Bio-inspired Drug Research Articles

Diseleno-albumin, a native bio-inspired drug free therapeutic protein induces apoptosis in lung cancer cells through mitochondrial oxidation

Macromolecular therapeutic is the emerging concept in the fields of drug delivery and drug discovery. The present study reports the design and development of a serum albumin based macromolecular chemotherapeutic by conjugating bovine serum albumin (BSA) with 3,3′-diselenodipropionic acid (DSePA), a pharmacologically active organo-diselenide (R-Se-Se-R). The reaction conditions were optimised to achieve the controlled conjugation of BSA with DSePA without causing any significant alteration in its physico-chemical properties or secondary structure and crosslinking. The chemical characterisation of the reaction product through various spectroscopic techniques viz., FT-IR, Raman, XPS, AAS and MALDI-TOF-MS, established the conjugation of about ∼5 DSePA molecules per BSA molecule. The DSePA conjugated BSA (Se-Se-BSA) showed considerable stability in aqueous and lyophilized forms. The cytotoxicity studies by involving cell lines of cancerous and non-cancerous origins indicated that Se-Se-BSA selectively inhibited the proliferation of cancerous cells. The cellular uptake studies by physically labelling Se-Se-BSA with curcumin and following its intracellular fluorescence confirmed that uptake efficiency of Se-Se-BSA was almost similar to that of native BSA. Finally, studies on the mechanism of action of Se-Se-BSA in the A549 (lung adenocarcinoma) cells revealed that it induced mitochondrial ROS generation followed by mitochondrial dysfunction, activation of caspases and apoptosis. Together, these results demonstrate a bio-inspired approach of exploring diselenide (-Se-Se-) grafted serum albumin as the potential drug free therapeutic for anticancer application.

Doxorubicin Conjugated γ-Globulin Functionalised Gold Nanoparticles: A pH-Responsive Bioinspired Nanoconjugate Approach for Advanced Chemotherapeutics.

Developing successful nanomedicine hinges on regulating nanoparticle surface interactions within biological systems, particularly in intravenous nanotherapeutics. We harnessed the surface interactions of gold nanoparticles (AuNPs) with serum proteins, incorporating a γ-globulin (γG) hard surface corona and chemically conjugating Doxorubicin to create an innovative hybrid anticancer nanobioconjugate, Dox-γG-AuNPs. γG (with an isoelectric point of ~7.2) enhances cellular uptake and exhibits pH-sensitive behaviour, favouring targeted cancer cell drug delivery. In cell line studies, Dox-γG-AuNPs demonstrated a 10-fold higher cytotoxic potency compared to equivalent doxorubicin concentrations, with drug release favoured at pH 5.5 due to the γ-globulin corona's inherent pH sensitivity. This bioinspired approach presents a novel strategy for designing hybrid anticancer therapeutics. Our study also explored the intricacies of the p53-mediated ROS pathway's role in regulating cell fate, including apoptosis and necrosis, in response to these treatments. The pathway's delicate balance of ROS emerged as a critical determinant, warranting further investigation to elucidate its mechanisms and implications. Overall, leveraging the robust γ-globulin protein corona on AuNPs enhances biostability in harsh serum conditions, augments anticancer potential within pH-sensitive environments, and opens promising avenues for bioinspired drug delivery and the design of novel anticancer hybrids with precise targeting capabilities.

PEO-b-PCL/Tween 80/cyclodextrin systems: from bioinspired fabrication to possible nasal administration of ropinirole hydrochloride.

In this study, we designed and developed systems composed of poly(ethylene-oxide)-b-poly(ε-caprolactone) block copolymers of different molecular weights and compositions, non-ionic surfactant, and cyclodextrins. The innovation of this study lies in the combination of these diverse biomaterials to create biomimetic and bioinspired drug delivery supramolecular structures. The systems were formed by the thin-film hydration method. Extensive physicochemical and morphological characterization was conducted using differential scanning calorimetry, light scattering techniques, microcalorimetry analysis, high-resolution ultrasound spectroscopy, surface tension measurements, fluorescence spectroscopy, cryogenic transmission electron microscopy images, and in vitro cytotoxicity evaluation. These innovative hybrid nanoparticles were found to be attractive candidates as drug delivery systems with unique properties by encompassing the physicochemical and thermotropic properties of both classes of materials. Subsequently, Ropinirole hydrochloride was used as a model drug for the purpose of this study. These systems showed a high RH content (%), and in vitro diffusion experiments revealed that more than 90% of the loading dose was released under pH and temperature conditions that simulate the conditions of the nasal cavity. Promising drug release performance was observed with all tested formulations, worth further investigation to explore both ex vivo permeation through the nasal mucosa and in vivo performance in an experimental animal model.

