Smart Carriers Research Articles

The computational quantum mechanical investigation of the functionalized boron nitride nanocage as the smart carriers for favipiravir drug delivery: a DFT and QTAIM analysis

Favipiravir (FPV) is an antiviral drug used for the cure of Influenza virus, Ebola virus, Lassa virus etc. because it has excellent preventing ability of entry/exit of the virus into/from the human cells. Boron nitride nanocages have already drawn enormous attention as the delivery vehicle of various drug molecules for their nontoxicity and other lucrative properties. In this research, we have scrutinized the adsorption mechanism of FPV molecule on the exterior surface of pristine, Zn functionalized, and Ni functionalized B12N12 (BN, Zn f-BN, and Ni f-BN) nanocages by applying the DFT/QTAIM method and B3LYP/6-31G(d,p) approach. The adsorption energy (EAd) data reveal that the functionalized BN adsorbents can adsorb FPV drug very efficiently compared with the pristine adsorbent (Highest EAd is −56.40 kcal/mol for FPV adsorbed Ni f-BN complex). The reduction of the HOMO-LUMO gap up to 67.79% indicates that this drug can be detected by the produced electrical signal very promisingly in the case of f-BN nanocages. The topological parameters also validate the ability of the f-BN nanocages to adsorb the FPV molecule. The effect of the biological environment of our investigated structures has been studied by using water as a solvent, and spontaneous adsorption with high solubility is observed in our calculations. This analysis also reveals that f-BN nanocages can be a potential nanocarrier for the delivery of FPV drug molecule. Communicated by Ramaswamy H. Sarma

Applications of metal–organic frameworks for oral delivery systems

AbstractMetal–organic frameworks (MOFs) have been developed to be intelligent delivery systems recently. However, MOFs as oral systems have been challenging. The purpose of this perspective is to briefly review the current applications of oral MOFs and the present dilemma of oral MOFs for humans. The destiny of MOFs‐based materials within the gastrointestinal tract and the blood are discussed, and the principles that guide the development of oral MOFs‐based materials are summarized. It is expected that this perspective will provide new insights on the design and development of oral MOF‐based materials as smart carriers for keeping human health.

Lipid Cubic Mesophases Combined with Superparamagnetic Iron Oxide Nanoparticles: A Hybrid Multifunctional Platform with Tunable Magnetic Properties for Nanomedical Applications.

Hybrid materials composed of superparamagnetic iron oxide nanoparticles (SPIONs) and lipid self-assemblies possess considerable applicative potential in the biomedical field, specifically, for drug/nutrient delivery. Recently, we showed that SPIONs-doped lipid cubic liquid crystals undergo a cubic-to-hexagonal phase transition under the action of temperature or of an alternating magnetic field (AMF). This transition triggers the release of drugs embedded in the lipid scaffold or in the water channels. In this contribution, we address this phenomenon in depth, to fully elucidate the structural details and optimize the design of hybrid multifunctional carriers for drug delivery. Combining small-angle X-ray scattering (SAXS) with a magnetic characterization, we find that, in bulk lipid cubic phases, the cubic-to-hexagonal transition determines the magnetic response of SPIONs. We then extend the investigation from bulk liquid-crystalline phases to colloidal dispersions, i.e., to lipid/SPIONs nanoparticles with cubic internal structure (“magnetocubosomes”). Through Synchrotron SAXS, we monitor the structural response of magnetocubosomes while exposed to an AMF: the magnetic energy, converted into heat by SPIONs, activates the cubic-to-hexagonal transition, and can thus be used as a remote stimulus to spike drug release “on-demand”. In addition, we show that the AMF-induced phase transition in magnetocubosomes steers the realignment of SPIONs into linear string assemblies and connect this effect with the change in their magnetic properties, observed at the bulk level. Finally, we assess the internalization ability and cytotoxicity of magnetocubosomes in vitro on HT29 adenocarcinoma cancer cells, in order to test the applicability of these smart carriers in drug delivery applications.

