Polyglycerol-Functionalized ß-Cyclodextrins as Crosslinkers in Thermoresponsive Nanogels for the Enhanced Dermal Penetration of Hydrophobic Drugs.

Thermoresponsive nanogels (tNGs) are promising candidates for dermal drug delivery. However, poor incorporation of hydrophobic drugs into hydrophilic tNGs limits the therapeutic efficiency. To address this challenge, ß-cyclodextrins (ß-CD) are functionalized by hyperbranched polyglycerol serving as crosslinkers (hPG-ßCD) to fabricate ßCD-tNGs. This novel construct exhibits augmented encapsulation of hydrophobic drugs, shows the appropriate thermal response to dermal administration, and enhances the dermal penetration of payloads. The structural influences on the encapsulation capacity of ßCD-tNGs for hydrophobic drugs are analyzed, while concurrently retaining their efficacy as skin penetration enhancers. Various synthetic parameters are considered, encompassing the acrylation degree and molecular weight of hPG-ßCD, as well as the monomer composition of ßCD-tNGs. The outcome reveals that ßCD-tNGs substantially enhance the aqueous solubility of Nile Red elevating to 120 µg mL-1 and augmenting its dermal penetration up to 3.33 µg cm-2. Notably, the acrylation degree of hPG-ßCD plays a significant role in dermal drug penetration, primarily attributed to the impact on the rigidity and hydrophilicity of ßCD-tNGs. Taken together, the introduction of the functionalized ß-CD as the crosslinker in tNGs presents a novel avenue to enhance the efficacy of hydrophobic drugs in dermatological applications, thereby offering promising opportunities for boosted therapeutic outcomes.

POxload: Machine Learning Estimates Drug Loadings of Polymeric Micelles.

Block copolymers, composed of poly(2-oxazoline)s and poly(2-oxazine)s, can serve as drug delivery systems; they form micelles that carry poorly water-soluble drugs. Many recent studies have investigated the effects of structural changes of the polymer and the hydrophobic cargo on drug loading. In this work, we combine these data to establish an extended formulation database. Different molecular properties and fingerprints are tested for their applicability to serve as formulation-specific mixture descriptors. A variety of classification and regression models are built for different descriptor subsets and thresholds of loading efficiency and loading capacity, with the best models achieving overall good statistics for both cross- and external validation (balanced accuracies of 0.8). Subsequently, important features are dissected for interpretation, and the DrugBank is screened for potential therapeutic use cases where these polymers could be used to develop novel formulations of hydrophobic drugs. The most promising models are provided as an open-source software tool for other researchers to test the applicability of these delivery systems for potential new drug candidates.

Amphiphilic Polypeptides Obtained by the Post-Polymerization Modification of Poly(Glutamic Acid) and Their Evaluation as Delivery Systems for Hydrophobic Drugs.

Synthetic poly(amino acids) are a unique class of macromolecules imitating natural polypeptides and are widely considered as carriers for drug and gene delivery. In this work, we synthesized, characterized and studied the properties of amphiphilic copolymers obtained by the post-polymerization modification of poly(α,L-glutamic acid) with various hydrophobic and basic L-amino acids and D-glucosamine. The resulting glycopolypeptides were capable of forming nanoparticles that exhibited reduced macrophage uptake and were non-toxic to human lung epithelial cells (BEAS-2B). Moreover, the developed nanoparticles were suitable for loading hydrophobic cargo. In particular, paclitaxel nanoformulations had a size of 170-330 nm and demonstrated a high cytostatic efficacy against human lung adenocarcinoma (A549). In general, the obtained nanoparticles were comparable in terms of their characteristics and properties to those based on amphiphilic (glyco)polypeptides obtained by copolymerization methods.

A Nanocrystal Platform Based on Metal-Phenolic Network Wrapping for Drug Solubilization.

