Hydrophilic Payloads Research Articles

Triple-Emulsion-Based Antibubbles: A Step Forward in Fabricating Novel Multi-Drug Delivery Systems.

Developing carriers capable of efficiently transporting both hydrophilic and lipophilic payloads is a captivating focus within the pharmaceutical and drug delivery research domain. Antibubbles, constituting an innovative encapsulation system designed for drug delivery purposes, have garnered scientific interest thanks to their distinctive water-in-air-in-water (W1/A/W2) structure. However, in contrast to their precursor, i.e., nanoparticle-stabilized W1/O/W2 double emulsion, traditional antibubbles lack the ability to accommodate a lipophilic payload, as the intermediary (volatile) oil layer of the emulsion is replaced by air during the antibubble fabrication process. Therefore, here, we report the fabrication of triple-emulsion-based antibubbles (O1/W1/A/W2), in which the inner aqueous phase was loaded with a nanoemulsion stabilized by various proteins, including whey, soy, or pea protein isolates. As model drugs, we employed the dyes Nile red in the oil phase and methylene blue in the aqueous phase. The produced antibubbles were characterized regarding their size distribution, entrapment efficiency, and stability. The produced antibubbles demonstrated substantial entrapment efficiencies for both lipophilic (ranging from 80% to 90%) and hydrophilic (ranging from 70% to 82%) components while also exhibiting an appreciable degree of stability during an extended rehydration period of two weeks. The observed variations among different antibubble variants were primarily attributed to differences in protein concentration rather than the type of protein used.

Centrifugally spun hybrid polyhydroxyalkanoate/dextran nanocapsule fiber matrix for the delivery of hydrophilic payloads

Biopolymeric micro- and nanofibers with active ingredients have gained significant attention for biological applications. However, the incorporation of hydrophilic compounds into hydrophobic matrices via spinning techniques remain rather unexplored. Here we report the incorporation of dextran nanocapsules (Dex-NCs) in centrifugally spun poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) fibers for the release of hydrophilic payloads. Inverse miniemulsion polymerization was employed to synthesize hydrophilic Dex-NCs with an average size of 0.25 µm. The Dex-NCs were embedded into PHBHHx via dual solvent centrifugal spinning at 0–7 wt% loading, resulting in beaded fibers with average fiber diameters of 4–6 µm. The effect of Dex-NC loading on the melting and crystallization behavior of PHBHHx was limited, while the strength and stiffness of the hybrid fibers was retained. The elongation of the hybrid fiber mats is reduced with increasing Dex-NC loading, but remains suitable for biological applications. Further, the in vitro release measurements showed a time dependent release of embedded Dex-NCs and the payload from the hybrid fibers. We anticipate this hybrid fiber matrix to be a starting point for the development of non-woven mats for slow release of hydrophilic payloads for biological applications, especially for medical wound dressings.

Current Advances in Specialised Niosomal Drug Delivery: Manufacture, Characterization and Drug Delivery Applications.

Development of nanomaterials for drug delivery has received considerable attention due to their potential for achieving on-target delivery to the diseased area while the surrounding healthy tissue is spared. Safe and efficiently delivered payloads have always been a challenge in pharmaceutics. Niosomes are self-assembled vesicular nanocarriers formed by hydration of a non-ionic surfactant, cholesterol or other molecules that combine to form a versatile drug delivery system with a variety of applications ranging from topical delivery to targeted delivery. Niosomes have advantages similar to those of liposomes with regards to their ability to incorporate both hydrophilic and hydrophobic payloads. Moreover, niosomes have simple manufacturing methods, low production cost and exhibit extended stability, consequently overcoming the major drawbacks associated with liposomes. This review provides a comprehensive summary of niosomal research to date, including the types of niosomes and critical material attributes (CMA) and critical process parameters (CPP) of niosomes and their effects on the critical quality attributes (CQA) of the technology. Furthermore, physical characterisation techniques of niosomes are provided. The review then highlights recent applications of specialised niosomes in drug delivery. Finally, limitations and prospects for this technology are discussed.