Preparation and in vitro evaluation of synthetic high-density lipoproteins as parenteral drug delivery system for tamoxifen citrate

The aim of this study was to develop a bioinspired drug delivery system for tamoxifen citrate (TC) based on synthetic high density lipoproteins (sHDL). For this purpose, sHDL nanoparticles were prepared from a mimetic peptide (5A peptide) and different lipids using thin film hydration method followed by sonication and thermal cycling. Various formulation parameters including lipid composition, lipid to peptide ratio, and drug to carrier ratio had a remarkable impact on the properties and the release pattern of the nanoparticles. The optimized formula (F14) displayed a spherical morphology, average diameter of (35.7±12.4) nm, and a zeta potential (ζ) equals to (-48.4± 0.5) mV. The encapsulation efficiency and drug loading of F14 were (96.5±0.7%) and (9.65±0.1%), respectively. Besides, F14 showed a good stability in human plasma for 24 hours. The encapsulation of the lipophilic drug within the hydrophobic core of the nanocarrier enabled a slow drug release from nanoparticles which follows a near zero order controlled mechanism. The promising results of this study opens an avenue for using sHDL as a delivery system for administration of TC intravenously. Therefore, the optimized formula is suggested to be subject for future analyses in terms of in vitro cytotoxicity against breast cancer cells and in vivo evaluation in tumor bearing animals.

Radiolabelled Extracellular Vesicles as Imaging Modalities for Precise Targeted Drug Delivery.

Extracellular vesicles (ECVs) have been abandoned as bio-inspired drug delivery systems (DDS) in the biomedical field. ECVs have a natural ability to cross over extracellular and intracellular barriers, making them superior to manufactured nanoparticles. Additionally, they have the ability to move beneficial biomolecules among far-flung bodily cells. These advantages and the accomplishment of favorable in vivo results convincingly show the value of ECVs in medication delivery. The usage of ECVs is constantly being improved, as it might be difficult to develop a consistent biochemical strategy that is in line with their useful clinical therapeutic uses. Extracellular vesicles (ECVs) have the potential to enhance the therapy of diseases. Imaging technologies, particularly radiolabelled imaging, have been exploited for non-invasive tracking to better understand their in vivo activity.

Erythro-Magneto-HA-Virosome: A Bio-Inspired Drug Delivery System for Active Targeting of Drugs in the Lungs.

Over the past few decades, finding more efficient and selective administration routes has gained significant attention due to its crucial role in the bioavailability, absorption rate and pharmacokinetics of therapeutic substances. The pulmonary delivery of drugs has become an attractive target of scientific and biomedical interest in the health care research area, as the lung, thanks to its high permeability and large absorptive surface area and good blood supply, is capable of absorbing pharmaceuticals either for local deposition or for systemic delivery. Nevertheless, the pulmonary drug delivery is relatively complex, and strategies to mitigate the effects of mechanical, chemical and immunological barriers are required. Herein, engineered erythrocytes, the Erythro–Magneto–Hemagglutinin (HA)–virosomes (EMHVs), are used as a novel strategy for efficiently delivering drugs to the lungs. EMHV bio-based carriers exploit the physical properties of magnetic nanoparticles to achieve effective targeting after their intravenous injection thanks to an external magnetic field. In addition, the presence of hemagglutinin fusion proteins on EMHVs’ membrane allows the DDS to anchor and fuse with the target tissue and locally release the therapeutic compound. Our results on the biomechanical and biophysical properties of EMHVs, such as the membrane robustness and deformability and the high magnetic susceptibility, as well as their in vivo biodistribution, highlight that this bio-inspired DDS is a promising platform for the controlled and lung-targeting delivery of drugs, and represents a valuable alternative to inhalation therapy to fulfill unmet clinical needs.

