Treating venous malformations with nanomedicines

Abstract

Venous malformations (VMs) are congenital vascular anomalies that cause pain, bleeding, and functional impairment, yet current first-line therapies such as sclerotherapy and surgical resection are limited by complications and high recurrence rates. Nanomedicine provides a promising alternative by exploiting the enhanced permeation and retention (EPR)-like effect to achieve selective accumulation of nanoparticles (NPs) within VMs. Preclinical studies support the use of NPs not only for improved drug delivery but also for non-pharmacologic based treatment, such as photothermal therapy. Furthermore, active targeting strategies involving surface-functionalized NPs offer the potential for enhanced specificity and treatment efficacy. Despite these advances, clinical translation faces challenges such as heterogeneity in EPR efficiency, depth-limited delivery, and pediatric safety concerns. Continued efforts to create more effective, pediatric-specific drug delivery systems are essential for developing safer, more efficient, and minimally invasive nanomedicine therapy for patients with VMs.

1. Introduction

Venous malformations (VMs) are a congenital vascular malformation affecting approximately 1 in every 10,000 individuals. The expansion of VMs can result in significant pain, bleeding, disfigurement, and organ dysfunction [1]. The development of VMs in both humans and mouse models is primarily congenitally associated with abnormalities of the phosphatidylinositol three kinase (PI3K)/AKT/mTOR pathway [2–4], an essential pathway for normal vascular development and angiogenesis. Despite advances in understanding the underlying pathophysiology, at present, there is no therapy that cures VMs [5].

Current management strategies for patients with VMs, such as sclerotherapy and surgical resection, are considered first-line interventions but have limitations [6]. Sclerotherapy, which uses irritants such as ethanol, polidocanol, or drug-loaded foam, can be complicated by tissue necrosis and nerve injury [7]. In addition, sclerotherapy requires technical skill to cannulate feeder vessels, which may require general anesthesia to perform the procedure [8]. Similarly, surgical resection can be technically challenging due to the poorly delineated, infiltrative nature of VMs, which can result in incomplete removal of the VM and substantial intraoperative blood loss [9]. Clinical trials of daily rapamycin (mTOR inhibitor) dosing slow VM growth, however when the drug is stopped (often secondary to systemic toxicities), the VMs expand [10]. These limitations highlight the critical unmet need for novel and more effective therapies.

Nanomedicine-based approaches have emerged as promising alternatives to overcome these challenges. Engineered nanoparticles (NPs) can be tailored to encapsulate therapeutic agents, improve drug solubility, and selectively accumulate in diseased tissues, thereby achieving sustained therapeutic effects with reduced systemic toxicity [11]. Beyond drug delivery, NPs can be functionalized with contrast agents (e.g., fluorescent dyes or MRI contrast agents) for high-resolution anatomical and functional imaging, enabling precise lesion delineation and treatment monitoring [12]. Furthermore, NPs fabricated from a diverse range of functional materials can be designed as activatable agents that respond to various external energy triggers such as near-infrared light (NIR), ultrasound, or electromagnetic fields to induce localized hyperthermia, mechanical stress, or other therapeutic effects [13]. While still in early stages of clinical translation, such strategies hold the potential to provide less invasive and more durable solutions compared to conventional therapies [14].

A key mechanism to NP accumulation in target tissues is the concept of the enhanced permeation and retention (EPR) effect [14]. First described in solid tumors, the EPR effect refers to the passive accumulation of nanoscale agents in tissues with abnormal vascular permeability and impaired lymphatic drainage [15]. When NPs reside in target tissues, they can function as a drug depot, increasing local drug concentration in these tissues and thereby increasing the therapeutic index. The EPR effect has been demonstrated in preclinical cancer models [15–17], and in other conditions such as choroidal neovascularization [18] and myocardial ischemia [19]. VMs are characterized by slow blood flow and are comprised of ectatic venous channels lined by abnormal endothelium with irregularly distributed smooth muscle cells [5]. We hypothesized that these features may support EPR-like nanoparticle accumulation.

