RESUMEN

The accumulation of photosensitizers (PSs) in lesion sites but not in other organs is an important challenge for efficient image guiding in photodynamic therapy. Cancer cells are known to express a significant number of albumin-binding proteins that take up albumin as a nutrient source. Here, we converted albumin to a novel BODIPY-like PS by generating a tetrahedral boron environment via a flick reaction. The formed albumin PS has almost the same 3-dimensional structural feature as free albumin because binding occurs at Sudlow Site 1, which is located in the interior space of albumin. An i.v. injection experiment in tumor-bearing mice demonstrated that the human serum albumin PS effectively accumulated in cancer tissue and, more surprisingly, albumin PS accumulated much more in the cancer tissue than in the liver and kidneys. The albumin PS was effective at killing tumor cells through the generation of reactive oxygen species under light irradiation. The crystal structure of the albumin PS was fully elucidated by X-ray crystallography; thus, further tuning of the structure will lead to novel physicochemical properties of the albumin PS, suggesting its potential in biological and clinical applications.

Asunto(s)

RESUMEN

BACKGROUND: The elastomechanical properties of nanocarriers have recently been discussed as important for the efficient delivery of various therapeutics. Some data indicate that optimal nanocarriers' elasticity can modulate in vivo nanocarrier stability, interaction with phagocytes, and uptake by target cells. Here, we presented a study to extensively analyze the in vivo behavior of LIP-SS liposomes that were modified by forming the silicone network within the lipid bilayers to improve their elastomechanical properties. We verified liposome pharmacokinetic profiles and biodistribution, including retention in tumors on a mouse model of breast cancer, while biocompatibility was analyzed on healthy mice. RESULTS: We showed that fluorescently labeled LIP-SS and control LIP-CAT liposomes had similar pharmacokinetic profiles, biodistribution, and retention in tumors, indicating that modified elasticity did not improve nanocarrier in vivo performance. Interestingly, biocompatibility studies revealed no changes in blood morphology, liver, spleen, and kidney function but indicated prolonged activation of immune response manifesting in increased concentration of proinflammatory cytokines in sera of animals exposed to all tested liposomes. CONCLUSION: Incorporating the silicone layer into the liposome structure did not change nanocarriers' characteristics in vivo. Further modification of the LIP-SS surface, including decoration with hydrophilic stealth polymers, should be performed to improve their pharmacokinetics and retention in tumors significantly. Activation of the immune response by LIP-SS and LIP-CAT, resulting in elevated inflammatory cytokine production, requires detailed studies to elucidate its mechanism.

Asunto(s)

RESUMEN

INTRODUCTION: The pretargeting approach consists of in vivo ligation between pre-injected antibodies and low-molecular-weight radiolabeled effectors. The advantage of the pretargeting approach is to improve a tumor-to-background ratio, but the disadvantage is to compromise tumor accumulation. In this study, we applied albumin binder (ALB) to the pretargeting approach to overcome low tumor accumulation. METHODS: We synthesized two novel trifunctional effectors containing an ALB moiety, a chelator, and a different tetrazine and two corresponding effectors without an ALB moiety. Albumin-binding assays and stability assays were performed using 111In-labeled effectors. Measurements of reaction rate constant were conducted using 111In-labeled effectors and anti-HER2 antibody trastuzumab modified by trans-cyclooctene, which drives the click reaction with tetrazine. Biodistribution studies using HER2-expressing tumor-bearing mice were performed with or without the pretargeting approach. RESULTS: In albumin-binding assays, ALB-containing effectors exhibited a marked binding to albumin. Two ALB-containing effectors showed the difference in the reactivity and the slight difference in the stability. In biodistribution studies without the pretargeting approach, two ALB-containing effectors showed different pharmacokinetics in blood retention. With the pretargeting approach, the tumor accumulation was improved by the introduction of ALB and the highest tumor accumulation was observed in using the ALB-containing effector with higher blood retention. CONCLUSION: These results suggest that the application of ALB to the pretargeting approach is effective to improve tumor accumulation, and the structure of tetrazine influences the utility of ALB-containing effectors.