Chemically Modified Extracellular Vesicles and Applications in Radiolabeling and Drug Delivery.

Extracellular vesicles (EVs) have been exploited as bio-inspired drug delivery systems (DDS) in the biomedical field. EVs have more advantages than synthetic nanoparticles: they are naturally equipped to cross extra- and intra-cellular barriers. Furthermore, they can deliver functional biomolecules from one cell to another even far away in the body. These advantages, along with obtained promising in vivo results, clearly evidenced the potential of EVs in drug delivery. Nevertheless, due to the difficulties of finding a chemical approach that is coherent with EVs’ rational clinical therapeutic use, those in the drug delivery community are expecting more from EVs’ use. Therefore, this review gathered knowledge of the current chemical approaches dealing with the conjugation of EVs for drugs and radiotracers.

Bioinspired drug delivery strategies for repurposing conventional antibiotics against intracellular infections.

Bacteria have developed a wealth of strategies to avoid and resist the action of antibiotics, one of which involves pathogens invading and forming reservoirs within host cells. Due to the poor cell membrane permeability, stability and retention of conventional antibiotics, this renders current treatments largely ineffective, since achieving a therapeutically relevant antibiotic concentration at the site of intracellular infection is not possible. To overcome such challenges, current antibiotics are 'repurposed' via reformulation using micro- or nano-carrier systems that effectively encapsulate and deliver therapeutics across cellular membranes of infected cells. Bioinspired materials that imitate the uptake of biological particulates and release antibiotics in response to natural stimuli are recently explored to improve the targeting and specificity of this 'nanoantibiotic' approach. In this review, the mechanisms of internalization and survival of intracellular bacteria are elucidated, effectively accentuating the current treatment challenges for intracellular infections and the implications for repurposing conventional antibiotics. Key case studies of nanoantibiotics that have drawn inspiration from natural biological particles and cellular uptake pathways to effectively eradicate intracellular pathogens are detailed, clearly highlighting the rational for harnessing bioinspired drug delivery strategies.

Advances in Drug Delivery and Theranostics

Advances in Drug Delivery and Theranostics

Bioinspired silk fibroin nano-delivery systems protect against 5-FU induced gastrointestinal mucositis in a mouse model and display antitumor effects on HT-29 colorectal cancer cells in vitro

Colorectal cancer (CRC), is the second cause of cancer-related deaths worldwide is one of the most prevalent types of cancers. Conventional treatment continues to rely on surgery, chemotherapy, and radiotherapy, but for advanced cases, adjuvant chemotherapy remains the main approach for improving surgical outcomes and lower the disease recurrence probability. Chemotherapy-induced gastrointestinal (GI) toxicity is the main dose-limiting factor for many chemotherapeutic regimens, including 5-FU, and one of the biggest oncological challenges. Up to 40% of the patients receiving 5-FU get mucositis, 10–15% of which develop severe symptoms. In this context, our study aimed to develop a bioinspired nanosized drug delivery system as a strategy to reduce 5-FU associated side effects, such as GI mucositis. To this end, SF-based nanoparticles were prepared and characterized in terms of size and morphology, as well as in terms of in vitro antitumoral activity on a biomimetic colorectal cancer model by investigation of apoptosis, DNA fragmentation, and release of reactive oxygen species. Additionally, the capacity of the SF-based nanocarriers to offer intestinal protection against 5-FU-induced GI mucositis was evaluated in vivo using a mouse model that mimics the chemotherapy-associated gut mucositis occurring in colorectal cancer. Our studies show that silk fibroin nanoparticles efficiently deliver 5-FU to tumor cells in vitro while protecting against drug-induced GI mucositis in a mouse model.

