In vivo Fate of Targeted Drug Delivery Carriers.

This review aimed to systematically investigate the intracellular and subcellular fate of various types of targeting carriers. Upon entering the body via intravenous injection or other routes, a targeting carrier that can deliver therapeutic agents initiates their journey. If administered intravenously, the carrier initially faces challenges presented by the blood circulation before reaching specific tissues and interacting with cells within the tissue. At the subcellular level, the car2rier undergoes processes, such as drug release, degradation, and metabolism, through specific pathways. While studies on the fate of 13 types of carriers have been relatively conclusive, these studies are incomplete and lack a comprehensive analysis. Furthermore, there are still carriers whose fate remains unclear, underscoring the need for continuous research. This study highlights the importance of comprehending the in vivo and intracellular fate of targeting carriers and provides valuable insights into the operational mechanisms of different carriers within the body. By doing so, researchers can effectively select appropriate carriers and enhance the successful clinical translation of new formulations.

Nowadays, scientists are actively researching nanocarrier drugs. After administration via injection or other methods, these drugs experience in the body and reach the target treatment site to relieve or cure symptoms. As research progresses, scientists are gaining more insights into the behavior of nanocarrier drugs in the body, which is useful in developing safer and more effective drugs. Historically, research has focused primarily on the drug itself. However, it is important to understand that the carrier that delivers and protects the drug (often described as the drug sitting in a "car" or under an "umbrella") plays an essential role in the drug's therapeutic effect. This paper aims to highlight the importance of the carrier's role, which is vital for developing new drugs and advancing basic research.

Spatiotemporal fate of nanocarriers-embedded dissolving microneedles: the impact of needle dissolving rate.

OBJECTIVE: Dissolving microneedles (DMNs) have shown great potential for transdermal drug delivery due to their excellent skin-penetrating ability and combination with nanocarriers (NCs) can realize targeted drug delivery. The objective of this study was to investigate the impact of microneedle dissolving rate on the in vivo fate of NC-loaded DMNs, which would facilitate the clinical translation of such systems. METHODS: Solid lipid nanoparticles (SLNs) were selected as the model NC for loading in DMNs, which were labeled by P4 probes with aggregation-quenching properties. Sodium hyaluronate acid (HA) and chitosan (CS), with different aqueous dissolving rates, were chosen as model tip materials. The effects of needle dissolving rate on the in vivo fate of NC-loaded DMNs was investigated by tracking the distribution of fluorescence signals after transdermal exposure. RESULTS: P4 SLNs achieved a deeper diffusion depth of 180 µm in DMN-HA with a faster dissolution rate, while the diffusion depth in DMN-CS with a slower dissolution rate was lower (140 µm). The in vivo experiments demonstrated that P4 SLNs had a T1/2 value of 12.14 h in DMN-HA, whilst a longer retention time was found in DMN-CS, with a T1/2 of 13.12 h. CONCLUSIONS: This study confirmed that the in vivo diffusion rate of NC-loaded DMNs was determined by the dissolving rate of DMNs materials and provided valuable guidance for the design and development of NC-loaded DMNs in the future.

Impact of the diseased lung microenvironment on the in vivo fate of inhaled particles.

Inhalation drug delivery is superior for local lung disease therapy. However, there are several unique absorption barriers for inhaled drugs to overcome, including limited drug deposition at the target site, mucociliary clearance, pulmonary macrophage phagocytosis, and systemic exposure. Moreover, the respiratory disease state can affect or even destroy the physiology of the lung, thus influencing the in vivo fate of inhaled particles compared with that in healthy lungs. Nevertheless, limited information is available on this effect. Thus, in this review, we present pathological changes of the lung microenvironment under varied respiratory diseases and their influence on the in vivo fate of inhaled particles; such insights could provide a basis for rational inhalation particle design based on specific disease states.

The In Vivo Biological Fate of Protein Corona: A Comparative PET Study of the Fate of Soft and Hard Protein Corona in Healthy Animal Models.