Asunto(s)

RESUMEN

OBJECTIVE: The marked success of prostate-specific membrane antigen (PSMA)-targeting radioligands with albumin binder (ALB) is attributed to the improvement of blood retention and tumor accumulation. [111In]In-PNT-DA1, our PSMA-targeting radioligand with ALB, also achieved improved tumor accumulation due to its prolonged blood retention. Although the advantage of ALBs is related to their reversible binding to albumin, the relationship between albumin-binding and tumor accumulation of PSMA-targeting radioligands remains unclear because of the lack of information about radioligands with stronger albumin-binding than ALBs. In this study, we designed and synthesized [111In]In-PNT-DM-HSA, a new radioligand that consists of a PSMA-targeting radioligand covalently bound to albumin. The pharmacokinetics of [111In]In-PNT-DM-HSA was compared with those of [111In]In-PNT-DA1 and [111In]In-PSMA-617, a non-ALB-conjugated radioligand, to evaluate the relationship between albumin-binding and tumor accumulation. METHOD: The [111In]In-PNT-DM-HSA was prepared by incubation of [111In]In-PNT-DM, a PSMA-targeting radioligand including a maleimide group, and human serum albumin (HSA). The ability of [111In]In-PNT-DM-HSA was evaluated by in vitro assays. A biodistribution study using LNCaP tumor-bearing mice was conducted to compare the pharmacokinetics of [111In]In-PNT-DM-HSA, [111In]In-PNT-DA1, and [111In]In-PSMA-617. RESULTS: The [111In]In-PNT-DM-HSA was obtained at a favorable radiochemical yield and high radiochemical purity. In vitro assays revealed that [111In]In-PNT-DM-HSA had fundamental characteristics as a PSMA-targeting radioligand interacting with albumin covalently. In a biodistribution study, [111In]In-PNT-DM-HSA and [111In]In-PNT-DA1 showed higher blood retention than [111In]In-PSMA-617. On the other hand, the tumor accumulation of [111In]In-PNT-DA1 was much higher than [111In]In-PNT-DM-HSA and [111In]In-PSMA-617. CONCLUSIONS: These results indicate that the moderate reversible binding of ALB with albumin, not covalent binding, may play a critical role in enhancing the tumor accumulation of PSMA-targeting radioligands.

Asunto(s)

RESUMEN

Improving the performance of nanocarriers remains a major challenge in the clinical translation of nanomedicine. Efforts to optimize nanoparticle formulations typically rely on tuning the surface density and thickness of stealthy polymer coatings, such as poly(ethylene glycol) (PEG). Here, we show that modulating the surface topography of PEGylated nanoparticles using bottlebrush block copolymers (BBCPs) significantly enhances circulation and tumor accumulation, providing an alternative strategy to improve nanoparticle coatings. Specifically, nanoparticles with rough surface topography achieve high tumor cell uptake in vivo due to superior tumor extravasation and distribution compared to conventional smooth-surfaced nanoparticles based on linear block copolymers. Furthermore, surface topography profoundly impacts the interaction with serum proteins, resulting in the adsorption of fundamentally different proteins onto the surface of rough-surfaced nanoparticles formed from BBCPs. We envision that controlling the nanoparticle surface topography of PEGylated nanoparticles will enable the design of improved nanocarriers in various biomedical applications.

Asunto(s)

RESUMEN

The tumor entrance of drug delivery systems, including therapeutic proteins and nanomedicine, plays an essential role in affecting the treatment outcome. Nanoparticle size is a critical but contradictory factor in making a trade-off among blood circulation, tumor accumulation, and penetration. Here, this work designs a series of single-molecule gadolinium (Gd)-based magnetic resonance imaging (MRI) nanoprobes with well-defined sizes to precisely explore the size-dependent tumor entrance in vivo. The MRI nanoprobes obtained by divergent synthesis contain a core molecule of macrocyclic Gd(III)-chelate and different layers of dendritic lysine units, mimicking globular protein. This work finds that the r1 relaxivity and MR imaging signals increase with the nanoparticle size. The nanoprobe with a lower limit of critical size threshold ≈8.0 nm achieves superior tumor accumulation and penetration. These single-molecule MRI nanoprobes can be served to precisely examine the size-related nanoparticle-biological interactions.