A “dual-guide” bioinspired drug delivery strategy of a macrophage-based carrier against postoperative triple-negative breast cancer recurrence

Recurrence after tumor resection is mainly caused by post-operative inflammation and residual cancer cells, which is a serious obstacle to breast cancer treatment. Traditional nanoparticles rely primarily on the enhanced permeability and retention (EPR) effect in well-vascularized tumors. In this study, a macrophage-based carrier is designed to enhance the efficiency of targeting to recurrent tumors through a “dual-guide” strategy. After tumor resection, a burst of inflammatory factors occurs in the resection wound, which can recruit monocytes/macrophages rapidly. Combined with the tropism of monocyte chemoattractant protein, a large number of macrophage-mediated carriers will be recruited to surgical recurrence sites. Octaarginine (RRRRRRRR, R8)-modified liposomes in macrophages contain two agents with different pharmacological mechanisms, paclitaxel (PTX) and resveratrol (Res), which have enhanced therapeutic effects. In vitro study demonstrated that macrophage-mediated carriers approach 4 T1 cells through an inflammatory gradient and reach recurrence tumors through a “dual-guide” strategy. Then, membrane fusion and inflammation-triggered release deliver the drug into the recurrent tumor cells. In vivo experiments show that macrophage-based carriers exhibit effective tumor-targeting ability, especially in post-operation situations. More importantly, macrophage-mediated liposomes encapsulated with PTX and Res inhibit tumor recurrence in both ectopic and orthotopic 4 T1 post-operative recurrence models.

Optically responsive delivery platforms: from the design considerations to biomedical applications

Abstract Drug carriers with intelligent functions are powerful therapeutic and diagnostic platforms in curing various diseases such as malignant neoplasms. These functions include the remote noninvasive activation of drug using physical impacts, e.g. light exposure. Combination of different therapeutic modalities (chemotherapy, photodynamic therapy, and so forth) with light-responsive carriers enables promising synergetic effect in tumour treatment. The main goal of this review article is to provide the state of the art on light-sensitive delivery systems with the identification of future directions and their implementation in tumour treatment. In particular, this article reviews the general information on the physical and chemical fundamental mechanisms of interaction between light and carrier systems (e.g. plasmonic and dielectric nanoparticles), the design of optically responsive drug carriers (plain and composite), and the mechanisms of light-driven controlled release of bioactive compounds in biological environment. The special focus is dedicated to the most recent advances in optically responsive bioinspired drug vehicles.

Post-production modifications of murine mesenchymal stem cell (mMSC) derived extracellular vesicles (EVs) and impact on their cellular interaction

In regards to their key role in intercellular communication, extracellular vesicles (EVs) have a strong potential as bio-inspired drug delivery systems (DDS). With the aim of circumventing some of their well-known issues (production yield, drug loading yield, pharmacokinetics), we specifically focused on switching the biological vision of these entities to a more physico-chemical one, and to consider and fine-tune EVs as synthetic vectors. To allow a rational use, we first performed a full physico-chemical (size, concentration, surface charge, cryoTEM), biochemical (western blot, proteomics, lipidomics, transcriptomics) and biological (cell internalisation) characterisation of murine mesenchymal stem cell (mMSC)-derived EVs. A stability study based on evaluating the colloidal behaviour of obtained vesicles was performed in order to identify optimal storage conditions. We evidenced the interest of using EVs instead of liposomes, in regards to target cell internalisation efficiency. EVs were shown to be internalised through a caveolae and cholesterol-dependent pathway, following a different endocytic route than liposomes. Then, we characterised the effect of physical methods scarcely investigated with EVs (extrusion through 50 nm membranes, freeze-drying, sonication) on EV size, concentration, structure and cell internalisation properties. Our extensive characterisation of the effect of these physical processes highlights their promise as loading methods to make EVs efficient delivery vehicles.

Bioinspired DNA self-assembly for targeted cancer cell imaging and drug delivery

In this study, a novel beansprout-like aptamer-tethered DNA assembly was developed for targeted cell imaging and drug delivery. The DNA self-assembly was consisted of two aptamer-tethered single-stranded DNAs (“cotyledons”) and a double-strand DNA (“hypocotyl”). With two cotyledons binding to the target cell’s membrane and a hypocotyl intercalated with drugs or fluorescent dyes, the DNA bean sprout (DNA BS) could deliver drugs to the target cancer cell as well as imaging them. The results show that DNA BS has stronger targeting ability, higher cellular uptake, and more efficient delivery of drugs to MCF-7 cells than the monovalent DNA assembly. This work provides a new way to design bioinspired drug carriers for live cell imaging and targeted drug delivery.

