Effect of Nanoparticle Weight on the Cellular Uptake and Drug Delivery Potential of PLGA Nanoparticles.

Biodegradable and biocompatible polymeric nanoparticles (NPs) stand out as a key tool for improving drug bioavailability, reducing the inherent toxicity, and targeting the intended site. Most importantly, the ease of polymer synthesis and its derivatization to add functional properties makes them potentially ideal to fulfill the requirements for intended therapeutic applications. Among many polymers, US FDA-approved poly(l-lactic-co-glycolic) acid (PLGA) is a widely used biocompatible and biodegradable co-polymer in drug delivery and in implantable biomaterials. While many studies have been conducted using PLGA NPs as a drug delivery system, less attention has been given to understanding the effect of NP weight on cellular behaviors such as uptake. Here we discuss the synthesis of PLGA NPs with varying NP weights and their colloidal and biological properties. Following nanoprecipitation, we have synthesized PLGA NP sizes ranging from 60 to 100 nm by varying the initial PLGA feed in the system. These NPs were found to be stable for a prolonged period in colloidal conditions. We further studied cellular uptake and found that these NPs are cytocompatible; however, they are differentially uptaken by cancer and immune cells, which are greatly influenced by NPs' weight. The drug delivery potential of these nanoparticles (NPs) was assessed using doxorubicin (DOX) as a model drug, loaded into the NP core at a concentration of 7.0 ± 0.5 wt % to study its therapeutic effects. The results showed that both concentration and treatment time are crucial factors for exhibiting therapeutic effects, as observed with DOX-NPs exhibiting a higher potency at lower concentrations. The observations revealed that DOX-NPs exhibited a higher cellular uptake of DOX compared to the free-DOX treatment group. This will allow us to reduce the recommended dose to achieve the desired effect, which otherwise required a large dose when treated with free DOX. Considering the significance of PLGA-based nanoparticle drug delivery systems, we anticipate that this study will contribute to the establishment of design considerations and guidelines for the therapeutic applications of nanoparticles.

Extracellular vesicles production and proteomic cargo varies with incubation time and temperature.

Extracellular vesicles (EVs) are heterogenous populations of proteolipid bi-layered vesicles secreted by cells as an important biological process. EVs cargo can reflect the cellular environmental conditions in which cells grow. The use of serum-free conditioned media to harvest EVs leads to stress-mediated cellular changes with longer incubation time and impacts EV production and functionality. This study aims to explore the role of incubation time and temperature on EV production and proteomic cargo. For this purpose, an optimized ultrafiltration-size exclusion chromatography-based technique is developed, which isolates small EVs ranging from 130 to 220 nm. The result shows higher EVs production in cancerous cells (K7M2) compared to noncancerous cells (NIH/3T3), which increases with longer incubation time and elevated temperature. Mass spectrometry-based proteomic characterization of EVs showed incubation time and temperature-dependent proteomic profile. A set of enriched EV proteins were identified in EVs isolated at nutrient-stress (72 h incubation time) and heat-stress (40 °C incubation temperature) environment. Enrichment of Serpinb1a in EVs isolated in heat stress was further validated via immunoblot. Gene enrichment analysis revealed that enriched EV proteins following nutrient stress were involved in negative regulation of transcription, response to oxidative stress, and protein folding. Likewise, enriched EV proteins following heat stress were involved in oxaloacetate and aspartate metabolism, and glutamate catabolic process. EVs isolated under nutrient stress showed pro-proliferative activity whereas EVs isolated under heat stress showed anti-proliferative activity. Our results show that incubation time and temperature can alter EV production, its proteomic cargo, and functionality, which can be used to design need-based standard isolation parameters for reproducible EV research.

Indocyanine-type Infrared-820 Encapsulated Polymeric Nanoparticle-Assisted Photothermal Therapy of Cancer.