Asunto(s)

RESUMEN

Liposomes composed of a rigid bilayer have high plasma stability; however, they can be challenged in efficacy due to complications in releasing the encapsulated drug as well as being internalized by the tumor cell. On the other hand, fusogenic liposomes may fuse with the plasmatic membrane and release encapsulated material directly into the cytoplasm. In a previous study, fusogenic liposomes composed of alpha-tocopheryl succinate (TS) and doxorubicin (DOX) were developed (pHSL-TS-DOX). These stabilized tumor growth and reduced toxicity compared to a commercial formulation. In the present study, we investigated whether cellular uptake or DOX accumulation in the tumor could justify the better performance of the pHSL-TS-DOX formulation. Release, deformability, and DOX plasmatic concentration studies were also carried out. pHSL-TS-DOX showed an adequate release profile and demonstrated characteristics of a deformable formulation. Data from apoptosis, cell cycle, and nuclear morphology studies have shown that the induction of cell death caused by pHSL-TS-DOX occurred more quickly. Higher DOX cellular uptake and tumor accumulation were observed when pHSL-TS-DOX was administered, demonstrating better drug delivery capacity. Therefore, better DOX uptake as well as tumor accumulation explain the great antitumor activity previously demonstrated for this formulation.

Asunto(s)

RESUMEN

Abnormal tumor vasculature is reported to severely hinder the therapeutic potency of diverse cancer therapeutics by restricting their intratumoral accumulation and/or causing therapeutic resistance. Herein, a microbubble-assisted ultrasonication technology (MAUT) of systemic administration of octafluoropropane-filled microbubbles together with tumor localized ultrasound (US) exposure is developed to generally promote intratumoral accumulation efficacy of three kinds of anti-tumor drugs with varying sizes through the cavitation effect-induced disruption of tumor blood vessels. MAUT was further shown to enable selective tumor hypoxia attenuation by filling microbubbles with high-purity oxygen and thus reducing the production of immunosuppressive lactic acids by suppressing glycolysis in cancer cells. Resultantly, MAUT markedly enhanced the therapeutic outcome of systemically administered anti-programmed death-1 (anti-PD-1) and chemotherapeutic doxorubicin (DOX) with and without using nanoscale liposomes as delivery vehicles. This work highlights that MAUT is a biocompatible yet versatile strategy to effectively reinforce the therapeutic potency of a broad range of cancer therapeutics, promising for future clinical usage.

Asunto(s)

RESUMEN

The biological properties of spherical nucleic acids (SNAs) are largely independent of nanoparticle core identity but significantly affected by oligonucleotide surface density. Additionally, the payload-to-carrier (i.e., DNA-to-nanoparticle) mass ratio of SNAs is inversely proportional to core size. While SNAs with many core types and sizes have been developed, all in vivo analyses of SNA behavior have been limited to cores >10 nm in diameter. However, "ultrasmall" nanoparticle constructs (<10 nm diameter) can exhibit increased payload-to-carrier ratios, reduced liver accumulation, renal clearance, and enhanced tumor infiltration. Therefore, we hypothesized that SNAs with ultrasmall cores exhibit SNA-like properties, but with in vivo behavior akin to traditional ultrasmall nanoparticles. To investigate, we compared the behavior of SNAs with 1.4-nm Au102 nanocluster cores (AuNC-SNAs) and SNAs with 10-nm gold nanoparticle cores (AuNP-SNAs). Significantly, AuNC-SNAs possess SNA-like properties (e.g., high cellular uptake, low cytotoxicity) but show distinct in vivo behavior. When intravenously injected in mice, AuNC-SNAs display prolonged blood circulation, lower liver accumulation, and higher tumor accumulation than AuNP-SNAs. Thus, SNA-like properties persist at the sub-10-nm length scale and oligonucleotide arrangement and surface density are responsible for the biological properties of SNAs. This work has implications for the design of new nanocarriers for therapeutic applications.