Stimuli-Free Transcuticular Delivery of Zn Microelement Using Biopolymeric Nanovehicles: Experimental, Theoretical, and In Planta Studies.

This paper reports one-step synthesis of polysaccharide-based nanovehicles, capable of transporting ionic zinc via plant cuticle without auxiliary stimulation. Delivery of highly hydrophilic nutritive microelements via the hydrophobic cuticle of plant foliage is one of the major challenges in modern agriculture. In traditional nutrition via roots, up to 80% of microelements permeate to soil and get wasted; therefore, foliar treatment is an environmentally and economically preferable alternative. Carboxymethyl cellulose (CMC) was modified to amphiphilic N-octylamide-derivative (CMC-8), which spontaneously self-assemble to nanovehicles. It was found that hydrophobic substituents endow a biopolymer with unexpected affinity toward a hydrophilic payload. CMC-8 nanovehicles effectively encapsulated ionic zinc (ZnSO4) and delivered it upon foliar application to pepper (Capsicum annuum) and tomato (Solanum lycopersicum) plants. Zinc uptake and translocation in plants were monitored by SEM-EDS and fluorescence microscopic methods. In planta monitoring of the carrier was done by labeling nanovehicles with fluorescent carbon dots. Three-dimensional (3-D) structural modeling and conformational dynamics explained the CMC-8 self-assembly mechanism and zinc coordination phenomenon upon introduction of hydrophobic substituents.

Hydrogen Sulfide-Responsive Bicontinuous Nanospheres.

Block copolymers (BCPs) that can self-assemble into particles and be triggered by disease-specific molecules such as hydrogen sulfide (H2S) have the potential to impact on drug delivery, decreasing off-target toxicities while increasing drug efficacy. However, the incorporation of H2S-responsive aryl azides into BCPs for self-assembly has been limited by heat, light, and radical sensitivities. In this study, a robust activator regenerated by the electron-transfer atom-transfer radical polymerization reaction was used to synthesize aryl-azide-containing BCPs under ambient conditions. Conditions controlling self-assembly of the BCPs into 150-200 nm particles and the physicochemical properties of the particles were investigated. The use of nanoprecipitation with tetrahydrofuran to promote self-assembly of the BCPs resulted in vesicle structures, while dimethylformamide or dimethylsulfoxide resulted in polymeric bicontinuous nanospheres (BCNs). Triggering of the BCPs and particles (vesicles or BCNs) via exposure to H2S revealed that unsubstituted aryl azides were readily reduced (by HS-), resulting in particle disruption or cross-linking. The relative polar nature of the particle bilayers containing unsubstituted aryl azides and the open structure of the BCNs did however limit encapsulation of small hydrophilic and hydrophobic payloads. Incorporation of a benzylamide substituent onto the aryl azide group increased the hydrophobicity of the particles and encapsulation of hydrophilic cargo but reduced sensitivity to H2S, likely due to the reduced penetration of HS- into the bilayer.

Entrapment of Hydrophilic and Hydrophobic Molecules in Beads Prepared from Isolated Denatured Whey Protein.

The oral route of administration is by far the most convenient route, especially in the treatment of chronic conditions. However, many therapeutics present formulation difficulties which make them unsuitable for oral delivery. Recently, we synthesized a denatured whey protein isolate (dWPI) bead entrapped with insulin. Our present goal was to assess the suitability of this delivery system to the delivery of other potential molecules, both hydrophilic and hydrophobic. Beads of 1.2–1.5 mm in diameter were entrapped with four payloads representing a range of solubilities. The water-soluble payloads were sodium fluorescein (SF) and FITC dextran 4000 Da (FD4), while the hydrophobic ones were Fast Green and curcumin. Encapsulation efficiency (EE) was 73%, 84%, 70%, and 83% for SF, FD4, Fast Green, and curcumin-loaded beads, respectively. The corresponding loading capacity for each bead was 0.07%, 1.1%, 0.75%, and 1.1%, respectively. Each payload produced different release profiles in simulated gastric fluid (SGF) and simulated intestinal fluids (SIF). SF released steadily in both SGF and SIF. FD4 and curcumin release was not substantial in any buffers, while Fast Green release was low in SGF and high in SIF. The differences in release behaviour were likely due to the varying properties of the payloads. The effect of proteolysis on beads suggested that enzymatic degradation of the whey bead may promote payload release. The beads swelled rapidly in SGF compared to SIF, which likely contributed to the release from the beads, which was largely governed by solvent diffusion and polymer relaxation. Our results offer a systematic examination of the behaviour of hydrophilic and hydrophobic payloads in a dWPI delivery system. These beads may be further designed to orally deliver poorly permeable macromolecules and poorly soluble small molecules of pharmaceutical interest.