Radiolabeling and nuclear imaging techniques are used to investigate the biodistribution patterns of the soft and hard protein corona around poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) after administration to healthy mice. Soft and hard protein coronas of 131I-labeled BSA or 131I-labeled serum are formed on PLGA NPs functionalized with either polyehtylenimine (PEI) or bovine serum albumin (BSA). The exchangeability of hard and soft corona is assessed in vitro by gamma counting exposing PLGA NPs with corona to non-labeled BSA, serum, or simulated body fluid. PEI PLGA NPs form larger and more stable coronas than BSA PLGA NPs. Soft coronas are more exchangeable than hard ones. The in vivo fate of PEI PLGA NPs coated with preformed 18F-labeled BSA hard and soft coronas is assessed by positron emission tomography (PET) following intravenous administration. While the soft corona shows a biodistribution similar to free 18F BSA with high activity in blood and kidney, the hard corona follows patterns characteristic of nanoparticles, accumulating in the lungs, liver, and spleen. These results show that in vivo fates of soft and hard corona are different, and that soft corona is more easily exchanged with proteins from the body, while hard corona is largely retained on the nanoparticle surface.

The Necessity to Investigate In Vivo Fate of Nanoparticle-Loaded Dissolving Microneedles.

Transdermal drug delivery systems are rapidly gaining prominence and have found widespread application in the treatment of numerous diseases. However, they encounter the challenge of a low transdermal absorption rate. Microneedles can overcome the stratum corneum barrier to enhance the transdermal absorption rate. Among various types of microneedles, nanoparticle-loaded dissolving microneedles (DMNs) present a unique combination of advantages, leveraging the strengths of DMNs (high payload, good mechanical properties, and easy fabrication) and nanocarriers (satisfactory solubilization capacity and a controlled release profile). Consequently, they hold considerable clinical application potential in the precision medicine era. Despite this promise, no nanoparticle-loaded DMN products have been approved thus far. The lack of understanding regarding their in vivo fate represents a critical bottleneck impeding the clinical translation of relevant products. This review aims to elucidate the current research status of the in vivo fate of nanoparticle-loaded DMNs and elaborate the necessity to investigate the in vivo fate of nanoparticle-loaded DMNs from diverse aspects. Furthermore, it offers insights into potential entry points for research into the in vivo fate of nanoparticle-loaded DMNs, aiming to foster further advancements in this field.

Current research trends of nanomedicines.

Owing to the inherent shortcomings of traditional therapeutic drugs in terms of inadequate therapeutic efficacy and toxicity in clinical treatment, nanomedicine designs have received widespread attention with significantly improved efficacy and reduced non-target side effects. Nanomedicines hold tremendous theranostic potential for treating, monitoring, diagnosing, and controlling various diseases and are attracting an unfathomable amount of input of research resources. Against the backdrop of an exponentially growing number of publications, it is imperative to help the audience get a panorama image of the research activities in the field of nanomedicines. Herein, this review elaborates on the development trends of nanomedicines, emerging nanocarriers, in vivo fate and safety of nanomedicines, and their extensive applications. Moreover, the potential challenges and the obstacles hindering the clinical translation of nanomedicines are also discussed. The elaboration on various aspects of the research trends of nanomedicines may help enlighten the readers and set the route for future endeavors.

Intravenous nanocrystals: fabrication, solidification, in vivo fate, and applications for cancer therapy.

INTRODUCTION: Intravenous nanocrystals (INCs) have shown intrinsic advantages in antitumor applications, particularly their properties of high drug loading, low toxicity, and controllable size. Therefore, it has a very bright application prospect as a drug delivery system. AREAS COVERED: The ideal formulation design principles, fabrication, solidification, in vivo fate of INCs, the applications in drug delivery system (DDS) and the novel applications are covered in this review. EXPERT OPINION: It is vital to select a suitable formulation and fabrication method to produce a stable and sterile INCs. Besides, the type of stabilizers and physical characteristics can also influence the in vivo fate of INCs, which is worthy of further studying. Based on wide researches about applications of INCs in cancer, biomimetic INCs are concerned increasingly for its favorable compatibility. The output of these studies suggested that INCs-based drug delivery could be a novel strategy for addressing the delivery of the drug that faces solubility, bioavailability, and toxicity problems.

FRET-based analysis on the structural stability of polymeric micelles: Another key attribute beyond PEG coverage and particle size affecting the blood clearance.

Various attributes of micelles, such as PEG density and particle size, are considered to be related to blood clearance. The structural stability of micelles is another key attribute that will affect the in vivo fate. This study employed fluorescence resonance energy transfer (FRET) analysis to guide the preparation of polymeric micelles with different structural stability. Micelles prepared using copolymers with longer hydrophobic blocks showed higher structural stability; emulsification was a better method than nanoprecipitation to prepare stable micelles. The fast chain exchange kinetics and the high-water content of micellar cores explained the low structural stability of those micelles. Moreover, this study highlighted the importance of structural stability that affected blood clearance in concert with PEG length and particle size. One-third of the small and stable micelles were detected in the blood 24 h after injection. While unstable micelles would be cleared from the circulation within 4 h. Notably, there would be a threshold of structural stability. Micelles with structural stability below this threshold were quickly cleared even if they possessed a longer PEG length and a smaller size. In contrast, higher structural stability allowed polymeric micelles to maintain higher integrity in vivo and enhance tumor accumulation and anti-tumor efficacy. In conclusion, this study systematically analyzed the importance of the structural stability of micelles on the in vivo fate.