Loading and release of\xa0cancer chemotherapy drugs utilizing simultaneous temperature and pH-responsive nanohybrid

BackgroundRecently, the development of nanocarriers and the improvement of their biochemical properties have became of great importance. Single-walled carbon nanotubes (SWCNT) have many applications in drug delivery systems (DDS) as a common carbon-based structure. In the current work, the penetration, co-loading, and co-release of Doxorubicin (DOX) and Paclitaxel (PAX), as two cancer chemotherapy agents, were investigated using a novel modified copolymer with functionalized SWCNT.ResultsThis study proposes a dual-responsive smart carrier that is sensitive to pH and temperature. The carrier consists of functionalized SWNT and Dimethyl acrylamide-trimethyl chitosan (DMAA-TMC) grafting on SWCNT. This suggested carrier was investigated by utilizing molecular simulations. Interaction energies between DOX, PAX, and carrier as well as the affinity of drugs to the nanocarrier were studied. The energy analysis of drug release and adsorption presented that DOX and PAX delivery using this carrier is selective and sensitive at healthy and cancerous conditions. The attraction of DMAA-TMC, as a biodegradable and biocompatible copolymer, with SWCNT showed that degradation mechanism in acidic environment deformed the copolymer. This leads to a smart release mechanism in an acidic cancerous tissue. Additionally, it improves hydrophilicity, optimum nano-particle size, and cell cytotoxicity concerns.ConclusionsThe simulation results manifested a significant contribution of DMAA-TMC in the adsorption and release of cancer chemotherapy drugs in normal and neoplastic tissues. The interaction of copolymer also improves the biocompatibility and biodegradability of the SWCNT. Smart drug delivery carrier can be a valuable nanohybrid for loading, transporting, and releasing of cancer chemotherapy drugs.Graphical abstract

Withdrawal: Quantitative Synthesis of Temperature-responsive Polymersomes by Multiblock Polymerization.

The current challenge for polymersomes is to prepare amphiphilic block polymers with not only well-defined molecular weight, but also precisely high-order multiblock structure in terms of the distribution of monomeric units along the chain. Here, we describe a synthesis of temperature-responsive polymersomes with precisely defined membrane structures using high-precision amphiphilic multiblock polymer via aqueous single electron transfer living radical polymerization (SET-LRP) in which poly(ethylene glycol) (PEG) macromolecules are used as initiators. We develop a one-pot, rapid and multistep sequential polymerization process with yields >99% within 30 min for each block, giving access to a wide range of high-precision multiblock polymers with very narrow molecular weight distributions (Ð ≤ 1.14). Synthesized multiblock polymers are used to form nano-sized polymersomes which are highly promising as smart carriers for high loading and triggered release of biopharmaceutics such as pharmaceutical proteins and peptides. This synthesis approach is environmentally friendly, fully translation and thus represents a significant advance in the design and synthesis of a new generation of polymer nanomaterials with precisely defined structures, which is highly attractive for applications in nanotechnology.

Smart Drug Delivery: Tumor Exosomes Reprogrammed by Low pH Are Efficient Targeting Vehicles for Smart Drug Delivery and Personalized Therapy against their Homologous Tumor (Adv. Sci. 10/2021)

In article number 2002787, Yugang Wang, Wei Wei, Guanghui Ma, and co-workers develop an exosome-based platform for smart drug delivery and personalized antitumor therapy. They discover that the exosomes released from low-pH treated tumor cells have the strong uptake efficiency and targeting ability for their parent cells. Such “magical” characteristics are based on a glycerolipid selfaggregation-enhanced uptake mechanism. These reprogrammed exosomes are further utilized as smart carriers for dual-loading of photosensitizer and chemodrug, which are capable of specifically accumulating in tumor tissue, selectively releasing chemodrug in response to the near-infrared irradiance and achieving safe and potent antitumor effects.

Smart gating porous particles as new carriers for drug delivery.

The design of smart drug delivery carriers has recently attracted great attention in the biomedical field. Smart carriers can specifically respond to physical and chemical changes in their environment, such as temperature, photoirradiation, ultrasound, magnetic field, pH, redox species, and biomolecules. This review summarizes recent advances in the integration of porous particles and stimuli-responsive gatekeepers for effective drug delivery. Their unique structural properties play an important role in facilitating the diffusion of drug molecules and cell attachment. Various techniques for fabricating porous materials, with their major advantages and limitations, are summarized. Smart gatekeepers provide advanced functions such as "open-close" switching by functionalized stimuli-responsive polymers on a particle's pores. These controlled delivery systems enable drugs to be targeted at specific rates, time programs, and sites of the human body. The gate structures, gating mechanisms, and controlled release mechanisms of each trigger are detailed. Current ongoing research and future trends in targeted drug delivery, tissue engineering, and regenerative medicine applications are highlighted.

Antibody-Functionalized Halloysite Nanotubes for Targeting Bacterial Cells.