Modulating Shape of Polyester Based Polymersomes using Osmotic Pressure.

Polymersomes are membrane-bound, bilayer vesicles created from amphiphilic block copolymers that can encapsulate both hydrophobic and hydrophilic payloads for drug delivery applications. Despite their promise, polymersomes are limited in application due to their spherical shape, which is not readily taken up by cells, as demonstrated by solid nanoparticle scientists. This article describes a salt-based method for increasing the aspect ratios of spherical poly(ethylene glycol) (PEG)- based polymersomes. This method can elongate polymersomes and ultimately control their final shape by adding sodium chloride in post-formation dialysis. Salt concentration can be varied, as described in this method, based on the hydrophobicity of the block copolymer being used as the base for the polymersome and the target shape. Elongated nanoparticles have the potential to better target the endothelium in larger diameter blood vessels, like veins, where margination is observed. This protocol can expand therapeutic nanoparticle applications by utilizing elongation techniques in tandem with the dual-loading, long-circulating benefits of polymersomes.

Hydrophilic and Double Hydrophilic/Hydrophobic Microcapsules using a Single, Thermally Responsive, Self-Sorting Dispersant

Encapsulating and storing hydrophilic payloads are still challenging nowadays. Here, a simple pathway is described to generate different water-filled microcapsule dispersions. We carefully chose a ...

Non-specific interactions of antibody-oligonucleotide conjugates with living cells

Antibody-Oligonucleotide Conjugates (AOCs) represent an emerging class of functionalized antibodies that have already been used in a wide variety of applications. While the impact of dye and drug conjugation on antibodies’ ability to bind their target has been extensively studied, little is known about the effect caused by the conjugation of hydrophilic and charged payloads such as oligonucleotides on the functions of an antibody. Previous observations of non-specific interactions of nucleic acids with untargeted cells prompted us to further investigate their impact on AOC binding abilities and cell selectivity. We synthesized a series of single- and double-stranded AOCs, as well as a human serum albumin-oligonucleotide conjugate, and studied their interactions with both targeted and non-targeted living cells using a time-resolved analysis of ligand binding assay. Our results indicate that conjugation of single strand oligonucleotides to proteins induce consistent non-specific interactions with cell surfaces while double strand oligonucleotides have little or no effect, depending on the preparation method.

Impact of Drug Conjugation and Loading on Target Antigen Binding and Cytotoxicity in Cysteine Antibody-Drug Conjugates.

Antibody-drug conjugates (ADCs) consist of a target-specific antibody that is covalently conjugated to a drug via a linker. ADCs are designed to deliver cytotoxic drugs (payloads), specifically to cancer cells, while minimizing systemic toxicity. Conventional cysteine conjugation typically results in the formation of ADC molecules containing a heterogeneous mixture of 2, 4, 6, and 8 drug-loaded species. The drug-to-antibody ratio (DAR) of the mixture represents the weighted average of these species. In this report, we have investigated the impact of the hydrophobicity of payloads and the overall drug loading on the in vitro binding and cytotoxicity of ADC species. Several ADCs were prepared by conventional cysteine conjugation using different payloads. ADC species with different DAR values were purified from the ADC mixture and characterized by standard analytical techniques. These ADC species were evaluated for target antigen binding using an immunoassay, enzyme-linked immunosorbent assay (ELISA). The potency was assessed using a cell-based cytotoxicity assay. These structure-function studies lead to a better understanding of factors that impact the in vitro target binding and cytotoxicity of ADC species. ADC species containing hydrophobic payloads with high DAR were found to have lower target binding by ELISA compared to that of the unconjugated antibody or the heterogeneous reference ADC with DAR ∼4. Under similar assay conditions, the ADCs conjugated to hydrophilic payloads did not show a significant impact on the target binding. The cytotoxic potency of ADC species increased with increasing level of drug loading in the cell-based cytotoxicity assay.