The preparation of drugs into nanocrystals represents a practical pharmaceutical technology to solubilize poorly water-soluble drugs and enhance bioavailability. However, commonly used stabilizers in nanocrystals like polymers and surfactants are frequently inefficient and cannot stabilize nanocrystals for an expected time. This study reports an exquisite platform for nanocrystal production based on a metal-phenolic network (MPN). MPN-wrapped nanocrystal particles (MPN-NPs) were fabricated through an anti-solvent precipitation method using tannic acid and FeIII or AlIII as coupling agents and characterized by dynamic light scattering, transmission electron microscope, ultraviolet and visible spectrophotometry, fourier-transform infrared spectroscopy, and X-ray powder diffraction. In vitro release, cytotoxicity, and stability were mainly studied with MPN-NPs loading paclitaxel. The suitability of MPN as a nanocrystal stabilizer was also investigated for other classical hydrophobic drugs, including simvastatin, andrographolide, atorvastatin calcium, ferulic acid, and famotidine. The results showed that MPN could effectively wrap and stabilize various drug nanocrystals apart from famotidine. The maximum solubilization of MPN towards atorvastatin calcium was up to 1587 folds, and it also exhibited an excellent solubilizing effect on other hydrophobic drugs. We disclosed that the drug was entrapped in MPN in the nanocrystal form, and there were distinct physiochemical interactions between MPN and the payload. Our findings suggested that MPN may be a promising platform for nanocrystal production to address the challenge of low solubility associated with hydrophobic drugs. Graphical abstract.

Photo-Responsive Polymersomes as Drug Delivery System for Potential Medical Applications.

Due to a strong retardation effect of o-nitrobenzyl ester on polymerization, it is still a great challenge to prepare amphiphilic block copolymers for polymersomes with a o-nitrobenzyl ester-based hydrophobic block. Herein, we present one such solution to prepare amphiphilic block copolymers with pure poly (o-nitrobenzyl acrylate) (PNBA) as the hydrophobic block and poly (N,N'-dimethylacrylamide) (PDMA) as the hydrophilic block using bulk reversible addition-fragmentation chain transfer (RAFT) polymerization of o-nitrobenzyl acrylate using a PDMA macro-RAFT agent. The developed amphiphilic block copolymers have a suitable hydrophobic/hydrophilic ratio and can self-assemble into photoresponsive polymersomes for co-loading hydrophobic and hydrophilic cargos into hydrophobic membranes and aqueous compartments of the polymersomes. The polymersomes demonstrate a clear photo-responsive characteristic. Exposure to light irradiation at 365 nm can trigger a photocleavage reaction of o-nitrobenzyl groups, which results in dissociation of the polymersomes with simultaneous co-release of hydrophilic and hydrophobic cargoes on demand. Therefore, these polymersomes have great potential as a smart drug delivery nanocarrier for controllable loading and releasing of hydrophilic and hydrophobic drug molecules. Moreover, taking advantage of the conditional releasing of hydrophilic and hydrophobic drugs, the drug delivery system has potential use in medical applications such as cancer therapy.

Cell Membrane Camouflaged Hydrophobic Drug Nanoflake Sandwiched with Photosensitizer for Orchestration of Chemo-Photothermal Combination Therapy.

Many candidate anticancer drugs have suffered from their intrinsic hydrophobicity, which poses several obstacles for clinical application. To overcome this challenge and further improve the performance, herein a nanocrystal-based biomimetic formulation with a sandwich structure is developed. As the core, flake shaped nanocrystals (NCs) with high loading of the hydrophobic drug hydroxycamptothecin (HCPT) are synthesized via a mild nanoprecipitation process by exploring the template effect of serum albumin. Meanwhile, the camouflaged cancer cell membrane (CM) composed of plentiful membrane proteins endows the NCs with homotypic targeting capacity at tumor sites. In addition, the photosensitizer indocyanine green sandwiched between NCs and CM not only converts near infrared light to heat for photothermal treatment but also improves the dissolution of HCPT NCs for chemotherapy. These features corporately achieve the orchestration of chemo-photothermal combination therapy and completely inhibit tumor growth with few adverse effects, showing promise as a new modality for the utilization of hydrophobic drugs to treat cancer.

Photopolymerized Micelle-Laden Hydrogels Can Simultaneously Form and Encapsulate Nanocrystals to Improve Drug Substance Solubility and Expedite Drug Product Design.

