nutritional supplementation with selenium (Se) can prevent Se deficiency in food-producing animals. Injection with slow-release formulations is a preferred method for free-range grazing sheep and cattle, and barium selenate (BaSeO4) provides optimal efficacy. This chemical can become a health risk to humans if the concentrated depot of an injection site is consumed, and consequently such use is recently banned in the EU. A possible replacement is selenomethionine (SeMet), a naturally occurring form of Se supplementation hitherto only administered orally. In four animal studies we found that injection with SeMet maintained nutritionally adequate concentrations of Se in blood and tissues of lambs for at least 191 days and in blood and milk of dairy cows for at least 95 days. Stereoisomer forms L- and DL-SeMet were functionally equivalent. This is the first demonstration that injectable SeMet can deliver efficacy similar to BaSeO4 but with less risk of undesirable residues in edible tissues.

Development of Novel High Density Gastroretentive Multiparticulate Pulsatile Tablet of Clopidogrel Bisulfate Using Quality by Design Approach.

Myocardial infarction, i.e., heart attack, is a fatal condition which is on the increase all over the world. It is reported that a large number of heart attack occur in morning hours which are attributable to platelet aggregation. Chronotherapy at this stage can be crucial. Clopidogrel bisulfate (CLB) is an antiplatelet agent and has become a drug of choice for prevention of heart attack. It is soluble in acidic pH and has a narrow absorption window. So, its long residence time in stomach is desirable. Therefore, a novel high density tablet was developed comprising multiparticulate pellets with pulsatile release necessary to maintain chronotherapy of heart attack. The pellets were prepared by extrusion-spheronization and coated in fluidized bed processor with different coating material to achieve pulsatile release. The size, shape of pellets, and drug release were evaluated. High density tablet containing coated pellets was formulated and evaluated for retention in stomach. Quality by design tools was used to design and optimize the processes. Timed release observed by dissolution study showed lag time of 6 h followed by burst release of drug up to 94% in 1 h. Density of tablets was found to be 2.2 g cm-3 which is more than gastric fluid. In vivo x-ray studies in rabbit revealed 8 h of gastric retention of tablet at the bottom of the stomach. Thus, CLB high density pulsatile system looks to open up a window of opportunity for developing formulations with drugs that are stable in gastric region and needed chronotheraupetic activity.

Poly (methyl vinyl ether-co-maleic acid) - Pectin based hydrogel-forming systems: Gel, film, and microneedles.

Cross-linking of natural and synthetic polymers is widely explored to achieve the desired material properties (mechanical strength, drug loading capacity, swelling and erosion rates). However, the potential of polymers produced by crosslinking poly (methyl vinyl ether-co-maleic acid) (PMVE/MA) and pectin (PE) in pharmaceutics is mainly unexplored so far. We have investigated the effect of various esterification conditions and pectin content on the physicochemical properties. Materials have been characterized by fourier transform infrared, differential scanning calorimetry and scanning electron microscopy. In addition, swelling and bioadhesive features of PMVE/MA-PE hydrogel systems were investigated. A band shift for the carbonyl group from 1706 to 1776cm-1, and glass transition (Tg) increased from 55.4±0.9°C to 119.5±0.3°C confirmed the formation of esterification reaction within the cross-linked films. Cross-linked PMVE/MA:PE films with a ratio of 5 demonstrated a superior mass increase when compared to 2.5, 3.125, 3.75, 6.25, and 7.5 ratios of the same hydrogel film. Formulations containing PMVE/MA and pectin with a ratio of 3.75 showed superior bioadhesive features. For the first time, we engineered three-dimensional printing based swell-able microneedle arrays made out of cross-linked PMVE/MA-PE. Microneedle arrays height and aspect ratio were ranged from 702.5±11.9µm to 726±23.3µm and 3.12±0.20 to 3.29±0.21, respectively. Cross-linked PMVE/MA-PE Microneedle arrays (10-2, 24h) indicated the least height loss, 22.33±4.15%, during axial compression test; whilst, transverse failure of cross-linked PMVE/MA-PE Microneedle arrays was varied from 0.15±0.05 to 0.25±0.04N/needle. In conclusion, we obtained a novel cross-linked polymer system with promising features of drug delivery and bio-analytical applications.

The preparation and evaluation of salt forms of linogliride with reduced solubilities as candidates for extended release.