Magnetic Nanostructure-Loaded Bicontinuous Nanospheres Support Multicargo Intracellular Delivery and Oxidation-Responsive Morphological Transitions.

Magnetic nanostructures (MNS) have a wide range of biological applications due to their biocompatibility, superparamagnetic properties, and customizable composition that includes iron oxide (Fe3O4), Zn2+, and Mn2+. However, several challenges to the biomedical usage of MNS must still be addressed, such as formulation stability, inability to encapsulate therapeutic payloads, and variable clearance rates in vivo. Here, we enhance the utility of MNS during controlled delivery applications via encapsulation within polymeric bicontinuous nanospheres (BCNs) composed of poly(ethylene glycol)-block-poly(propylene sulfide) (PEG-b-PPS) copolymers. PEG-b-PPS BCNs have demonstrated versatile encapsulation and delivery capabilities for both hydrophilic and hydrophobic payloads due to their unique and highly organized cubic phase nanoarchitecture. MNS-embedded BCNs (MBCNs) were thus coloaded with physicochemically diverse molecular payloads using the technique of flash nanoprecipitation and characterized in terms of their structure and in vivo biodistribution following intravenous administration. Retention of the internal aqueous channels and cubic architecture of MBCNs were verified using cryogenic transmission electron microscopy and small-angle X-ray scattering, respectively. MBCNs demonstrated improvement in magnetic resonance imaging (MRI) contrast enhancement (r2 relaxivity) as compared to free MNS, which in combination with scanning transmission electron microscopy and energy-dispersive X-ray spectroscopy evidenced the clustering and continued access to water of MNS following encapsulation. Furthermore, MBCNs were found to be noncytotoxic and able to deliver their hydrophilic and hydrophobic small-molecule payloads both in vitro and in vivo. Finally, the oxidation sensitivity of the hydrophobic PPS block allowed MBCNs to undergo a unique, triggerable transition in morphology into MNS-bearing micellar nanocarriers. In summary, MBCNs are an attractive platform for the delivery of molecular and nanoscale payloads for diverse on-demand and sustained drug delivery applications.

One‐Step Generation of Core–Gap–Shell Microcapsules for Stimuli‐Responsive Biomolecular Sensing

AbstractThe versatile design of stimuli‐responsive microparticles embedding valuable biomolecules has great potential in a variety of engineering fields, such as sensors, actuators, drug delivery, and catalysis. Here, results are reported on thermoresponsive core–gap–shell (TCGS) microcapsules made of poly(N‐isopropylacrylamide) (PNIPAm), which encapsulate hydrophilic payloads in a simple and stable manner. These are realized by a one‐step microfluidic approach using the phase separation of a supersaturated aqueous solution of NIPAm. Various designs of the microcapsules are achieved by individual control of the swelling or by incorporating pH‐responsive comonomers of the inner core and outer shell. The gap, i.e., the space between the inner core and outer shell, can be loaded with cargo‐like nanoparticles. The outer shell can serve as a stimuli‐responsive gateway for the transport of smaller molecules from the external solution. It is shown that the TCGS microcapsules are suitable as temperature controllable glucose sensors and hold promise in the design of controllable enzymatic reactions. The proposed platform provides an avenue for developing a new‐generation of microparticles for diverse and efficient engineering applications.