Formulation technologies are critical for increasing the efficacy of drug products containing poorly soluble hydrophobic drugs, which compose roughly 70% of small molecules in commercial pipelines. Nanomedicines, such as nanocrystal formulations and amorphous solid suspensions, are effective approaches to increasing solubility. However, existing techniques require additional processing into a final dosage form, which strongly influences drug delivery and clinical performance. To enhance hydrophobic drug product efficacy and clinical throughput, a hydrogel material is developed as a sacrificial template to simultaneously form and encapsulate nanocrystals. These hydrogels contain micelles chemically bound to the hydrogel matrix, where the surfactant structure dictates the crystal size and drug loading. Therefore, nanocrystals can be produced in high yield (up to 90% drug loading, by weight) with precisely controlled sizes as small as 4 nm independently of hydrogel composition. Nanocrystals and surfactant are then released together to increase the solubility up to 70 times above bulk crystalline material. By integrating nanocrystals into a final dosage form, micelle-laden hydrogels simplify hydrophobic drug product design.

Enhancement of hydrosolubility and in vitro antiproliferative properties of chalcones following encapsulation into ß-cyclodextrin/cellulose-nanocrystal complexes.

This paper describes the preparation of two chalcone/ß-cyclodextrin/cellulose-nanocrystals complexes and the study of their antiproliferative activities against two colorectal and two prostatic cancer cell lines. The aim of this work was to enhance hydrosolubility of chalcones thanks to the hydrophilic character of cellulose nanocrystals. These latter were linked, through ionic interactions, to a cationic derivative of ß-cyclodextrins whose lipophilic cavity allowed the encapsulation of hydrophobic chalcones: 3-hydroxy-3',4,4',5'-tetramethoxychalcone (1) and 3',4,4',5'-tetramethoxychalcone (2). First, we showed that encapsulation allowed hydrosolubilization of chalcones. Then, chalcone/ß-cyclodextrin/cellulose-nanocrystals complexes demonstrated enhanced in vitro antiproliferative activities, compared to the corresponding free-chalcones.

Design and biological activity of novel stealth polymeric lipid nanoparticles for enhanced delivery of hydrophobic photodynamic therapy drugs.

Advances in in vivo stability and preferential tumor uptake of cancer nanomedicine are warranted for effective chemotherapy. Here, we describe a novel nanoformulation using an unconventional polymeric tubule-forming phospholipid, DC8,9PC. We report that DC8,9PC transitions to stable vesicles (LNPs) in the presence of PEGylated lipid (DSPE-PEG2000); the resulting DC8,9PC:DSPE-PEG2000 LNPs efficiently included a hydrophobic PDT drug, HPPH. Remarkably, these LNPs incorporated unusually high DSPE-PEG2000 concentrations; LNP10-HPPH and LNP20-HPPH (10 & 20 mol% PEGylated lipid, respectively) exhibited >90% serum stability at 37 °C. Increased PEGylation in the LNPs correlated with enhanced tumor accumulation in intravenously injected HT29 tumor mouse xenographs. Colon-26 bearing BALB/c mice, intravenously injected with LNP20-HPPH showed superior PDT efficacy and animal survival (no tumor recurrence up to 100 days) as compared to a formulation currently used in clinical trials. Taken together, we present a simple stealth binary lipid nanosystem with enhanced efficiency of tumor accumulation and superior therapeutic efficacy.

Micellar solubilization of poorly water-soluble drugs: effect of surfactant and solubilizate molecular structure.

OBJECTIVE: This study aims to clarify the role of surfactant and drug molecular structures on drug solubility in micellar surfactant solutions. SIGNIFICANCE: (1) Rationale for surfactant selection is provided; (2) the large data set can be used for validation of the drug solubility parameters used in oral absorption models. METHODS: Equilibrium solubility of two hydrophobic drugs and one model hydrophobic steroid in micellar solutions of 19 surfactants was measured by HPLC. The drug solubilization locus in the micelles was assessed by UV spectrometry. RESULTS: Danazol is solubilized much more efficiently than fenofibrate by ionic surfactants due to ion-dipole interactions between the charged surfactant head groups and the polar steroid backbone. Drug solubilization increases linearly with the increase of hydrophobic chain length for all studied surfactant types. Addition of 1-3 ethylene oxide (EO) units in the head group of dodecyl sulfate surfactants reduces significantly the solubilization of both studied drugs and decreases linearly the solubilization locus polarity of fenofibrate. The locus of fenofibrate solubilization is in the hydrophobic core of nonionic surfactant micelles and in the palisade layer of ionic surfactant micelles. CONCLUSIONS: Highest drug solubility can be obtained by using surfactants molecules with long chain length coupled with hydrophilic head group that provides additional drug-surfactant interactions (i.e. ion-dipole) in the micelles.