Organic small-molecule photosensitizers are well-characterized and known for the light-responsive treatment modality including photodynamic therapy. Compared with ultraviolet-visible (UV-vis) light used in conventional photodynamic therapy with organic photosensitizers, near-infrared (NIR) light from 700 to 900 nm is less absorbed and scattered by biological tissue such as hemoglobin, lipids, and water, and thus, the use of NIR excitation can greatly increase the penetration depth and emission. Additionally, NIR light has lower energy than UV-vis that can be beneficial due to less activation of fluorophores present in tissues upon NIR irradiation. However, the low water stability, nonspecific distribution, and short circulation half-life of the organic photosensitizers limit its broad biological application. NIR responsive small-molecule fluorescent agents are the focus of extensive research for combined molecular imaging and hyperthermia. Recently a new class of NIR dye, IR-820 with excitation and emission wavelengths of 710 and 820 nm, has been developed and explored as an alternative platform to overcome some of the limitations of the most commonly used gold nanoparticles for photothermal therapy of cancer. Herein, we synthesized a core-shell biocompatible nanocarrier envelope made up of a phospholipid conjugated with poly(ethylene glycol) as a shell, while poly(lactic glycolic acid) (PLGA) was used as a core to encapsulate IR-820 dye. The IR-820-loaded nanoparticles were prepared by nanoprecipitation and characterized for their physicochemical properties and photothermal efficiency. These nanoparticles were monodispersed and highly stable in physiological pH with the hydrodynamic size of 103 ± 8 nm and polydispersity index of 0.163 ± 0.031. The IR-820-loaded nanocarrier showed excellent biocompatibility in the dark, whereas remarkable phototoxicity was observed with breast cancer cells (MCF-7) upon NIR laser excitation. Therefore, the IR-820-loaded phospholipid mimicking biodegradable lipid-polymer composite nanoparticles could have great potential for cancer theranostics.

Re-engineered imaging agent using biomimetic approaches.

Recent progress in biomedical technology, the clinical bioimaging, has a greater impact on the diagnosis, treatment, and prevention of disease, especially by early intervention and precise therapy. Varieties of organic and inorganic materials either in the form of small molecules or nano-sized materials have been engineered as a contrast agent (CA) to enhance image resolution among different tissues for the detection of abnormalities such as cancer and vascular occlusion. Among different innovative imaging agents, contrast agents coupled with biologically derived endogenous platform shows the promising application in the biomedical field, including drug delivery and bioimaging. Strategy using biocomponents such as cells or products of cells as a delivery system predominantly reduces the toxic behavior of its cargo, as these systems reduce non-specific distribution by navigating its cargo toward the targeted location. The hypothesis is that depending on the original biological role of the naïve cell, the contrast agents carried by such a system can provide corresponding natural designated behavior. Therefore, by combining properties of conventional synthetic molecules and nanomaterials with endogenous cell body, new solutions in the field of bioimaging to overcome biological barriers have been offered as innovative bioengineering. In this review, we will discuss the engineering of cell and cell-derived components as a delivery system for various contrast agents to achieve clinically relevant contrast for diagnosis and study underlining mechanism of disease progression. This article is categorized under: Nanotechnology Approaches to Biology > Cells at the Nanoscale Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Biocompatible FePO4 Nanoparticles: Drug Delivery, RNA Stabilization, and Functional Activity.

FePO4 NPs are of special interest in food fortification and biomedical imaging because of their biocompatibility, high bioavailability, magnetic property, and superior sensory performance that do not cause adverse organoleptic effects. These characteristics are desirable in drug delivery as well. Here, we explored the FePO4 nanoparticles as a delivery vehicle for the anticancer drug, doxorubicin, with an optimum drug loading of 26.81% ± 1.0%. This loading further enforces the formation of Fe3+ doxorubicin complex resulting in the formation of FePO4-DOX nanoparticles. FePO4-DOX nanoparticles showed a good size homogeneity and concentration-dependent biocompatibility, with over 70% biocompatibility up to 80 µg/mL concentration. Importantly, cytotoxicity analysis showed that Fe3+ complexation with DOX in FePO4-DOX NPs enhanced the cytotoxicity by around 10 times than free DOX and improved the selectivity toward cancer cells. Furthermore, FePO4 NPs temperature-stabilize RNA and support mRNA translation activity showing promises for RNA stabilizing agents. The results show the biocompatibility of iron-based inorganic nanoparticles, their drug and RNA loading, stabilization, and delivery activity with potential ramifications for food fortification and drug/RNA delivery.

Global Trends in Cancer Nanotechnology: A Qualitative Scientific Mapping Using Content-Based and Bibliometric Features for Machine Learning Text Classification.