Abstract 5205: Melflufen, a peptide-conjugated alkylator, shows efficacy in breast cancer cell lines

Abstract Introduction: Melflufen is a lipophilic peptide-conjugated alkylator currently in phase 3 trial for the treatment of late stage multiple myeloma. Due to its lipophilic nature it readily enters cells where it is cleaved by peptidases leading to entrapment and enrichment of hydrophilic alkylator payloads. Since peptidases are often upregulated in many cancer types, melflufen represents an attractive candidate for cancer therapy. Here, we have analysed the efficacy of the known alkylator melphalan and melflufen in isogenic normal and cancerous breast epithelial cell lines D492 and D492HER2 as well as the triple-negative MDA-MB-231 cell line using both 2D and 3D cell cultures and in vivo studies. Methods and results: Cell viability and cell proliferation studies unveiled that all cell lines were affected by melphalan and melflufen in both conditions but to a distinct extent. Melphalan treated cells needed quite high drug dosages to see an effect. In contrast, when treated with melflufen both cancerogenic D492HER2 and MDA-MB-231 lines were more sensitive than the normal-derived D492 line. Immunofluorescence staining showed that the sensitivity was lower in 3D culture compared to 2D culture. Western blot analysis and immunostaining revealed that treatment with melflufen induced profound DNA damage. Through comparison with the commonly used anti-cancer drug doxorubicin in cell viability studies we were able to show that melflufen was significantly more effective in reducing cellular growth. Chicken chorioallantoic membrane (CAM) assays showed comparable effects in vivo. The effect of melflufen in D492HER2 was attenuated if cells were pre-treated with the aminopeptidase inhibitor bestatin confirming the role of aminopeptidases in mediating the effect of melflufen in breast cancer cells. The aminopeptidase CD13 has been shown to facilitate melflufen cleavage. By separating both D492 and D492HER2 cells into CD13high and CD13low subpopulations and subsequently treating them with melflufen, we demonstrated increased melflufen sensitivity in the CD13high compared to CD13low population in D492HER2. Furthermore, siRNA knockdown of CD13 reduced the efficacy of melflufen corroborating its role in melflufen hydrolysis. Interestingly, knockdown of two other aminopeptidases, LAP3 and DPP7, led to similar efficacy reduction, suggesting that other aminopeptidases can facilitate melflufen to melphalan conversion. Conclusion: In this study, we have shown that melflufen is a highly efficient and selective anti neoplastic agent in breast cancer cell lines in-vitro and in-vivo and its efficacy is facilitated by expression of aminopeptidases including CD13, LAP3 and DPP7 indicating that melflufen could be a potent drug in breast cancer cells expressing high level of aminopeptidases. Citation Format: Alexander Schepsky, Gunnhildur A. Traustadottir, Jon Petur Joelsson, Saevar Ingthorsson, Jennifer Kricker, Jon T. Bergthyorsson, Katrina B. Petursdottir, Thorkell Gudjonsson, Ana Slipicevic, Fredrik Lehmann, Thorarinn Gudjonsson. Melflufen, a peptide-conjugated alkylator, shows efficacy in breast cancer cell lines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5205.

Melflufen, a peptide-conjugated alkylator, is an efficient anti-neo-plastic drug in breast cancer cell lines.