Multicompartment Theranostic Nanoemulsions Stabilized by a Triphilic Semifluorinated Block Copolymer.

The presence of a perfluorocarbon block in a multiblock polymer has been shown to be an additional driving force toward nanoparticle assembly. In the preparation of nanoemulsions, this perfluorocarbon block also provides enhanced particle stability. Herein, the synthesis of a new triphilic, semifluorinated copolymer, M2F8H18, is introduced. This ABC type block copolymer can be used to formulate extremely stable nanoemulsions, assembled around a lipophilic droplet, with lifetimes of one year or more. The central oil droplet can stably solubilize high concentrations of hydrophobic drugs, making this system an ideal drug delivery vehicle. The incorporation of the perfluorocarbon block modulates drug release from the lipophilic core via the surrounding fluorous shell. Fluorous imaging agents incorporated into the fluorous shell prolong drug release even further as well as provide potent 19F-MRI contrast ability. In vitro studies show that these nanoemulsions efficiently inhibit cancer cell growth, thus providing a theranostic drug delivery system.

Preloading of Hydrophobic Anticancer Drug into Multifunctional Nanocarrier for Multimodal Imaging, NIR-Responsive Drug Release, and Synergistic Therapy.

Applications of hydrophobic drug-based nanocarriers (NCs) remain largely limited because of their low loading capacity. Here, development of a multifunctional hybrid NC made of a magnetic Fe3O4 core and a mesoporous silica shell embedded with carbon dots (CDs) and paclitaxel (PTX), and covered by another layer of silica is reported. The NC is prepared via a one-pot process under mild condition. The PTX loading method introduced in this study simplifies drug loading process and demonstrates a high loading capacity due to mesoporous silica dual-shell structure, supramolecular π-stacking between conjugated rings of PTX molecules, and aromatic rings of the CDs in the hybrid NC. The CDs serve as both confocal and two-photon fluorescence imaging probes, while the Fe3O4 core serves as a magnetic resonance imaging contrast agent. Significantly, NC releases PTX in response to near infrared irradiation as a result of local heating of the embedded CDs and the heating of CDs also provides an additional therapeutic effect by thermally killing cancer cells in tumor in addition to the chemotherapeutic effect of released PTX. Both in vitro and in vivo results show that NC demonstrates high therapeutic efficacy through a synergistic effect from the combined chemo-photothermal treatments.

Passively Targeted Curcumin-Loaded PEGylated PLGA Nanocapsules for Colon Cancer Therapy In Vivo.

Clinical applications of curcumin for the treatment of cancer and other chronic diseases have been mainly hindered by its short biological half-life and poor water solubility. Nanotechnology-based drug delivery systems have the potential to enhance the efficacy of poorly soluble drugs for systemic delivery. This study proposes the use of poly(lactic-co-glycolic acid) (PLGA)-based polymeric oil-cored nanocapsules (NCs) for curcumin loading and delivery to colon cancer in mice after systemic injection. Formulations of different oil compositions are prepared and characterized for their curcumin loading, physico-chemical properties, and shelf-life stability. The results indicate that castor oil-cored PLGA-based NC achieves high drug loading efficiency (≈18% w(drug)/w(polymer)%) compared to previously reported NCs. Curcumin-loaded NCs internalize more efficiently in CT26 cells than the free drug, and exert therapeutic activity in vitro, leading to apoptosis and blocking the cell cycle. In addition, the formulated NC exhibits an extended blood circulation profile compared to the non-PEGylated NC, and accumulates in the subcutaneous CT26-tumors in mice, after systemic administration. The results are confirmed by optical and single photon emission computed tomography/computed tomography (SPECT/CT) imaging. In vivo growth delay studies are performed, and significantly smaller tumor volumes are achieved compared to empty NC injected animals. This study shows the great potential of the formulated NC for treating colon cancer.