Halloysite nanotubes (HNTs) are naturally occurring tubular clay particles which have emerged in recent years as a promising nanomaterial for numerous applications. Specifically, HNTs’ large pore volume and high specific surface area in combination with their biocompatibility make them ideal nanocarriers for bioactive compounds. This research aims to design and synthesize functionalized HNTs, which could selectively bind to target bacterial cells in suspension. Such a system can allow us to treat target cells within a challenging heterogeneous population, such as contaminated ecosystems or gut flora. HNTs functionalization is achieved by immobilizing specific antibodies onto the nanotube surface. The synthetic route is realized by the following subsequent steps: acidic etching of the HNTs, silanization of reactive surface hydroxyls, conjugation of protein A, and oriented immobilization of the antibody. HNT functionalization is studied by a set of analytical techniques including attenuated total reflectance Fourier-transform infrared spectroscopy, zeta potential measurements, thermal gravimetric analysis, scanning and transmission electron microscopy, as well as fluorescence microscopy. The selective binding of the functionalized HNTs to their target bacteria is observed upon incubation with live homogenous and heterogeneous cultures using fluorescence microscopy and high-throughput flow cytometry. Plate count and live/dead staining experiments demonstrate the biocompatibility of the antibody-HNT hybrid with its target bacteria. The suggested HNT-based smart carrier constitutes a generic platform for targeted delivery that could be selectively tailored against any microorganism by facile antibody adjustment.

Legume proteins are smart carriers to encapsulate hydrophilic and hydrophobic bioactive compounds and probiotic bacteria: A review.

Encapsulation is a promising technological process enabling the protection of bioactive compounds against harsh storage, processing, and gastrointestinal tract (GIT) conditions. Legume proteins (LPs) are unique carriers that can efficiently encapsulate these unstable and highly reactive ingredients. Stable LPs-based microcapsules loaded with active ingredients can thus develop to be embedded into processed functional foods. The recent advances in micro- and nanoencapsulation process of an extensive span of bioactive health-promoting probiotics and chemical compounds such as marine and plant fatty acid-rich oils, carotenoid pigments, vitamins, flavors, essential oils, phenolic and anthocyanin-rich extracts, iron, and phytase by LPs as single wall materials were highlighted. A technical summary of the use of single LP-based carriers in designing innovative delivery systems for natural bioactive molecules and probiotics was made. The encapsulation mechanisms, encapsulation efficiency, physicochemical and thermal stability, as well as the release and absorption behavior of bioactives were comprehensively discussed. Protein isolates and concentrates of soy and pea were the most common LPs to encapsulate nutraceuticals and probiotics. The microencapsulation of probiotics using LPs improved bacteria survivability, storage stability, and tolerance in the in vitro GIT conditions. Moreover, homogenization and high-pressure pretreatments as well as enzymatic cross-linking of LPs significantly modify their structure and functionality to better encapsulate the bioactive core materials. LPs can be attractive delivery devices for the controlled release and increased bioaccessibility of the main food-grade bioactives.

α-Tocopherol-loaded reactive oxygen species-scavenging ferrocene nanocapsules with high antioxidant efficacy for wound healing

The elevated production of reactive oxygen species (ROS) in wounded sites triggers a series of harmful effects, including cellular senescence, fibrotic scar formation, and inflammation. Therefore, alleviating oxidative stress in the microenvironment of wounded sites might promote regenerative wound healing. Generally, ROS-scavenging nanocapsules are effective for treating wounds owing to their anti-oxidative stress activity and targeted effects. In this study, a highly versatile ferrocene functional polymer was synthesized by one-pot radical polymerization, for formulating self-assembled ferrocene nanocapsules (FNCs), which could function as smart carriers of an antioxidant, α-tocopherol (TP), with high stability and loading efficiency. The FNCs showed ROS-sensitive properties, as demonstrated using dynamic light scattering, transmission electron microscopy, and the controlled release of a model drug in an ROS microenvironment. The antioxidant activity of TP-loaded FNCs, analyzed using 2,2-diphenyl-1-picrylhydrazyl assay, was significantly higher than that of unloaded TP. Furthermore, TP-loaded FNCs repressed oxidative damage to mouse NIH 3T3 fibroblasts and reduced intracellular ROS production according to an in vitro antioxidant assay. Most importantly, TP-loaded FNCs showed good biocompatibility and greatly facilitated the healing of infected wounds, as demonstrated using a scratch assay. Therefore, TP-loaded FNCs have potential as an ROS-mediated drug delivery system to treat various oxidative stress-associated diseases.