Melphalan flufenamide (hereinafter referred to as “melflufen”) is a peptide‐conjugated drug currently in phase 3 trials for the treatment of relapsed or refractory multiple myeloma. Due to its lipophilic nature, it readily enters cells, where it is converted to the known alkylator melphalan leading to enrichment of hydrophilic alkylator payloads. Here, we have analysed in vitro and in vivo the efficacy of melflufen on normal and cancerous breast epithelial lines. D492 is a normal‐derived nontumorigenic epithelial progenitor cell line whereas D492HER2 is a tumorigenic version of D492, overexpressing the HER2 oncogene. In addition we used triple negative breast cancer cell line MDA‐MB231. The tumorigenic D492HER2 and MDA‐MB231 cells were more sensitive than normal‐derived D492 cells when treated with melflufen. Compared to the commonly used anti‐cancer drug doxorubicin, melflufen was significantly more effective in reducing cell viability in vitro while it showed comparable effects in vivo. However, melflufen was more efficient in inhibiting metastasis of MDA‐MB231 cells. Melflufen induced DNA damage was confirmed by the expression of the DNA damage proteins ƴH2Ax and 53BP1. The effect of melflufen on D492HER2 was attenuated if cells were pretreated with the aminopeptidase inhibitor bestatin, which is consistent with previous reports demonstrating the importance of aminopeptidase CD13 in facilitating melflufen cleavage. Moreover, analysis of CD13high and CD13low subpopulations of D492HER2 cells and knockdown of CD13 showed that melflufen efficacy is mediated at least in part by CD13. Knockdown of LAP3 and DPP7 aminopeptidases led to similar efficacy reduction, suggesting that also other aminopeptidases may facilitate melflufen conversion. In summary, we have shown that melflufen is a highly efficient anti‐neoplastic agent in breast cancer cell lines and its efficacy is facilitated by aminopeptidases.

3D-printed microfluidic chip for the preparation of glycyrrhetinic acid-loaded ethanolic liposomes.

18-α-Glycyrrhetinic acid (GA) is a bioactive compound extracted from licorice that exhibits many biological and pharmacological effects such as anti-inflammatory and antioxidant activities on the skin. However, its lipophilic nature results in poor bioavailability that limits clinical applications. Liposomes, presenting the ability to carry both hydrophobic and hydrophilic payloads and a good cytocompatibility, are effective to overcome this barrier. Furthermore, the addition of permeation enhancers such as ethanol into liposomal formulations helps the diffusion of these systems through the skin barrier. Here, we aimed to formulate GA-loaded ethanolic liposomes, using a natural soybean lecithin via a microfluidic approach. Using a fused deposition modeling (FDM) 3D printer we customized a microfluidic chip, and manufactured vesicles that presented spherical shape with a size of 202±5.2nm, a narrow size distribution and a good stability over a period of 30days. After reaching a drug encapsulation efficiency of 63.15±2.2%, liposomes were evaluated for their cytocompatibility and skin permeation potentiality after hydrogelation using xanthan gum. The in vitro release and permeation studies were performed using Franz diffusion cells comparing two different media and three synthetic membranes including a polymeric skin-mimicking membrane. The selected formulation presented no cytotoxicity and an increased permeation compared to GA saturated hydrogel. It could perform therapeutically better effects than conventional formulations containing free GA, as prolonged and controlled release topical dosage forms, which may lead to improved efficiency and better patient compliance.

A pH-responsive silica–metal–organic framework hybrid nanoparticle for the delivery of hydrophilic drugs, nucleic acids, and CRISPR-Cas9 genome-editing machineries

Efficient delivery of hydrophilic drugs, nucleic acids, proteins, and any combination thereof is essential for various biomedical applications. Herein, we report a straightforward, yet versatile approach to efficiently encapsulate and deliver various hydrophilic payloads using a pH-responsive silica–metal–organic framework hybrid nanoparticle (SMOF NP) consisting of both silica and zeolitic imidazole framework (ZIF). This unique SMOF NP offers a high loading content and efficiency, excellent stability, and robust intracellular delivery of a variety of payloads, including hydrophilic small molecule drugs (e.g., doxorubicin hydrochloride), nucleic acids (e.g., DNA and mRNA), and genome-editing machineries (e.g., Cas9-sgRNA ribonucleoprotein (RNP), and RNP together with donor DNA (e.g., RNP + ssODN)). The superior drug delivery/gene transfection/genome-editing efficiencies of the SMOF NP are attributed to its pH-controlled release and endosomal escape capabilities due to the proton sponge effect enabled by the imidazole moieties in the SMOF NPs. Moreover, the surface of the SMOF NP can be easily customized (e.g., PEGylation and ligand conjugation) via various functional groups incorporated into the silica component. RNP-loaded SMOF NPs induced efficient genome editing in vivo in murine retinal pigment epithelium (RPE) tissue via subretinal injection, providing a highly promising nanoplatform for the delivery of a wide range of hydrophilic payloads.