Asunto(s)

RESUMEN

Introduction: Photodynamic therapy (PDT) has attracted increasing attention for tumor treatment because of its minimal invasiveness and specific spatiotemporal selectivity. However, insufficient tumor accumulation and low cellular uptake of photosensitizers limit its therapeutic efficacy. Methods: In this study, flexible hollow human serum albumin/catalase nanocapsules (HSA/CATs) were created using a core-assisted protein-coating method and combined with the photosensitizer chlorin e6 (HSA/CAT@Ce6) for PDT. Results and Discussion: Transmission electron microscopy (TEM) images demonstrate that HSA/CAT nanocapsules are flexible, with a uniform diameter (310 nm) and a well-defined hollow structure. Thanks to their flexibility, HSA/CAT@Ce6 nanocapsules show a higher cellular uptake than rigid nanoparticles. The nanocapsules effectively generate reactive oxygen species (ROS) in 4T1 cells because of their high cellular uptake and catalytic capacity, remarkably enhancing their in vitro PDT efficacy. In addition, the in vivo tumor accumulation of HSA/CAT@Ce6 nanocapsules is significantly larger than that of rigid nanoparticles and Ce6, meaning they are highly effective in tumor cell ablation. This demonstrates that our flexible nanoplatform holds great promise for enhancing PDT of tumor.

Asunto(s)

RESUMEN

RNA interference (RNAi) mediated by short interfering RNA (siRNA) is a promising method for cancer treatment, but the clinical application is hampered by several limitations, including metabolic instability, lack of tumor specificity, and poor cellular uptake. To meet these challenges, we have explored the possibility of structure modification of siRNA with artificial bases for property optimization. A series of siRNAs functionalized with different numbers of hydrophobic base F are prepared for screening. The interactions of plasma proteins with F-base-modified siRNA (F-siRNA) are investigated, and it is identified that the interaction with serum albumin is dominant. Experiments revealed that the introduction of F bases conferred modified siRNA with improved tumor-specific accumulation, prolonged circulatory retention time, and better tissue permeability. Mechanistic studies indicated that the F base induces the formulation of a stable siRNA-albumin complex, which transports siRNA to tumor tissues selectively owing to an enhanced permeability and retention (EPR) effect of albumin. The F base also facilitates the binding of siRNA to transport-associated proteins on the cell membrane, enabling its cellular internalization. Together, these data demonstrate that F base modification confers siRNA-enhanced cellular uptake and biostability and specific accumulation in tumor tissue, which provides a new approach for the development of siRNA-based cancer therapeutics.

RESUMEN

Photodynamic therapy (PDT) has been widely used for the local treatment of a variety of cancer. To improve the therapeutic effect, delicate nanoparticles loading photosensitizers (PSs) have been designed to improve the accumulation of PSs in tumor. Different from the anti-cancer drugs for chemotherapy or immunotherapy, the delivery of PSs requires rapid tumor accumulation followed by quick elimination to reduce the potential risk of phototoxicity. However, owing to the nature of prolonged blood circulation of the nanoparticles, the conventional nanoparticulate delivery systems may decelerate the clearance of PSs. Here, we present a tumor-targeted delivery approach termed "IgG-hitchhiking" strategy through a self-assembled PSs nanostructure, according to the intrinsic binding between the photosensitizer pheophorbide A (PhA) and immunoglobulin (IgG). We utilize the intravital fluorescence microscopic imaging to uncover that the nanostructures (IgG:PhA NPs) increase the extravasation of PhA into tumor within the first hour post intravenous injection compared with free PhA, correlating with an improved efficacy of PDT. After ∼1 h post-injection, a quick decrease in the PhA amount in the tumor is observed, while the tumor IgG level is continuously increasing. The disparity of the tumor distribution between PhA and IgG allows the quick elimination of the PSs for minimized skin phototoxicity. Our results provide a direct evidence of the enhanced accumulation and elimination of the PSs in the tumor microenvironment through the "IgG-hitchhiking" approach. This strategy presents a promising tumor-targeted delivery approach for the PSs in lieu of the existing strategy for enhanced PDT with minimal toxicity in clinic.

Asunto(s)

RESUMEN

Despite the numerous advantages of nanomedicines, their therapeutic efficacy is hampered by biological barriers, including fast in vivo clearance, poor tumor accumulation, inefficient penetration, and cellular uptake. Herein, cross-linked supersmall micelles based on zwitterionic hyperbranched polycarbonates can overcome these challenges for efficiently targeted drug delivery. Biodegradable acryloyl/zwitterion-functionalized hyperbranched polycarbonates are synthesized by a one-pot sequential reaction of Michael-type addition and ring-opening polymerization, followed by controlled modification with carboxybetaine thiol. Cross-linked supersmall zwitterionic micelles (X-CBMs) are readily prepared by straightforward self-assembly and UV cross-linking. X-CBMs exhibit prolonged blood circulation because of their cross-linked structure and zwitterion decoration, which resist protein corona formation and facilitate escaping RES recognition. Combined with the advantage of supersmall size (7.0 nm), X-CBMs mediate high tumor accumulation and deep penetration, which significantly enhance the targeted antitumor outcome against the 4T1 tumor model by administration of the paclitaxel (PTX) formulation (X-CBM@PTX).