This study presents a new way to investigate comprehensive trends in cancer nanotechnology research in different countries, institutions, and journals providing critical insights to prevention, diagnosis, and therapy. This paper applied the qualitative method of bibliometric analysis on cancer nanotechnology using the PubMed database during the years 2000-2021. Inspired by hybrid medical models and content-based and bibliometric features for machine learning models, our results show cancer nanotechnology studies have expanded exponentially since 2010. The highest production of articles in cancer nanotechnology is mainly from US institutions, with several countries, notably the USA, China, the UK, India, and Iran as concentrated focal points as centers of cancer nanotechnology research, especially in the last five years. The analysis shows the greatest overlap between nanotechnology and DNA, RNA, iron oxide or mesoporous silica, breast cancer, and cancer diagnosis and cancer treatment. Moreover, more than 50% of the information related to the keywords, authors, institutions, journals, and countries are considerably investigated in the form of publications from the top 100 journals. This study has the potential to provide past and current lines of research that can unmask comprehensive trends in cancer nanotechnology, key research topics, or the most productive countries and authors in the field.

Zn-based physiometacomposite nanoparticles: distribution, tolerance, imaging, and antiviral and anticancer activity.

The aim of this study was to investigate the distribution, tolerance, and anticancer and antiviral activity of Zn-based physiometacomposites (PMCs). Manganese, iron, nickel and cobalt-doped ZnO, ZnS or ZnSe were synthesized. Cell uptake, distribution into 3D culture and mice, and biochemical and chemotherapeutic activity were studied by fluorescence/bioluminescence, confocal microscopy, flow cytometry, viability, antitumor and virus titer assays. Luminescence and inductively coupled plasma mass spectrometry analysis showed that nanoparticle distribution was liver >spleen >kidney >lung >brain, without tissue or blood pathology. Photophysical characterization as ex vivo tissue probes and LL37 peptide, antisense oligomer or aptamer delivery targeting RAS/Ras binding domain (RBD) was investigated. Treatment at 25 µg/ml for 48 h showed ≥98-99% cell viability, 3D organoid uptake, 3-log inhibition of ß-Galactosidase and porcine reproductive respiratory virus infection. Data support the preclinical development of PMCs for imaging and delivery targeting cancer and infectious disease.

Iron(iii) chelated paramagnetic polymeric nanoparticle formulation as a next-generation T 1-weighted MRI contrast agent.

Magnetic resonance imaging (MRI) is a routinely used imaging technique in medical diagnostics. To enhance the quality of MR images, contrast agents (CAs) are used, which account for nearly 40% of MRI exams in the clinic globally. The most used CAs are gadolinium-based CAs (GBCAs) but the use of GBCAs has been linked with metal-deposition in vital organs. Gadolinium deposition has been shown to be correlated with nephrogenic systemic fibrosis, a fibrosis of the skin and internal organs. Therefore, there is an unmet need for a new CA alternative to GBCAs for T 1-weighted Ce-MRI. Herein, we designed paramagnetic ferric iron(iii) ion-chelated poly(lactic-co-glycolic)acid nanoparticle formulation and routinely examined their application in Ce-MRI using clinical and ultra-high-field MRI scanners. Nanoparticles were monodispersed and highly stable at physiological pH over time with the hydrodynamic size of 130 ± 12 nm and polydispersity index of 0.231 ± 0.026. The T 1-contrast efficacy of the nanoparticles was compared with commercial agent gadopentetate dimeglumine, called Magnevist®, in aqueous phantoms in vitro and then validated in vivo by visualizing an angiographic map in a clinical MRI scanner. Relaxivities of the nanoparticles in an aqueous environment were r 1 = 10.59 ± 0.32 mmol-1 s-1 and r 1 = 3.02 ± 0.14 mmol-1 s-1 at 3.0 T and 14.1 T measured at room temperature and pH 7.4, respectively. The clinically relevant magnetic field relaxivity is three times higher compared to the Magnevist®, a clinical GBCA, signifying its potential applicability in clinical settings. Moreover, iron is an endogenous metal with known metabolic safety, and the polymer and phospholipids used in the nanoconstruct are biodegradable and biocompatible components. These properties further put the proposed T 1 agent in a promising position in contrast-enhanced MRI of patients with any disease conditions.

Strategic reconstruction of macrophage-derived extracellular vesicles as a magnetic resonance imaging contrast agent.