Comparative study of pluronic-chitosan and pluronic-guar gum composite thermogels

Triblock copolymers display, in water, a rich phase behavior with changes in temperature and concentration that makes them particularly attractive for many industrial and biomedical applications. In an attempt to develop smart carriers with improved properties, additives such as polysaccharides are often included in the poloxamer formulations. In the present work, we examine and compare the associative properties of concentrated aqueous solutions of pluronic F127 in presence of chitosan and guar gum. Dynamic light scattering was used to analyze the effects of the two polysaccharides on the different self-assembled structures formed within these solutions as a function of temperature from the micellization to the sol-gel transition. The most marked differences between the two systems can be observed above the sol-gel transition, where the analysis of the correlation functions evidenced the presence of three processes: a fast process that represents unimers diffusion, an intermediate process related to individual hydrated micelles, and a slow mode due to the presence of large micellar aggregates. We hypothesize that the different molecular weight and ionic character of the polysaccharides are responsible for the different size of the diffusing entities as well for the nature of the bonds which hold together the extended network between micelles formed above the sol-gel transition.

MD and DFT calculations on the structural variations of amino-cyclodextrin as a pH-sensitive carrier for smart carriage and release of Doxorubicin

Cyclodextrins have been widely employed as nanocarriers due to their unique structure and proper controlled drug delivery as well as nontoxicity, water solubility, and proper capacity to carry hydrophobic drugs. In addition, pH-sensitized compounds have found particular importance in the field of anticancer drug delivery. In this study, the structure of amino-β-cyclodextrin was theoretically explored as a pH-sensitive and smart carrier for Doxorubicin anticancer drug. To this end, quantum chemical calculation methods and molecular dynamics (MD) simulations were applied on amino-β-cyclodextrin to assess its ability to carry Doxorubicin anticancer drug. Quantum chemistry results indicated a deformation in the nanocarrier during protonation. Moreover, interaction energy and quantum molecular describers confirm the drug storage under non-protonated conditions and its release under protonation conditions. Hydrogen bonding, carrier-drug energy, and center of mass (COM) distances (obtained from MD simulation) also suggest drug carrying and releasing under non-protonated and protonated conditions, respectively.

Development and characterization of chitosan based polymer composite nanofibre as a smart carrier system for microbial immobilization

Electrospinning is a versatile and efficient technique which uses high electric field to produce ultrafine fibres from polymers. Nanofibers are widely used in biomedical and tissue engineering as scaffolds, sensors, filters, membranes, batteries, protective clothing, Wound dressing and as a catalyst. In agriculture, it is applied for controlled and targeted release of bioactive compounds. The main aim of this study was to develop E-spun nanofibre using biopolymer that act as a smart carrier system for beneficial bacteria to use it in seed coating. Polymer composite nanofibre was developed using chitosan and polyvinyl alcohol (PVA) by experimenting different ratio of PVA/Chitosan. The e-spin solution containing PVA and chitosan in the ratio of 8:2 was found to be optimum in producing fibre with desired diameter. The developed fibre was further characterized By Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM) and Fourier Transform Infra-Red (FTIR) spectroscopy. The electron micrograph images provide the morphological structure of the PVA/Chitosan polymer composite nanofibre (100-150nm). Fourier Transform Infrared Spectroscopic (FTIR) measurement exhibited the interaction and existence of relevant functional groups of both PVA and chitosan in the nanocomposite fibres. This study provides a simple approach for the development of non-wovens that acts as a smart carrier to immobilize microbes which can be used for seed coating.

Nanoparticles as Smart Carriers for Enhanced Cancer Immunotherapy.

Cancer immunotherapy has emerged as a promising strategy for the treatment of many forms of cancer by stimulating body's own immune system. This therapy not only eradicates tumor cells by inducing strong anti-tumor immune response but also prevent their recurrence. The clinical cancer immunotherapy faces some insurmountable challenges including high immune-mediated toxicity, lack of effective and targeted delivery of cancer antigens to immune cells and off-target side effects. However, nanotechnology offers some solutions to overcome those limitations, and thus can potentiate the efficacy of immunotherapy. This review focuses on the advancement of nanoparticle-mediated delivery of immunostimulating agents for efficient cancer immunotherapy. Here we have outlined the use of the immunostimulatory nanoparticles as a smart carrier for effective delivery of cancer antigens and adjuvants, type of interactions between nanoparticles and the antigen/adjuvant as well as the factors controlling the interaction between nanoparticles and the receptors on antigen presenting cells. Besides, the role of nanoparticles in targeting/activating immune cells and modulating the immunosuppressive tumor microenvironment has also been discussed extensively. Finally, we have summarized some theranostic applications of the immunomodulatory nanomaterials in treating cancers based on the earlier published reports.