2. EPR-like effect in venous malformations

To explore whether NPs can selectively accumulate in VMs through an EPR-like effect, the biodistribution of fluorescently labeled (with fluorophore Alex-647) hollow silica NPs coated with polyethylene glycol (HSNP-647) were examined in a murine model of VMs [20]. Briefly, particles sized 20–180 nm, known to accumulate through EPR in other models [21,22], were injected intravenously (i.e., systemically) into immunodeficient (nu/nu) mice bearing VM-like lesions made from human umbilical endothelial cells (HUVEC) expressing the TIE2-L914F mutation, a common driver of human VMs (HUVEC-TIE2-L914F). The HUVEC-TIE2-L914F mouse model results in VMs that closely resemble VMs in humans [23]. At 24 hours post-injection, VMs and major organs were harvested and imaged ex vivo using an in vivo imaging system (IVIS) to quantify fluorescence relative to saline-injected controls. 20–50 nm NPs had the greatest accumulation (compared to larger particles) in the VMs [20], consistent with observations in other systems [24–26]. These results not only confirm the presence of an EPR-like effect in murine VMs but also provide the foundation for exploring broader nanomedicine treatment approaches for VMs.

3. Potential applications of nanomedicine in venous malformations

NPs represent a versatile platform for therapeutic and diagnostic development. Based on the type of NP, they can have high loading capacity for small-molecule drugs and/or therapeutic nucleic acids [27], while surface modifications allow for conjugation with targeting ligands and/or imaging agents [28]. Such systems may expand treatment options by improving local drug concentration, prolonging drug/NP retention, and reducing systemic toxicity [18,29]. Evidence from oncology and other disease models indicates that once retained within lesions, NPs can serve multiple functional roles [30].

While nanoparticle-based drug delivery systems for VMs are worth pursuing, so are non-pharmacological approaches, such as thermal ablation with photothermal therapy (PTT). PTT induces cell death through the heat generated by photothermal agents when irradiated with light of specific wavelengths, such as near-infrared (NIR). NIR is a light source already clinically used for imaging, and safety guidelines have been established. Systemic injection of 30–50 nm gold nanoshells in the HUVEC-TIE2-L914F murine VM model resulted in gold accumulation within VMs [31]. Subsequent irradiation of the VMs with NIR light resulted in localized heating, inducing significant VM regression or complete elimination of the VMs in some cases [31]. The penetration of NIR light is deeper than that of other wavelengths (such as LED), and thus may be effective for VMs located a few centimeters below the skin surface [32,33]. However, for larger VMs or for VMs deeply located tens of centimeters below the skin surface, emerging strategies such as the use of NIR-II wavelengths [34], and ultrasound-triggered [35] techniques may help extend the applicability of photothermal therapy. It is also possible that for larger VMs, repeated irradiation events would be required.

Compared with sclerotherapy, NP-based treatment strategies may be less invasive, requiring venipuncture rather than direct cannulation of feeder vessels. In addition, NPs can be designed to target disease tissues after systemic injection, to allow controlled release of drugs, and to co-deliver multiple therapeutic agents.

4. Clinical challenges and design considerations

While the EPR-like effect provides a compelling rationale for nanomedicine in VMs, several design challenges must be addressed prior to clinical translation. Consistent with observations in solid tumors, smaller particles had better accumulation in VMs [20,31]. However, in the murine VM model, NPs made of different materials, shapes, or surface charges may exhibit different magnitudes of accumulation and should be tested [36]. Not all particles can be made within the size range for optimal accumulation in VMs. For example, while micelles can be made in this size range, liposomes or polymeric microspheres are difficult to make < 100 nm [23]. Like in other systems, there is a trade-off between smaller particles, with the best accumulation, and larger particles, which tend to have better drug loading.

Beyond passive accumulation, active targeting strategies such as using peptide [37] and/or antibody [38] modified NPs may further enhance accumulation beyond the EPR effect. However, the VMs forming cells (HUVEC-TIE2-L914F) share many receptors with other endothelial cells, raising concerns about off-target effects for constitutively expressed ligands. To overcome this, activable ligands that remain caged during circulation and are uncaged when activated represent an alternative approach. We have shown in bioengineered human vascular networks constructed through the co-implantation of endothelial and mesenchymal stem cells, that the accumulation of 19 nm NPs (modified with cell penetration peptide caged by a photolabile chemical protecting group) via the EPR effect can be further enhanced by photo-triggered NP targeting [39], similar to the effects reported in other systems [18,19]. Here, EPR-like effects enhanced NP accumulation four-fold and accumulation was further enhanced 17-fold with active targeting [39]. Beyond light triggering, ultrasound-trigged [40] and magnetically guided [41] drug delivery systems may offer better tissue penetration for the treatment of VMs located in deeper tissue. Alternatively, repeated administration of NPs or irradiation may be required.