A contrast agent (CA) in magnetic resonance imaging (MRI) is now an essential add-on to obtain high-quality contrast-enhanced anatomical images for disease diagnosis and monitoring the treatment response. However, the rapid elimination of CAs by the immune system and excretion by the renal route has limited its application. As a result, the CA dose for effective contrast is ever-increasing, resulting in toxic side effects such as gadolinium (Gd) related nephrogenic systemic fibrosis (NSF) toxicity. Considering the widespread application of Gd-based CAs, it is now very important to revisit their formulation in order to improve their local concentration and minimize their dose while achieving clinical goals. Therefore, we have adapted a unique strategy to maximize Gd delivery to the target site using macrophage cell-derived extracellular vesicles (EVs) reconstructed with a Gd-conjugated liposomal system herein called gadolinium infused hybrid EVs (Gd-HEVs). We hypothesize that Gd-HEVs, owing to the presence of immune cell-derived EV protein cargo, can effectively disguise themselves as a biological entity, prolong the retention time for contrast enhancement, and show tumor specificity. Incorporation of Gd into nanoformulations can enhance the longitudinal relaxivity r1 by reducing the tumbling rate of paramagnetic metal complexes. Here, Gd-HEVs showed a higher r1 relaxivity of 9.86 mM-1 s-1 compared to 3.98 mM-1 s-1 of Magnevist® at an equivalent Gd concentration, when measured by clinical 3T MRI. This will allow us to reduce the clinically used Gd concentration about three-fold while maintaining contrast in the clinical window thereby supporting our hypothesis. Furthermore, Gd-HEVs showed a preferential cellular interaction and accumulation towards cancer cells compared to non-cancer cells, both in vitro and in vivo. More importantly, Gd-HEVs showed excellent contrast enhancement in the blood vasculature with a higher retention time compared to its counterpart, Magnevist®. Our study successfully showed that the incorporation of Gd in the EV framework can help to enhance the contrast ability, and therefore it can be a platform technology for the development of safer MRI contrast agents.

pH-responsive cationic liposome for endosomal escape mediated drug delivery.

Endosomal degradation of the nanoparticle is one of the major biological barriers associated with the drug delivery system. Nanoparticles are internalized in the cell via different endocytosis pathways, where they are first delivered to early endosomes which mature to the late endosome and to the lysosome. During this journey, NP encounters a harsh chemical environment resulting in the degradation of NP and its content. This process is collectively called as intracellular defenses against foreign materials. Therefore, to avoid this degradative fate, the endosomal escape technique has been explored following membrane fusion or membrane destabilization mechanisms. However, these methods are limited to the application due to non-specific membrane fusion. To overcome this limitation, we have designed pH-responsive liposome made up of 3ß-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol hydrochloride (DC-liposome) in which the cationic nitrogen of the ammonium moiety occupies only ∼2.5 % of the molecule. Such a small percentage of the cationic moiety is sufficient enough to exhibit pH-responsive properties while maintaining the biocompatibility of the DC-liposome. DC-liposome showed pH-dependent cationic properties due to the protonation of DC-moiety at acidic pH. The fluorescence-based experiment confirmed pH-dependent fusogenic properties of DC-liposome. Furthermore, the endosomal colocalization study revealed higher localization of DC-liposome in the early endosome compared to that of the late endosome, suggesting possible endosomal escape. Elevated cationic and fusogenic properties of DC-liposome at acidic pH can mediate membrane fusion with anionic endosomal membrane via electrostatic interaction, thereby causing endosomal escape. Moreover, doxorubicin-loaded DC-liposome showed higher cytotoxicity than that of free doxorubicin further supporting our clam of endosomal escape. These findings suggest the potential of DC-liposome to break the endosomal barriers to enhance the therapeutic efficacy thereby guiding us in design consideration in the field of stimuli-responsive delivery agents.

Amino/Amido Conjugates Form to Nanoscale Cobalt Physiometacomposite (PMC) Materials Functionally Delivering Nucleic Acid Therapeutic to Nucleus Enhancing Anticancer Activity via Ras-Targeted Protein Interference.

Aberrant splicing and protein interaction of Ras binding domain (RBD) are associated with melanoma drug resistance. Here, cobalt or nickel doped zinc oxide (ZnO) physiometacomposite (PMC) materials bind to RNA and peptide shown by Ninhydrin staining, UV-vis, Fourier transform infrared, and circular dichroism spectroscopy. PMCs deliver splice switching oligomer (SSO) into melanoma cells or 3-D tumor spheroids shown by flow cytometry, fluorescence microscopy, and bioluminescence. Stability in serum, liver, or tumor homogenate up to 48 h and B16F10 melanoma inhibition ≥98-99% is shown. These data suggest preclinical potential of PMC for delivery of SSO, RBD, or other nucleic acid therapeutic and anticancer peptides.