Investigation of nanotubes as the smart carriers for targeted delivery of mercaptopurine anticancer drug

Mercaptopurine (MCP) is an anticancer drug that is used to treat acute lymphoblastic leukemia. The therapeutic effect of the mercaptopurine limits its severe side effects like other cytotoxic (anti-cancer) drugs. Nanostructures or nanoparticles can be widely used as potential drug carriers for diagnosis and treatment of cancer. In the current study, the boron nitride nanotube (BNNT) and carbon nanotube (CNT) were studied as the delivery carriers of MCP using the density functional theory (DFT) calculations and molecular dynamics (MDs) simulation studies. To further understand the electronic properties of mercaptopurine, the partial density of states (PDOS) was calculated. The PDOS results depicted that the electronic features of the MCP do not change after the adsorption on the surface of the nanotubes. More stability of the MCP/BNNT complexes may be attributed to the existence of the intermolecular hydrogen bonds (H-bonds) between the hydrogen atoms of the MCP molecule and the N atoms of the BNNT. The results of the quantum theory of atoms in molecules (QTAIM) confirmed the presence of H-bonds in these complexes. Moreover, MD simulation studies were done in the presence of five drug molecules. The results revealed that the strongest van der Waals (vdW) interaction energy was found between the BNNT and MCP among the studied nanotubes, indicating the BNNT is a better nanocarrier than carbon nanotube for delivery of the MCP drug within the biological systems. In general, the obtained results may present helpful information on the nature of the interactions between mercaptopurine anticancer drug with BNNT and/or CNT. Communicated by Ramaswamy H. Sarma

Simultaneous doxorubicin encapsulation and in-situ microfluidic micellization of bio-targeted polymeric nanohybrids using dichalcogenide monolayers: A molecular in-silico study

The rate of Riboflavin (RF) consumption in cancerous cells is interestingly high and this might imply the use of RF ligand in nanocarriers in order to target anticancer drugs into cancer cells. This study aimed to develop a hybrid drug carrier of Doxorubicin (DOX) loaded on RF targeted micelles composed of hydrophobic polylactic-glycolic acid (PLGA) and hydrophilic polyethylene glycol (PEG). In this regard, a simultaneous encapsulation of DOX and in-situ micellization as well as the self-assembly of PLGA-PEG-RF molecules were investigated. Moreover, the effects of microfluidic environment and transition metal dichalcogenide (TMD) nanolayers on the micellization properties (e.g., stability, size, and self-assembly interaction energies) of nanocarriers were simulated for the first time. To this purpose, the simulations were performed using two non-microfluidic methods as well as a novel microfluidic one. The molecular simulations revealed that all of the selected TMDs, especially MoSe2, had a great impact on the stability and size of nanocarriers. MoSe2 significantly enhanced the loading capacity as well as the stability of RF-targeted micelles and reduced the size of nanocarriers. Likewise, the results of various analyses demonstrated that the microfluidic method is the most effective way to synthesize nanocarriers with higher stability and smaller particle size. Hence, the use of MoSe2 monolayer, micelle containing RF, and microfluidic method were believed to be the best approach in order to improve the quality of micelles. The present work sheds new light on the use of TMDs in the synthesis of smart carriers for cancer treatment.

Molecularly Imprinted Polymer-Based Smart Prodrug Delivery System for Specific Targeting, Prolonged Retention, and Tumor Microenvironment-Triggered Release.

Prodrug and drug delivery systems are two effective strategies for improving the selectivity of chemotherapeutics. Molecularly imprinted polymers (MIPs) have emerged as promising carriers in targeted drug delivery for cancer treatment, but they have not yet been integrated with the prodrug strategy. Reported here is an MIP‐based smart prodrug delivery system for specific targeting, prolonged retention time, and tumor microenvironment‐triggered release. 5′‐Deoxy‐5‐fluorocytidine (DFCR) and sialic acid (SA) were used as a prodrug and a marker for tumor targeting, respectively. Their co‐imprinted nanoparticles were prepared as a smart carrier. Prodrug‐loaded MIP specifically and sustainably accumulated at the tumor site and then gradually released. Unlike conventional prodrug designs, which often require in‐liver bioconversion, this MIP‐based prodrug delivery is liver‐independent but tumor‐dependent. Thus, this study opens new access to the development of smart prodrug delivery nanoplatforms.