Macroalgal Polysaccharides in Biomimetic Nanodelivery Systems.

Imitating nature in the design of bio-inspired drug delivery systems resulted in several success stories. However, the practical application of biomimicry is still largely unrealized owing to the fact that we tend to copy the shape more often than the whole biology. Interesting chemistry of polysaccharides provides endless possibilities for drug complex formation and creation of delivery systems with diverse morphological and surface properties. However, the type of biological response, which may be induced by these systems, remains largely unexploited. Considering the most current research for the given topic, in this review, we will try to present the integrative approaches for the design of biomimetic DDS's with improved therapeutic or theranostic effects based on different algal polysaccharides that exert multiple biological functions. Algal polysaccharides may provide building blocks for bioinspired drug delivery systems capable of supporting the mechanical properties of nanomedicines and mimicking various biological processes by molecular interactions at the nanoscale. Numerous research studies demonstrate the efficacy and safety of multifunctional nanoparticles integrating several functions in one delivery system, composed of alginate, carrageenan, ulvan, fucoidan and their derivatives, intended to be used as bioartificial microenvironment or for diagnosis and therapy of different diseases. Nanodimensional structure of polysaccharide DDS's shows substantial influence on the bioactive motifs potential availability for interaction with a variety of biomolecules and cells. Evaluation of the nano dimensional structure-activity relationship is crucial for unlocking the full potential of the future application of polysaccharide bio-mimicking DDS in modern diagnostic and therapeutic procedures.

Bio-inspired keratin-based core-crosslinked micelles for pH and reduction dual-responsive triggered DOX delivery

Facile bio-inspired approach has been developed to prepare novel DOX-loaded chicken feather keratin-based core-crosslinked micelles (DOX/Ker-PEG CCMs) for pH and reduction dual-responsive tumor-specific intracellular triggered DOX delivery, by oxidation crosslinking the DOX/Ker-PEG micelles which were simply self-assembled by adjusting solution pH value to 10. The final DOX/Ker-PEG CCMs with a mean hydrodynamic diameter of 152 nm were obtained with a drug loading capacity (DLC) of 24.8%. The in vitro controlled release profiles demonstrated the pH and reduction dual-responsive triggered release of DOX from the developed bio-inspired drug delivery system (DDS), with a cumulative release of 58% within 3 days in a sustained release manner in the stimulated tumor intracellular microenvironment, while a low premature drug leakage of 14% occurred in the normal physiological medium. Furthermore, the MTT assays demonstrated that the graft copolymer Ker-PEG58 possessed excellent cytocompatibility, while the DOX/Ker-PEG CCMs exhibited an enhanced anti-tumor efficacy on the HepG2 cells than the free DOX.

Slow-targeted release of a ruthenium anticancer agent from vitamin B12 functionalized marine diatom microalgae.

Herein we report the synthesis of a new biomaterial designed for targeted delivery of poorly water-soluble inorganic anticancer drugs, with a focus on colorectal cancer. Diatomaceous earth microparticles derived from marine microalgae were coated with vitamin B12 (cyanocobalamin) as a tumor targeting agent and loaded with the well-known anticancer agents cisplatin, 5-fluorouracil (5-FU), and a tris-tetraethyl[2,2'-bipyridine]-4,4'-diamine-ruthenium(ii) complex. The successful functionalization of the biomaterial was demonstrated by different analytical techniques and by synthesizing an organometallic fluorescein analogue of cyanocobalamin detectable by confocal laser scanning microscopy. The drug releasing properties were evaluated for all three species. We found that while cisplatin and 5-FU are rapidly lost from the material, the ruthenium complex showed an unprecedented release profile, being retained in the material up to 5 days in aqueous media but readily released in lipophilic environments as in the cell membrane. The increased adherence of the B12 coated diatoms to colorectal cancer cell line HT-29 and breast cancer cell line MCF-7 was demonstrated in vitro. In both cases, the adherence of the B12 modified diatoms was at least 3 times higher than that of the unmodified ones and was correlated with the increased transcobalamin II (TC(II)) and transcobalamin II receptor (TC(II)-R) expression of the targeted tissue. Our results suggest that this type of B12 modified diatoms could be a promising tool to achieve targeted delivery of water insoluble inorganic complexes to tumor tissues by acting as a micro-shuttle interacting with the sites of interest before delivering the drug in the vicinity of the tumor tissue.