Integration of gadolinium in nanostructure for contrast enhanced-magnetic resonance imaging.

Magnetic resonance imaging (MRI) is a routinely used imaging technique in medical diagnostics, which is further enhanced with the use of contrast agents (CAs). The most commonly used CAs are gadolinium-based contrast agents (GBCAs), in which gadolinium (Gd) is chelated with organic chelating agents (linear or cyclic). However, the use of GBCA is related to toxic side effect due to the release of free Gd3+ ions from the chelating agents. The repeated use of GBCAs has led to Gd deposition in various major organs including bone, brain, and kidneys. As a result, the use of GBCA has been linked to the development of nephrogenic systemic fibrosis (NSF). Due to the GBCA associated toxicities, some clinically approved GBCAs have been limited or revoked recently. Therefore, there is an urgent need for the development of new strategies to chelate and stabilize Gd3+ ions for contrast enhancement, safety profile, and selective imaging of a pathological site. Toward this endeavor, GBCAs have been engineered using different nanoparticulate systems to improve their stability, biocompatibility, and pharmacokinetics. Throughout this review, some of the important strategies for engineering small molecular Gd3+ chelates into a nanoconstruct is discussed. We focus on the development of GBCAs as liposomes, mesoporous silica nanoparticles (MSNs), polymeric nanocarriers, and plasmonic nanoparticles-based design strategies to improve safety and contrast enhancement for contrast enhanced-magnetic resonance imaging (Ce-MRI). We also discuss the in-vitro/in-vivo properties of strategically designed nanoscale MRI CAs, its potentials, and limitations. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Diagnostic Tools > Diagnostic Nanodevices Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials.

Biodistribution of gadolinium- and near infrared-labeled human umbilical cord mesenchymal stromal cell-derived exosomes in tumor bearing mice.

We speculate that exosomes derived from human umbilical cord mesenchymal stromal cells (HUC-MSCs) will accumulate within tumors and have the potential for both tumor location or drug delivery. Methods: To determine proof of concept, HUC-MSC exosomes were labeled with an MRI contrast agent, gadolinium, or a near infrared dye. Exosome accumulation within ectopic osteosarcoma tumor-bearing mice was determined by 14.1 T MRI or bioimaging over 24-48 h after injection. In vitro studies examine the accumulation and physiological effect of exosomes on human and mouse osteosarcoma cell lines by MTT assay, confocal microscopy, and flow cytometry. Results: Systemic HUC-MSC exosomes accumulated continuously in tumor over a 24-48 h post-injection period. In contrast, synthetic lipid nanoparticles accumulate in tumor only for the first 3 h post-injection. Conclusion: These results suggest that HUC-MSCs exosomes accumulate within human or mouse osteosarcoma cells in vitro and in vivo over a 24 to 48 h after infusion.

Macrophage-derived exosome-mimetic hybrid vesicles for tumor targeted drug delivery.

Extracellular vesicles (EVs) are phospholipid and protein constructs which are continuously secreted by cells in the form of smaller (30-200 nm) and larger (micron size) particles. While all of these vesicles are called as EVs, the smaller size are normally called as exosomes. Small EVs (sEVs) have now been explored as a potential candidate in therapeutics delivery owing to their endogenous functionality, intrinsic targeting property, and ability to cooperate with a host defense mechanism. Considering these potentials, we hypothesize that immune cell-derived sEVs can mimic immune cell to target cancer. However, different sEVs isolation technique reported poor yield and loss of functional properties. To solve this problem, herein we hybridized sEVs with synthetic liposome to engineer vesicles with size less than 200 nm to mimic the size of exosome and named as hybrid exosome (HE). To achieve this goal, sEVs from mouse macrophage was hybridized with synthetic liposome to engineer HE. The fluorescence-based experiment confirmed the successful hybridization process yielding HE with the size of 177 ±â€¯21 nm. Major protein analysis from Blot techniques reveal the presence of EV marker proteins CD81, CD63, and CD9. Differential cellular interaction of HE was observed when treated with normal and cancerous cells thereby supporting our hypothesis. Moreover, a water-soluble doxorubicin was loaded in HE. Drug-loaded HE showed enhanced toxicity against cancer cells and pH-sensitive drug release in acidic condition, benefiting drug delivery to acidic cancer environment. These results suggest that the engineered HE would be an exciting platform for tumor-targeted drug delivery. STATEMENT OF SIGNIFICANCE: Extracellular vesicles (EVs) are phospholipid and protein constructs which are continuously secreted by cells in the human body. These vesicles can efficiently deliver their parental biomolecules to the recipient cells and assist in intracellular communication without a direct cell-to-cell contact. Moreover, they have the ability to perform some of the molecular task similar to that of its parent cells. For example, exosome derived from immune cells can seek for diseased and/or inflammatory cells by reading the cell surface proteins. However, different EVs isolation techniques reported poor yield and loss of functional properties. Therefore, to overcome this limitation, we herein propose to re-engineer immuno-exosome with a synthetic liposome as a refined biomimetic nanostructure for the delivery of doxorubicin (clinical drug) for breast cancer treatment.