Molecularly Imprinted Polymer‐Based Smart Prodrug Delivery System for Specific Targeting, Prolonged Retention, and Tumor Microenvironment‐Triggered Release

AbstractProdrug and drug delivery systems are two effective strategies for improving the selectivity of chemotherapeutics. Molecularly imprinted polymers (MIPs) have emerged as promising carriers in targeted drug delivery for cancer treatment, but they have not yet been integrated with the prodrug strategy. Reported here is an MIP‐based smart prodrug delivery system for specific targeting, prolonged retention time, and tumor microenvironment‐triggered release. 5′‐Deoxy‐5‐fluorocytidine (DFCR) and sialic acid (SA) were used as a prodrug and a marker for tumor targeting, respectively. Their co‐imprinted nanoparticles were prepared as a smart carrier. Prodrug‐loaded MIP specifically and sustainably accumulated at the tumor site and then gradually released. Unlike conventional prodrug designs, which often require in‐liver bioconversion, this MIP‐based prodrug delivery is liver‐independent but tumor‐dependent. Thus, this study opens new access to the development of smart prodrug delivery nanoplatforms.

Improved self-healing performance of polymeric nanocomposites reinforced with talc nanoparticles (TNPs) and urea-formaldehyde microcapsules (UFMCs)

The present work reports the self-healing performance of the epoxy based polymeric nanocomposite coatings containing different concentrations (1 and 3 wt%) of talc nanoparticles (TNPs) modified with sodium nitrate (NaNO3), and a fixed amount (5 wt%) of urea-formaldehyde microcapsules (UFMCs) encapsulated with linseed oil (LO). The polymeric nanocomposites were developed, coated on polished steel substrates, and their structural, thermal, and self-healing characteristics were investigated using various techniques. The successful loading (~wt 10%) of NaNO3 into TNPs, which can be ascribed to the involvement of physio-chemical adsorption mechanism, is validated and proceeds without altering the TNPs parent lamellae structure. The performed tests elucidated that the self-release of the corrosion inhibitor (NaNO3) from TNPs is sensitive to the pH of the solution and immersion time. In addition, the release of the linseed oil (self-healing agent) from UFMCs in response to the external damage was found to be a time-dependent process. The superior self-healing and corrosion inhibition performance of the protective polymeric nanocomposites coatings containing 3 wt% TNPs and UFMCs/LO are proven using the electrochemical impedance spectroscopy (EIS) studies. A careful selection of smart carriers, inhibitor, and self-healing agent compatible with polymeric matrix has enabled to attain decent self-healing and convincing corrosion inhibition efficiency of 99.9% and 99.5%, respectively, for polymeric nanocomposites coatings containing 3 and 1 wt% TNPs, making them attractive for many industrial applications.

Effect of ligand conjugation site on the micellization of Bio-Targeted PLGA-Based nanohybrids: A computational biology approach

In this study, the effect of ligand binding position on the polymeric nanoparticles (NPs) is based on poly(lactic-co-glycolic acid) (PLGA) with two different polymer chain length at the atomistic level was presented. We explored the conjugation of riboflavin (RF) ligand from the end of the ribityl chain (N-10) to the polymer strands as well as from the amine group on the isoalloxazine head (N-3). The energy interactions for all samples revealed that the NPs containing ligands from N-10 positions have higher total attraction energies and lower stability in comparison with their peers conjugated from N-3. As NPs containing RF conjugated from N-3 exhibit the lower energy level with 20% and 10% of RF-containing composition for lower and higher. The introduction of RF from the N-10 position in any composition has increased the energy level of nanocarriers. The results of Gibb's free energy confirm the interatomic interaction energies trend where the lowest Gibbs free energy level for N-3 NPs occurs at 20 and 10% of RF-containing polymer content for PLGA10- and PLGA11- based NPs. Furthermore, with N-10 samples based on both polymers, non-targeted models form the stablest particles in each category. These findings are further confirmed with molecular docking analysis which revealed affinity energy of RF toward polymer chain from N-3 and N-10 are −981.57 kJ/mole and −298.23 kJ/mole, respectively. This in-silico study paves the new way for molecular engineering of the bio-responsive PLGA-PEG-RF micelles and can be used to nanoscale tunning of smart carriers used in cancer treatment. Communicated by Ramaswamy H. Sarma