Salts of linogliride with reduced solubilities were prepared and evaluated as potential candidates for extended-release oral dosage forms. A once-daily dose of 300-800 mg was intended. Seven acids were selected: p-acetamidobenzoic, benzoic, p-hydroxybenzoic, 3-hydroxy-2-naphthoic, 1-napsylic, pamoic, and p-toluenesulfonic acids but only four salts were able to be prepared in suitable quantities for evaluation: linogliride pamoate, p-hydroxybenzoate, 3-hydroxy-2-naphthoate, and 1-napsylate. The pH-solubility profiles of the four new salts, free base, and fumarate salt were compared over the pH 1.43-8.3 range and the intrinsic dissolution rates of the four new salts and the free base were determined at pH 1.43, 4.4, and 7.5. The range of the pH-solubility profile and intrinsic dissolution rates of the p-hydroxybenzoate salt were less than the free base and fumarate and higher than the other three new salts. The pH-solubilities and intrinsic dissolution rates of the 1-napsylate salt were pH-independent. The solubilities and intrinsic dissolution rates of the pamoate and 3-hydroxy-2-naphthoate were higher at pH 1.4-3.4 than at higher pH. At pH 4.4 and higher, the solubilities were essentially the same, in the 1-2 mg/mL range. The intrinsic dissolution rates were also very low and not very different. Dissolution studies with capsules containing 800 mg doses of the pamoate, 1-napsylate, free base, and fumarate performed in a dissolution medium of pH beginning at 2.2 and ending at 6.8 demonstrated that the pamoate and 1-napsylate salt forms dissolved slower and could be useful as extended-release forms.

Utilization of ionotropic gelation technique for bioavailability enhancement of cinnarizine: in-vitro optimization and in-vivo performance in human.

Gastro retentive drug delivery system techniques were adopted to deliver drugs having narrow absorption window from a particular site in the GIT. Therefore, gastro retentive dosage forms were retained in the stomach, thus improving absorption and bioavailability would be improved consequently. In this study, cinnarizine (CNZ) was employed as the model drug. CNZ is a poorly soluble basic drug, suffering from low and erratic bioavailability. This is attributed to its pH-dependant solubility (highly soluble at pH < 4). CNZ is characterized by short half-life (3-6 h). Accordingly, floating CNZ emulsion gel calcium pectinate beads were developed. A mixture design was employed to study the effect of the percent of LM pectin (A), the percent of GMO (B) and the percent of Labrafac Lipophile (C) simultaneously on the percent of drug released and loaded. The optimized floating CNZ emulsion gel calcium pectinate beads and Stugeron® (the marketed reference product) were compared through a pharmacokinetic study carried on healthy human volunteers. Fortunately, simple floating CNZ emulsion gel calcium pectinate beads were prepared with zero-order release profile for 12 h. A promising in-vivo CNZ controlled release dosage form with higher bioavailability, when compared to once daily administration of Stugeron® tablets was achieved.

Preparation and evaluation of floating tablets of pregabalin.

Floating tablets of pregabalin were prepared using different concentrations of the gums (xanthan gum and guar gum), Carbopol 974P NF and HPMC K100. Optimized formulations were studied for physical tests, floating time, swelling behavior, in vitro release studies and stability studies. In vitro drug release was higher for tablet batches containing guar and xanthan gum as compared to the batches containing Carbopol 974P NF. Tablet batches were subjected to stability studies and evaluated by different parameters (drug release, drug content, FTIR and DSC studies). The optimized tablet batch was selected for in vivo pharmacodynamic studies (PTZ induced seizures). The results obtained showed that the onset of jerks and clonus were delayed and extensor phase was abolished with time in treated groups. A significant difference (p > 0.05) was observed in control and treated group behavior indicating an excellent activity of the formulation for a longer period (>12 h).

Rationally Engineering Phototherapy Modules of Eosin-Conjugated Responsive Polymeric Nanocarriers via Intracellular Endocytic pH Gradients.

Spatiotemporal switching of respective phototherapy modes at the cellular level with minimum side effects and high therapeutic efficacy is a major challenge for cancer phototherapy. Herein we demonstrate how to address this issue by employing photosensitizer-conjugated pH-responsive block copolymers in combination with intracellular endocytic pH gradients. At neutral pH corresponding to extracellular and cytosol milieu, the copolymers self-assemble into micelles with prominently quenched fluorescence emission and low (1)O2 generation capability, favoring a highly efficient photothermal module. Under mildly acidic pH associated with endolysosomes, protonation-triggered micelle-to-unimer transition results in recovered emission and enhanced photodynamic (1)O2 efficiency, which synergistically actuates release of encapsulated drugs, endosomal escape, and photochemical internalization processes.