Antibody-Drug Conjugate Payloads; Study of Auristatin Derivatives.

Auristatins are important payloads used in antibody drug conjugates (ADCs), and the most well-known compound family member, monomethyl auristatin (MMAE), is used in two Food and Drug Administration (FDA)-approved ADCs, Adcetris® and Polivy®. Multiple other auristatin-based ADCs are currently being evaluated in human clinical trials and further studies on this class of molecule are underway by several academic and industrial research groups. Our group's main focus is to investigate the structure-activity relationships (SAR) of novel auristatins with the goal of applying these to next generation ADCs. Modifications of the auristatin backbone scaffold have been widely reported in the chemical literature focusing on the terminal subunits: P1 (N-terminus) and P5 (C-terminus). Our approach was to modulate the activity and hydrophilic character through modifications of the central subunits P2-P3-P4 and thorough SAR study on the P5 subunit. Novel hydrophilic auristatins were observed to have greater potency in vitro and displayed enhanced in vivo antitumor activity when conjugated via protease-cleavable linkers and delivered intracellularly. Analysis of ADC aggregation also indicated that novel hydrophilic payloads enabled the synthesis of high-drug-to-antibody ratio (DAR) ADCs that were resistant to aggregation. Modification of the central peptide subunits also resulted in auristatins with potent cytotoxic activity in vitro and these azide-modified auristatins contain a handle for linker attachment from the central portion of the auristatin backbone.

Low-intensity light-induced drug release from a dual delivery system comprising of a drug loaded liposome and a photosensitive conjugate

This study reports the development of a binary drug delivery system consisting of charged liposomes and an oppositely charged peptide–photosensitiser conjugate. Liposomes were prepared with phosphatidyl-l-serine as a negatively charged lipid. Calcein, a fluorophore marker, and doxorubicin, an anticancer drug, were used as model hydrophilic loads. The conjugate consisted of a positively charged arginine-rich peptide synthesised by solid-phase peptide synthesis, and a phthalocyanine derivative with characteristic absorption around 685 nm. Illumination of the binary system with far-red light of 12–15 mW/cm2 intensity resulted in 5- to 15-fold increase in release of payloads from the liposomes. The mechanism of drug release was based on photosensitised oxidation of lipids destabilising the liposomal membrane. The cytotoxicity of the liposomes loaded with doxorubicin was tested on B16-F10 melanoma and Y79 retinoblastoma cells. The cytotoxicity of the illuminated binary system in melanoma cell line was significantly higher as compared to the system without illumination. The components of the binary system can be individually prepared and stored with greater storage stability. However, their combination will allow for substantial release of hydrophilic payload from the liposomes under externally applied light.

The Burden of Relapsed/Refractory Multiple Myeloma: An Indirect Comparison of Health-Related Quality of Life Burden across Different Types of Advanced Cancers at Baseline and after Treatment Based on HORIZON (OP-106) Study of Melflufen Plus Dexamethasone

The Burden of Relapsed/Refractory Multiple Myeloma: An Indirect Comparison of Health-Related Quality of Life Burden across Different Types of Advanced Cancers at Baseline and after Treatment Based on HORIZON (OP-106) Study of Melflufen Plus Dexamethasone

Clinical Activity of Melflufen in Patients with Triple-Class Refractory Multiple Myeloma and Poor-Risk Features in an Updated Analysis of HORIZON (OP-106), a Phase 2 Study in Patients with Relapsed/Refractory Multiple Myeloma Refractory to Pomalidomide and/or Daratumumab

Clinical Activity of Melflufen in Patients with Triple-Class Refractory Multiple Myeloma and Poor-Risk Features in an Updated Analysis of HORIZON (OP-106), a Phase 2 Study in Patients with Relapsed/Refractory Multiple Myeloma Refractory to Pomalidomide and/or Daratumumab