The feasibility of oral targeted drug delivery: Gut immune to particulates?

Targeted drug delivery is constantly updated with a better understanding of the physiological and pathological features of various diseases. Depending on high safety, good compliance and many other undeniable advantages, attempts have been undertaken to complete an intravenous-to-oral conversion of targeted drug delivery. However, oral delivery of particulates to systemic circulation is highly challenging due to the biochemical aggressivity and immune exclusion in the gut that restrain absorption and access to the bloodstream. Little is known about the feasibility of targeted drug delivery via oral administration (oral targeting) to a remote site beyond the gastrointestinal tract. To this end, this review proactively contributes to a special dissection on the feasibility of oral targeting. We discussed the theoretical basis of oral targeting, the biological barriers of absorption, the in vivo fate and transport mechanisms of drug vehicles, and the effect of structural evolution of vehicles on oral targeting as well. At last, a feasibility analysis on oral targeting was performed based on the integration of currently available information. The innate defense of intestinal epithelium does not allow influx of more particulates into the peripheral blood through enterocytes. Therefore, limited evidence and lacking exact quantification of systemically exposed particles fail to support much success with oral targeting. Nevertheless, the lymphatic pathway may serve as a potentially alternative portal of peroral particles into the remote target sites via M-cell uptake.

Nanosuspensions technology as a master key for nature products drug delivery and In vivo fate.

The drug nanosuspensions is a universal formulation approach for improved drug delivery of hydrophobic drugs and one the most promising approaches for increasing the biopharmaceutical performance of poorly water-soluble drug substances, especially for nature products. This review aimed to summarize the nanosuspensions preparation approaches and the main technological difficulties encountered in nanosuspensions development, such as guidelines for stabilizers screening, in vivo fate of the intravenously administrated nanosuspensions, and how to realize the intravenously target delivery was reviewed. Furthermore, challenges of nanosuspensions for the nature products delivery also was discussed and commented. Therefore, it hoped to provide reference and assistance for the nanosuspensions production, stabilizers usage, and predictability of in vivo fate and controllability of targeting delivery of the nature products nanosuspensions.

Demonstrating Biological Fate of Nanoparticle-Loaded Dissolving Microneedles with Aggregation-Caused Quenching Probes: Influence of Application Sites.

Integrating dissolving microneedles (DMNs) and nanocarriers (NC) holds great potential in transdermal drug delivery because it can simultaneously overcome the stratum corneum barrier and achieve efficient and controlled drug delivery. However, different skin sites with different thicknesses and compositions can affect the transdermal diffusion of NC-loaded DMNs. There are few reports on the biological fate (especially transdermal diffusion) of NC-loaded DMNs, and inaccurate bioimaging information of intact NC limits the accurate understanding of the in vivo fate of NC-loaded DMNs. The aggregation-caused quenching (ACQ) probes P4 emitted intense fluorescence signals in intact NC while quenched after the degradation of NC, had been demonstrated the feasibility of label intact NC. In this study, P4 was loaded in solid lipid nanoparticles (SLNs), and further encapsulated into DMNs, to track the transdermal diffusion of SLNs delivered at different skin sites. The results showed that SLNs had excellent stability after being loaded into DMNs with no significant changes in morphology and fluorescence properties. The in vivo live and ex vivo imaging showed that the transdermal diffusion rate of NC-loaded DMNs was positively correlated with skin thickness, with the order ear > abdomen > back. In conclusion, this study confirmed the site-dependency of transdermal diffusion in NC-loaded DMNs.

Current research trends of nanomedicines

Owing to the inherent shortcomings of traditional therapeutic drugs in terms of inadequate therapeutic efficacy and toxicity in clinical treatment, nanomedicine designs have received widespread attention with significantly improved efficacy and reduced non-target side effects. Nanomedicines hold tremendous theranostic potential for treating, monitoring, diagnosing, and controlling various diseases and are attracting an unfathomable amount of input of research resources. Against the backdrop of an exponentially growing number of publications, it is imperative to help the audience get a panorama image of the research activities in the field of nanomedicines. Herein, this review elaborates on the development trends of nanomedicines, emerging nanocarriers, in vivo fate and safety of nanomedicines, and their extensive applications. Moreover, the potential challenges and the obstacles hindering the clinical translation of nanomedicines are also discussed. The elaboration on various aspects of the research trends of nanomedicines may help enlighten the readers and set the route for future endeavors.