Asunto(s)

RESUMEN

Lactosomes™ are biocompatible nanoparticles that can be used for cancer tissue imaging and drug delivery. Lactosomes are polymeric micelles formed by the self-assembly of biodegradable amphiphilic block copolymers composed of hydrophilic polysarcosine and hydrophobic poly-L-lactic acid chains. The particle size can be controlled in the range of 20 to 100 nm. Lactosomes can also be loaded with hydrophobic imaging probes and photosensitizers, such as indocyanine green. Indocyanine green-loaded lactosomes are stable for long-term circulation in the blood, allowing for accumulation in cancer tissues. Such lactosomes function as a photosensitizer, which simultaneously enables fluorescence diagnosis and photodynamic therapy. This review provides an overview of lactosomes with respect to molecular design, accumulation in cancer tissue, and theranostics applications. The use of lactosomes can facilitate the treatment of cancers in unresectable tissues, such as glioblastoma and head and neck cancers, which can lead to improved quality of life for patients with recurrent and unresectable cancers. We conclude by describing some outstanding questions and future directions for cancer theranostics with respect to clinical applications.

RESUMEN

Extracellular vesicles (EVs), including microparticles and exosomes, have emerged as potential tools for tumor targeting delivery during the past years. Recently, mass of strategies are applied to assist EVs to accumulate and penetrate into deep tumor sites. In this review, EVs from different cells with unique innate characters and engineered approaches (e.g. chemical engineering, genetical engineering and biomimetic engineering) as drug delivery systems to enhance tumor accumulation and penetration are summarized. Meanwhile, efficient biological function modulation (e.g. extracellular matrix degradation, mechanical property regulation and transcytosis) is introduced to facilitate tumor accumulation and penetration of EVs. Finally, the prospects and challenges on further clinical applications of EVs are discussed.

Asunto(s)

RESUMEN

Nanomedicines have shown a promising strategy for cancer therapy because of their higher safety and efficiency relative to small-molecule drugs, while the dense extracellular matrix (ECM) in tumors often acts as a physical barrier to hamper the accumulation and diffusion of nanoparticles, thus compromising the anticancer efficacy. To address this issue, two major strategies including degrading ECM components and inhibiting ECM formation have been adopted to enhance the therapeutic efficacies of nanomedicines. In this review, we summarize the recent progresses of tumor ECM modulating strategies for enhanced antitumor therapy of nanomedicines. Through degrading ECM components or inhibiting ECM formation, the accumulation and diffusion of nanoparticles in tumors can be facilitated, leading to enhanced efficacies of chemotherapy and phototherapy. Moreover, the ECM degradation can improve the infiltration of immune cells into tumor tissues, thus achieving strong immune response to reject tumors. The adoptions of these two ECM modulating strategies to improve the efficacies of chemotherapy, phototherapy, and immunotherapy are discussed in detail. A conclusion, current challenges and outlook are then given.

RESUMEN

Gold nanoparticles (AuNPs) are continuing to gain popularity in the field of nanotechnology. New methods are continuously being developed to tune the particles' physicochemical properties, resulting in control over their biological fate and applicability to in vivo diagnostics and therapy. This review focuses on the effects of varying particle size on optical properties, opsonization, cellular internalization, renal clearance, biodistribution, tumor accumulation, and toxicity. We review the common methods of synthesizing ultrasmall AuNPs, as well as the emerging constructs termed ultrasmall-in-nano-an approach which promises to provide the desirable properties from both ends of the AuNP size range. We review the various applications and outcomes of ultrasmall-in-nano constructs in vitro and in vivo.