Bio-inspired drug delivery systems: an emerging platform for targeted cancer therapy.

The quest for an ideal cancer treatment has led to the exploration of a variety of platforms to facilitate highly desirable and efficient drug delivery. As most anticancer drugs possess therapeutic potency to destroy tumor cells, there is a need to steer the compounds to their required sites using site-specific drug delivery vehicles. This has inspired the investigation of various natural particulates and biomaterials for the purpose. Bio-inspired platforms that directly mimic natural components in the body have demonstrated their ability to serve as one of the most versatile and innovative drug delivery systems in cancer therapy and diagnosis. The primary advantage of this innovation lies in the fundamental changes in systemic biodistribution that non-native drug delivery does not possess. This review will try to provide a comprehensive understanding and a succinct evaluation of various intelligent bio-inspired delivery platforms, which have become prominent in recent studies. Recent innovative examples and their advantages and limitations as well as future clinical potential will also be thoroughly discussed.

Expanding the Therapeutic Potential of the Iron Chelator Deferasirox in the Development of Aqueous Stable Ti(IV) Anticancer Complexes.

The recent X-ray structure of titanium(IV)-bound human serum transferrin (STf) exhibiting citrate as a synergistic anion reveals a difference in Ti(IV) coordination versus iron(III), the metal endogenously delivered by the protein to cells. This finding enriches our bioinspired drug design strategy for Ti(IV)-based anticancer therapeutics, which applies a family of Fe(III) chelators termed chemical transferrin mimetic (cTfm) ligands to inhibit Fe bioavailability in cancer cells. Deferasirox, a drug used for iron overload disease, is a cTfm ligand that models STf coordination to Fe(III), favoring Fe(III) binding versus Ti(IV). This metal affinity preference drives deferasirox to facilitate the release of cytotoxic Ti(IV) intracellularly in exchange for Fe(III). An aqueous speciation study performed by potentiometric titration from pH 4 to 8 with micromolar levels of Ti(IV) deferasirox at a 1:2 ratio reveals exclusively Ti(deferasirox)2 in solution. The predominant complex at pH 7.4, [Ti(deferasirox)2]2-, exhibits the one of the highest aqueous stabilities observed for a potent cytotoxic Ti(IV) species, demonstrating little dissociation even after 1 month in cell culture media. UV-vis and 1H NMR studies show that the stability is unaffected by the presence of biomolecular Ti(IV) binders such as citrate, STf, and albumin, which have been shown to induce dissociation or regulate cellular uptake and can alter the activity of other antiproliferative Ti(IV) complexes. Kinetic studies on [Ti(deferasirox)2]2- transmetalation with Fe(III) show that a labile Fe(III) source is required to induce this process. The initial step of this process occurs on the time scale of minutes, and equilibrium for the complete transmetalation is reached on a time scale of hours to a day. This work reveals a mechanism to deliver Ti(IV) compounds into cells and trigger Ti(IV) release by a labile Fe(III) species. Cellular studies including other cTfm ligands confirm the Fe(III) depletion mechanism of these compounds and show their ability to induce early and late apoptosis.

Biomimetic and bioinspired nanoparticles for targeted drug delivery.

In drug targeting, the urgent need for more effective and less iatrogenic therapies is pushing toward a complete revision of carrier setup. After the era of 'articles used as homing systems', novel prototypes are now emerging. Newly conceived carriers are endowed with better biocompatibility, biodistribution and targeting properties. The biomimetic approach bestows such improved functional properties. Exploiting biological molecules, organisms and cells, or taking inspiration from them, drug vector performances are now rapidly progressing toward the perfect carrier. Following this direction, researchers have refined carrier properties, achieving significant results. The present review summarizes recent advances in biomimetic and bioinspired drug vectors, derived from biologicals or obtained by processing synthetic materials with a biomimetic approach.