The feasibility of oral targeted drug delivery: Gut immune to particulates?

Targeted drug delivery is constantly updated with a better understanding of the physiological and pathological features of various diseases. Depending on high safety, good compliance and many other undeniable advantages, attempts have been undertaken to complete an intravenous-to-oral conversion of targeted drug delivery. However, oral delivery of particulates to systemic circulation is highly challenging due to the biochemical aggressivity and immune exclusion in the gut that restrain absorption and access to the bloodstream. Little is known about the feasibility of targeted drug delivery via oral administration (oral targeting) to a remote site beyond the gastrointestinal tract. To this end, this review proactively contributes to a special dissection on the feasibility of oral targeting. We discussed the theoretical basis of oral targeting, the biological barriers of absorption, the in vivo fate and transport mechanisms of drug vehicles, and the effect of structural evolution of vehicles on oral targeting as well. At last, a feasibility analysis on oral targeting was performed based on the integration of currently available information. The innate defense of intestinal epithelium does not allow influx of more particulates into the peripheral blood through enterocytes. Therefore, limited evidence and lacking exact quantification of systemically exposed particles fail to support much success with oral targeting. Nevertheless, the lymphatic pathway may serve as a potentially alternative portal of peroral particles into the remote target sites via M-cell uptake.

Ionic co-aggregates (ICAs) based oral drug delivery: Solubilization and permeability improvement.

Due to the overwhelming percentage of poorly water-soluble drugs, pharmaceutical industry is in urgent need of efficient approaches for solubilization and permeability improvement. Salts consisting of lipophilic fatty acid anions and hydrophilic choline cations are found to be surface active and able to form ionic co-aggregates (ICAs) in water. Choline oleate-based ICAs significantly enhance oral absorption of paclitaxel (PTX) as compared with cremophor EL-based micelles (MCs). Aggregation-caused quenching probes enable tracking of intact ICAs in in vivo transport and cellular interaction. Prolonged intestinal retention of ICAs than MCs implies stronger solubilizing capability in vivo. Ex vivo imaging of major organs and intestinal tracts suggests transepithelial transport of intact ICAs. Cellular studies support the enhanced absorption of PTX and transmembrane transport of intact ICAs. In conclusion, ICAs, consisting of lipophilic ions and hydrophilic counter-ions, are of great potential in delivery of poorly water-soluble drugs by enhancing solubility and permeability.

The in vivo fate of polymeric micelles.

This review aims to provide a systemic analysis of the in vivo, as well as subcellular, fate of polymeric micelles (PMs), starting from the entry of PMs into the body. Few PMs are able to cross the biological barriers intact and reach the circulation. In the blood, PMs demonstrate fairly good stability mainly owing to formation of protein corona despite controversial results reported by different groups. Although the exterior hydrophilic shells render PMs "long-circulating", the biodistribution of PMs into the mononuclear phagocyte systems (MPS) is dominant as compared with non-MPS organs and tissues. Evidence emerges to support that the copolymer poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) is first broken down into pieces of PEG and PLA and then remnants to be eliminated from the body finally. At the cellular level, PMs tend to be internalized via endocytosis due to their particulate nature and disassembled and degraded within the cell. Recent findings on the effect of particle size, surface characteristics and shape are also reviewed. It is envisaged that unraveling the in vivo and subcellular fate sheds light on the performing mechanisms and gears up the clinical translation of PMs.

Cell-based drug delivery systems and their in vivo fate.

Cell-based drug delivery systems (DDSs) have received attention recently because of their unique biological properties and self-powered functions, such as excellent biocompatibility, low immunogenicity, long circulation time, tissue-homingcharacteristics, and ability to cross biological barriers. A variety of cells, including erythrocytes, stem cells, and lymphocytes, have been explored as functional vectors for the loading and delivery of various therapeutic payloads (e.g., small-molecule and nucleic acid drugs) for subsequent disease treatment. These cell-based DDSs have their own unique in vivo fates, which are attributed to various factors, including their biological properties and functions, the loaded drugs and loading process, physiological and pathological circumstances, and the body's response to these carrier cells, which result in differences in drug delivery efficiency and therapeutic effect. In this review, we summarize the main cell-based DDSs and their biological properties and functions, applications in drug delivery and disease treatment, and in vivo fate and influencing factors. We envision that the unique biological properties, combined with continuing research, will enable development of cell-based DDSs as friendly drug vectors for the safe, effective, and even personalized treatment of diseases.