RESUMEN

Magnetic resonance-guided focused ultrasound (MRgFUS) is a promising non-invasive surgical technique with spatial specificity and minimal off-target effects. Despite the expanding clinical applications, the major obstacles associated with MRgFUS still lie in low magnetic resonance imaging (MRI) sensitivity and safety issues. High ultrasound power is required to resist the energy attenuation during the delivery to the tumor site and may cause damage to the surrounding healthy tissues. Herein, a surface modification strategy is developed to simultaneously strengthen MRI and ultrasound ablation of MRgFUS by prolonging Fe3O4 nanoparticles' blood circulation and tumor-environment-triggered accumulation and retention at the tumor site. Specifically, reactive oxygen species-labile methoxy polyethylene glycol and pH-responsive DNA cross-linkers are modified on the surface of Fe3O4 nanoparticles, which can transform nanoparticles into aggregations through the cascade responsive reactions at the tumor site. Notably, DNA is selected as the pH-responsive cross-linker because of its superior biocompatibility as well as the fast and sensitive response to the weak acidity of 6.5-6.8, corresponding to the extracellular pH of tumor tissues. Due to the significantly enhanced delivery and retention amount of Fe3O4 nanoparticles at the tumor site, the MRI sensitivity was enhanced by 1.7-fold. In addition, the ultrasound power was lowered by 35% to reach a sufficient thermal ablation effect. Overall, this investigation demonstrates a feasible resolution to promote the MRgFUS treatment by enhancing the therapeutic efficacy and reducing the side effects, which will be helpful to guide the clinical practice in the future.

Asunto(s)

RESUMEN

Maximizing the tissue-targeting efficiency of nanomaterials while also protecting them from rapid clearance from the bloodstream and limiting their immunogenicity remains a central problem in the field of systemic-administered nanomedicine. Herein, we introduce a generalizable strategy to simultaneously increase tumor accumulation, prolong blood circulation, and limit nonspecific immune activation of nanomaterials via peptide-based, tumor-responsive, "sheddable" coatings. Spherical nucleic acids (SNAs) were designed and synthesized to contain an exterior coating composed of zwitterionic polypeptides with recognition sequences for tumor-associated proteases. In the presence of matrix metalloproteinases (MMPs), the polypetide coating is rapidly cleaved, leading to increased cellular uptake of these SNAs, relative to SNAs containing nonsheddable shells. Moreover, the zwitterionic nature of the polypeptide shell shields the SNAs from immune system recognition, which extends their blood circulation time and improves tumor accumulation and in vivo cellular uptake relative to control SNAs with no protective coating. Taken together, these results indicate that this strategy is a viable method for increasing nanoparticle tumor accumulation and can have utility for the systemic delivery of oligonucleotides and nanomaterials to target cells in vivo with low immunogenicity.

Asunto(s)

RESUMEN

Arsenic trioxide (ATO) has efficient anticancer effect on hepatocellular carcinoma (HCC) in clinical trials, but its off-target distribution and side effects have limited its use. Here, we demonstrate an albumin-embellished ATO-loaded polyethylene glycol-polycaprolactone-polyethyleneimine (PEG-PCL-PEI) nanoparticle (AATONP) to enhance the tumor distribution and intratumor drug release of ATO for HCC therapy. AATONP is prepared by surface embellishment with albumin on the cationic ATO-loaded PEG-PCL-PEI nanoparticles (CATONP). Albumin embellishment can reduce the cationic material's hemolytic toxicity in blood cells while maintaining the rapid internalization and lysosome escape abilities of the positively charged CATONP. AATONP provides sustained and low pH-responsive drug release, facilitating the targeted drug release in the intratumor acidic microenvironment. Moreover, AATONP can significantly improve the circulation time and tumor distribution of ATO via albumin-mediated transcytosis in HCC tumor-bearing mice. Compared with free ATO and the clinically used nanomedicine Genexol/PM, AATONP shows potent antitumor activity against a human HCC xenograft mouse model, leading to a higher tumor inhibition rate of 89.4% in HCC therapy. In conclusion, this work presents an efficient strategy to achieve tumor accumulation and the intratumor drug release of ATO for HCC therapy. An albumin-embellished arsenic trioxide (ATO)-loaded polyethylene glycol-polycaprolactone-polyethyleneimine nanoparticle (AATONP) is designed to enhance tumor distribution and intratumor drug release of ATO for hepatocellular carcinoma therapy. AATONP can achieve enhanced tumor distribution via albumin-mediated transcytosis and exhibit intratumor drug release of ATO via tumor acidic microenvironment-response, leading to potent antitumor activity.

Asunto(s)