Biomimetic surface modification of discoidal polymeric particles.

The rationale for the design of drug delivery nanoparticles is traditionally based on co-solvent self-assembly following bottom-up approaches or in combination with top-down approaches leading to tailored physiochemical properties to regulate biological responses. However, the optimal design and control of material properties to achieve specific biological responses remain the central challenge in drug delivery research. Considering this goal, we herein designed discoidal polymeric particles (DPPs) whose surfaces are re-engineered with isolated red blood cell (RBC) membranes to tailor their pharmacokinetics. The RBC membrane-coated DPPs (RBC-DPPs) were found to be biocompatible in cell-based in vitro experiments and exhibited extended blood circulation half-life. They also demonstrated unique kinetics at later time points in a mouse model compared to that of bare DPPs. Our results suggested that the incorporation of biomimicry would enable the biomimetic particles to cooperate with systems in the body such as cells and biomolecules to achieve specific biomedical goals.

The influence of polyethylene glycol passivation on the surface plasmon resonance induced photothermal properties of gold nanorods.

Gold nanorods (AuNRs) possess unique photothermal properties due to their strong plasmonic absorption in the near-infrared region of the electromagnetic spectrum. They have been explored widely as an alternative or a complement to chemotherapy in cancer treatment. However, the use of AuNRs as an injectable medicine is greatly hindered by their stability in biological media. Therefore, studies have been focused on improving the stability of AuNRs by introducing biocompatible surface functionalizations such as polyethylene glycol (PEG) coatings. However, these coatings can affect heat conduction and alter their photothermal behavior. Herein, we studied how functionalization of AuNRs with PEG chains of different molecular weights determined the temperature distribution of suspensions under near-infrared irradiation, cell uptake in vitro, and hyperthermia-induced cytotoxicity. Thermogravimetric analysis of the PEG-conjugated AuNRs exhibited slightly different PEG mass fractions of 12.0%, 12.7%, and 18.5% for PEG chains with molecular weights of 2, 5, and 10 kDa, respectively, implying distinct structures for PEG brushes. When exposed to near-infrared radiation, we found greater temperatures and temperature gradients for longer PEG chains, while rapid aggregation was observed in unmodified (raw) AuNRs. The effect of the PEG coating on heat transport was investigated using molecular dynamics simulations, which revealed the atomic scale structure of the PEG brushes and demonstrated lower thermal conductivity for PEG-coated AuNRs than for unmodified AuNRs. We also characterized the uptake of the AuNRs into mouse melanoma cells in vitro and determined their ability to kill these cells when subjected to near-infrared radiation. For all PEG-coated AuNRs, exposure to 10 s of near-infrared radiation significantly reduced cell viability relative to unirradiated controls, with this viability further decreasing with increasing AuNR doses, indicating potential phototherapeutic effects. The 5 kDa PEG coating appeared to yield the best performance, yielding significant phototoxicity at even the lowest dose considered (0.5 µg mL-1), while also exhibiting high colloidal stability, which could help in rational design consideration of AuNRs for NIR induced photothermal therapy.

Natural killer cell membrane infused biomimetic liposomes for targeted tumor therapy.