Starch-based carriers of paclitaxel: A systematic review of carriers, interactions, and mechanisms.

Paclitaxel, a clinical chemotherapy drug commonly used in the past few years, is greatly limited by its low therapeutic index. Starch and its derivatives have gained wide interest from researchers owing to their unique hydrophilic and hydrophobic properties resulting from their various modifications, which exert the effect-enhancing and toxicity-reducing activity to paclitaxel in vivo and in vitro. This review summarizes the research progress toward different kinds of starch-based carriers, whether oral or injectable. In addition, we discuss the complex properties of starch derivatives toward physically complexed or chemically conjugated paclitaxel. The corresponding complex configurations are suggested. Starch-based carriers can act as permeability enhancers because they may interact with the unstirred water layer that separates hydrophobic drugs from biological membranes, even altering the barrier properties of the membrane. The information presented in this review may be used as a reference for future hydrophobic drug carrier studies.

The long-circulating effect of pegylated nanoparticles revisited via simultaneous monitoring of both the drug payloads and nanocarriers.

The long-circulating effect is revisited by simultaneous monitoring of the drug payloads and nanocarriers following intravenous administration of doxorubicin (DOX)-loaded methoxy polyethylene glycol-polycaprolactone (mPEG-PCL) nanoparticles. Comparison of the kinetic profiles of both DOX and nanocarriers verifies the long-circulating effect, though of limited degree, as a result of pegylation. The nanocarrier profiles display fast clearance from the blood despite dense PEG decoration; DOX is cleared faster than the nanocarriers. The nanocarriers circulate longer than DOX in the blood, suggesting possible leakage of DOX from the nanocarriers. Hepatic accumulation is the highest among all organs and tissues investigated, which however is reversely proportionate to blood circulation time. Pegylation and reduction in particle size prove to extend circulation of drug nanocarriers in the blood with simultaneous decrease in uptake by various organs of the mononuclear phagocytic system. It is concluded that the long-circulating effect of mPEG-PCL nanoparticles is reconfirmed by monitoring of either DOX or the nanocarriers, but the faster clearance of DOX suggests possible leakage of a fraction of the payloads. The findings of this study are of potential translational significance in design of nanocarriers towards optimization of both therapeutic and toxic effects.

The effects of protein corona on in vivo fate of nanocarriers.

With the emerging advances in utilizing nanocarriers for biomedical applications, a molecular-level understanding of the in vivo fate of nanocarriers is necessary. After administration into human fluids, nanocarriers can attract proteins onto their surfaces, forming an assembled adsorption layer called protein corona (PC). The formed PC can influence the physicochemical properties and subsequently determine nanocarriers' biological behaviors. Therefore, an in-depth understanding of the features and effects of the PC on the nanocarriers' surface is the first and most important step towards controlling their in vivo fate. This review introduces fundamental knowledge such as the definition, formation, composition, conformation, and characterization of the PC, emphasizing the in vivo environmental factors that control the PC formation. The effect of PC on the physicochemical properties and thus biological behaviors of nanocarriers was then presented and thoroughly discussed. Finally, we proposed the design strategies available for engineering PC onto nanocarriers to manipulate them with the desired surface properties and achieve the best biomedical outcomes.

Whole-body PET tracking of a d-dodecapeptide and its radiotheranostic potential for PD-L1 overexpressing tumors.

Peptides that are composed of dextrorotary (d)-amino acids have gained increasing attention as a potential therapeutic class. However, our understanding of the in vivo fate of d-peptides is limited. This highlights the need for whole-body, quantitative tracking of d-peptides to better understand how they interact with the living body. Here, we used mouse models to track the movement of a programmed death-ligand 1 (PD-L1)-targeting d-dodecapeptide antagonist (DPA) using positron emission tomography (PET). More specifically, we profiled the metabolic routes of [64Cu]DPA and investigated the tumor engagement of [64Cu/68Ga]DPA in mouse models. Our results revealed that intact [64Cu/68Ga]DPA was primarily eliminated by the kidneys and had a notable accumulation in tumors. Moreover, a single dose of [64Cu]DPA effectively delayed tumor growth and improved the survival of mice. Collectively, these results not only deepen our knowledge of the in vivo fate of d-peptides, but also underscore the utility of d-peptides as radiopharmaceuticals.