While EPR is well established in preclinical animal oncology models, the EPR effect in human solid tumor models is variable, and patient-to-patient differences are significant even within the same disease type [22]. EPR is influenced by tumor type, tumor size, perfusion, interstitial fluid pressure, and the microenvironment [42]. A similar degree of heterogeneity is likely present in patients with VMs, though this has not been studied. Future studies aimed at quantifying vascular leakiness and blood flow within individual VMs may provide predictive biomarkers for EPR responsiveness. Vascular permeability could be assessed using dynamic contrast-enhanced MRI [43,44], while blood flow could be measured by Doppler [45] or contrast-enhanced ultrasound [46]. Such noninvasive imaging techniques would allow quantitative characterization of lesion physiology and enable stratification of patients most likely to benefit from EPR-based nanomedicine.

If NP accumulation in VMs following systemic delivery proves challenging, direct injection into the VM feeder vessels could be considered, combining nanomedicine with interventional radiology clinical practice. This approach could enhance accumulation and minimize off-target delivery. Given that VMs are often present in children, pediatric-specific clinical trials should be considered. Nanomedicines must undergo rigorous evaluation of long-term biodistribution, immune compatibility, and potential developmental toxicity [47].

5. Future perspective

Our findings provide compelling evidence that NP accumulation within murine VMs can occur following systemic administration. The next phase of this research will involve studying particle properties that enhance NP accumulation within the endothelial cells that form VMs, confirming the EPR effect in patients with VMs, and exploring the combination of the EPR effect with active/stimulus-triggered targeting. For clinical translation, nanomedicine approaches will need to be adapted to real-world anatomical and technical constraints. Image-guided methods, such as MRI or ultrasound, could enable the accurate localization of NPs in VMs. Vascular leakiness and blood flow characteristics may help identify patients who are most likely to benefit from EPR-mediated delivery. Additionally, catheter-based delivery routes may be necessary for certain anatomical locations to maximize efficacy and minimize off-target delivery of NPs. Together, these translational strategies will be essential to make nanomedicine a promising direction for improving the treatment of VMs. With further validation, we anticipate that the use of nanomedicines to treat patients with VMs could provide a safer, more effective, and lesion-specific alternative to existing systemic or invasive therapies.

6. Conclusion

Nanomedicine offers a new treatment approach to treating VMs, aiming to overcome the significant limitations of current standard therapies. The preclinical evidence summarized here demonstrates that through the EPR-like effect NPs can accumulate within VMs, facilitating highly targeted drug delivery or non-pharmacological strategies such as photothermal ablation. The integration of EPR-like effect, active targeting and stimulus-triggered techniques promises to further enhance the precision and efficacy of these interventions. However, translating these promising strategies into clinical practice will require overcoming several challenges, such as understanding the extent of the EPR-effect in patients with VMs, optimizing NP design and delivery methods, and ensuring safety in pediatric patients. With these advances, nanomedicine has the potential to deliver treatment options for VMs that are safer, more effective, and tailored to individual patient needs.

Article highlights.

• Venous malformations (VMs) are congenital vascular anomalies with limited effective treatment options, highlighting the need for innovative therapeutic approaches.

• Preclinical studies demonstrate that nanoparticles measuring 20–50 nm can passively accumulate in VMs via an EPR-like effect, supporting the potential of nanomedicine-based therapies for VMs.

• Non-pharmacological nanomedicine approaches, such as near infrared-triggered photothermal therapy using gold nanoshells, have shown efficacy in shrinking or eliminating VMs in animal models.

• Nanomedicine approaches offer promise for targeted drug delivery, improved imaging, and stimulus responsive treatment approaches, such as photothermal ablation.

• Challenges for clinical translation include understanding the extent of the EPR-effect among patients with VMs, optimizing nanoparticle design and delivery methods, and ensuring safety in pediatric patients.