Hydrogel-Based Drug Delivery Systems for Poorly Water-Soluble Drugs.

Hydrogels are three-dimensional materials that can withstand a great amount of water incorporation while maintaining integrity. This allows hydrogels to be very unique biomedical materials, especially for drug delivery. Much effort has been made to incorporate hydrophilic molecules in hydrogels in the field of drug delivery, while loading of hydrophobic drugs has not been vastly studied. However, in recent years, research has also been conducted on incorporating hydrophobic molecules within hydrogel matrices for achieving a steady release of drugs to treat various ailments. Here, we summarize the types of hydrogels used as drug delivery vehicles, various methods to incorporate hydrophobic molecules in hydrogel matrices, and the potential therapeutic applications of hydrogels in cancer.

Swellable hollow periodic mesoporous organosilica capsules with ultrahigh loading capacity for hydrophobic drugs.

As a new kind of drug carrier, practical applications of hollow periodic mesoporous organosilica (HPMO) have been greatly limited by their low loading capacity for hydrophobic drugs. In this work, we demonstrated the preparation of HPMO capsules with tunable shell thickness by using 1,2-bis(triethoxysilyl)ethane as the precursor. The capsules with thin shells and thus low Young's modulus showed excellent swellability to organic solvents containing hydrophobic drugs. As a result, hydrophobic drugs, i.e., paclitaxel (PTX) could be loaded into the hollow interior of the HPMO capsules with 4 nm shell at an efficiency of ca. 120 %. The as-prepared PTX-loaded HPMO capsules were dispersible in aqueous media and showed improved performance in killing cancer cells compared to free PTX.

Hydrophobicity-enhanced ferritin nanoparticles for efficient encapsulation and targeted delivery of hydrophobic drugs to tumor cells.

Ferritin, a naturally occurring iron storage protein, has gained significant attention as a drug delivery platform due to its inherent biocompatibility and capacity to encapsulate therapeutic agents. In this study, we successfully genetically engineered human H ferritin by incorporating 4 or 6 tryptophan residues per subunit, strategically oriented towards the inner cavity of the nanoparticle. This modification aimed to enhance the encapsulation of hydrophobic drugs into the ferritin cage. Comprehensive characterization of the mutants revealed that only the variant carrying four tryptophan substitutions per subunit retained the ability to disassemble and reassemble properly. As a proof of concept, we evaluated the loading capacity of this mutant with ellipticine, a natural hydrophobic indole alkaloid with multimodal anticancer activity. Our data demonstrated that this specific mutant exhibited significantly higher efficiency in loading ellipticine compared to human H ferritin. Furthermore, to evaluate the versatility of this hydrophobicity-enhanced ferritin nanoparticle as a drug carrier, we conducted a comparative study by also encapsulating doxorubicin, a commonly used anticancer drug. Subsequently, we tested both ellipticine and doxorubicin-loaded nanoparticles on a promyelocytic leukemia cell line, demonstrating efficient uptake by these cells and resulting in the expected cytotoxic effect.

Promising strategies for improving oral bioavailability of poor water-soluble drugs.

INTRODUCTION: Oral administration of poorly water-soluble drugs (PWSDs) is generally related to low bioavailability, leading to high drug doses, multiple side effects, and low patient compliance. Thus, different strategies have been developed to increase drug solubility and dissolution in the gastrointestinal tract, opening new venues for these drugs. AREAS COVERED: This review outlines the current challenges in PWSD formulation development and the strategies to overcome the oral barriers and increase their solubility and bioavailability. Conventional strategies include altering crystalline and molecular structures and modifying oral solid dosage forms. In contrast, novel strategies comprise micro- and nanostructured systems. Recent representative studies involving how these strategies have improved the oral bioavailability of PWSDs were also reviewed and reported. EXPERT OPINION: New approaches to enhance PWSD bioavailability have sought to improve water solubility and dissolution rates, drug protection by overcoming biological barriers, and increased absorption. Still, only a handful of studies have focused on quantifying the increase in bioavailability. Improving the oral bioavailability of PWSDs remains an exciting unexplored field of research and has become an important issue for successfully developing pharmaceutical products.