Therapeutic efficacy of a systemic drug delivery largely depends on the targeting design of the delivery system, which tackles with circulatory traffic and prevents the nonspecific distribution of the drug in the wide range of vital organs. A drawing attention has been given to a biomimetic cloaking of the synthetic drug delivery nanoparticle using mammalian cell-ghosts, which has shown the installment of the biological complexity of the original cells thereby acting as naïve cells, to precisely delivery drug to the intended target. Align towards this direction; we developed a membrane camouflage fusogenic liposomal delivery system "NKsome" for targeted tumor therapy using Natural Killer (NK) cell-ghost, which naturally undergoes immunosurveillance of diseased/stress cells. The engineered NKsome shows successful retention of NK cell membrane-associated targeting protein on its surface. With its excellent biocompatibility, NKsome shows a higher affinity towards cancer than normal cells as demonstrated by in vitro flow-passage assay, and exhibits enhanced tumor homing efficiency in-vivo with an extended plasma residence time of 18 h. Moreover, the therapeutic potential of doxorubicin-loaded NKsome shows promising antitumor activity in vivo against MCF-7 induced tumor model. Overall results illustrate the therapeutic advantages of NK cell biomimicry capable of communicating like immune cells for cooperative drug delivery.

Nano-confinement-driven enhanced magnetic relaxivity of SPIONs for targeted tumor bioimaging.

Superparamagnetic iron oxide nanoparticles (SPIONs) are highly biocompatible and have a versatile synthetic technique based on coprecipitation, reduction-precipitation, and hydrothermal methods, where Fe3+ and Fe2+ react in aqueous solutions; both these ions are present in our body and have clear metabolic pathways; therefore, they have attracted extensive research interest and development in the field of diagnostic imaging and therapy. However, most SPION-based clinical diagnostic contrast agents are discontinued due to severe pain, low transverse magnetic relaxivity range of 80-180 mM-1 s-1, shorter circulation half-life, and lack of disease specificity. Therefore, in this study, we engineered a bone cancer-targeted hybrid nanoconstruct (HNC) with a high transverse magnetic relaxivity of 625 mM-1 s-1, which was significantly higher than that of clinical contrast agents. The engineered HNC is peripherally decorated with a bone-seeking agent, alendronic acid-conjugated phospholipid, exhibiting a hydrodynamic size of 80 nm with a negative surface potential, -35 mV. The interior skeleton of the HNC is composed of biodegradable and biocompatible poly(l-lactic-co-glycolic acid) (PLGA), in which 5 nm SPIONs are confined. We have successfully tuned the distance between the confined SPIONs from 0.5 to 4 nm, as revealed by transmission electron microscopy (TEM) images and magnetic resonance image (MRI) phantoms. This cluster confinement dramatically enhances magnetic relaxivity possibly due to the increase in net local magnetization due to proximal field inhomogeneity. In an in vitro examination, 80% of HNC is found to bind with hydroxyapatite (HAp), which when characterized by TEM shows a painting of SPIONs over a HAp crystal. HNC is found to accumulate in mouse osteosarcoma tumor (K7M2 tumor model); both MRI and histological examination of the tumor show the potential of HNC as targeting agents for diagnosis of tumor in the bone.

Drug Delivery Nanoparticles with Locally Tunable Toxicity Made Entirely from a Light-Activatable Prodrug of Doxorubicin.

PURPOSE: A major challenge facing nanoparticle-based delivery of chemotherapy agents is the natural and unavoidable accumulation of these particles in healthy tissue resulting in local toxicity and dose-limiting side effects. To address this issue, we have designed and characterized a new prodrug nanoparticle with controllable toxicity allowing a locally-delivered light trigger to convert the payload of the particle from a low to a high toxicity state. METHODS: The nanoparticles are created entirely from light-activatable prodrug molecules using a nanoprecipitation process. The prodrug is a conjugate of doxorubicin and photocleavable biotin (DOX-PCB). RESULTS: These DOX-PCB nanoparticles are 30 times less toxic to cells than doxorubicin, but can be activated to release pure therapeutic doxorubicin when exposed to 365 nm light. These nanoparticles have an average diameter of around 100 nm and achieve the maximum possible prodrug loading capacity since no support structure or coating is required to prevent loss of prodrug from the nanoparticle. CONCLUSIONS: These light activatable nanoparticles demonstrate tunable toxicity and can be used to facilitate future therapy development whereby light delivered specifically to the tumor tissue would locally convert the nanoparticles to doxorubicin while leaving nanoparticles accumulated in healthy tissue in the less toxic prodrug form.