Smart Polymeric Micelles for Anticancer Hydrophobic Drugs.

Cancer has become one of the deadliest diseases in our society. Surgery accompanied by subsequent chemotherapy is the treatment most used to prolong or save the patient's life. Still, it carries secondary risks such as infections and thrombosis and causes cytotoxic effects in healthy tissues. Using nanocarriers such as smart polymer micelles is a promising alternative to avoid or minimize these problems. These nanostructured systems will be able to encapsulate hydrophilic and hydrophobic drugs through modified copolymers with various functional groups such as carboxyls, amines, hydroxyls, etc. The release of the drug occurs due to the structural degradation of these copolymers when they are subjected to endogenous (pH, redox reactions, and enzymatic activity) and exogenous (temperature, ultrasound, light, magnetic and electric field) stimuli. We did a systematic review of the efficacy of smart polymeric micelles as nanocarriers for anticancer drugs (doxorubicin, paclitaxel, docetaxel, lapatinib, cisplatin, adriamycin, and curcumin). For this reason, we evaluate the influence of the synthesis methods and the physicochemical properties of these systems that subsequently allow an effective encapsulation and release of the drug. On the other hand, we demonstrate how computational chemistry will enable us to guide and optimize the design of these micelles to carry out better experimental work.

Lipomics: A Potential Carrier for the Intravenous Delivery of Lipophilic and Hydrophilic Drugs.

In the present work, we propose the development of a novel carrier that does not need organic solvents for its preparation and with the potential for the intravenous delivery of lipophilic and hydrophilic drugs. Named lipomics, this is a mixed colloid of micelles incorporated within a liposome. This system was designed through ternary diagrams and characterized by physicochemical techniques to determine the particle size, zeta potential, shape, morphology, and stability properties. The lipomics were subjected to electron microscopy (SEM, TEM, and STEM) to evaluate their physical size and morphology. Finally, pharmacokinetic studies were performed by radiolabeling the lipomics with Technetium-99m chelated with BMEDA to evaluate the in vivo biodistribution through techniques of molecular imaging (microSPECT/CT) in rats. Radiolabeling efficiency was used to compare the encapsulation efficiency of the hydrophilic and lipophilic molecules in lipomics and liposomes. According to the results, lipomics are potentially carriers of lipophilic and hydrophilic drugs.

Re-engineering the inner surface of ferritin nanocage enables dual drug payloads for synergistic tumor therapy.

Rationale: With the advantages of tumor-targeting, pH-responsive drug releasing, and biocompatibility, ferritin nanocage emerges as a promising drug carrier. However, its wide applications were significantly hindered by the low loading efficiency of hydrophobic drugs. Herein, we redesigned the inner surface of ferritin drug carrier (ins-FDC) by fusing the C- terminus of human H ferritin (HFn) subunit with optimized hydrophobic peptides. Methods: Hydrophobic and hydrophilic drugs were encapsulated into the ins-FDC through the urea-dependent disassembly/reassembly strategy and the natural drug entry channel of the protein nanocage. The morphology and drug loading/releasing abilities of the drug-loaded nanocarrier were then examined. Its tumor targeting character, system toxicity, application in synergistic therapy, and anti-tumor action were further investigated. Results: After optimization, 39 hydrophobic Camptothecin and 150 hydrophilic Epirubicin were encapsulated onto one ins-FDC nanocage. The ins-FDC nanocage exhibited programed drug release pattern and increased the stability and biocompatibility of the loaded drugs. Furthermore, the ins-FDC possesses tumor targeting property due to the intrinsic CD71-binding ability of HFn. The loaded drugs may penetrate the brain blood barrier and accumulate in tumors in vivo more efficiently. As a result, the drugs loaded on ins-FDC showed reduced side effects and significantly enhanced efficacy against glioma, metastatic liver cancer, and chemo-resistant breast tumors. Conclusions: The ins-FDC nanocarrier offers a promising novel means for the delivery of hydrophobic compounds in cancer treatments, especially for the combination therapies that use both hydrophobic and hydrophilic chemotherapeutics.