**4.1 Liposomal formulation of verteporfin**

In 2000, both Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved a liposomal formulation of verteporfin [44]. In fact, encapsulating drugs in liposomes shield drugs from degradation by metabolic enzymes on conjunctiva, cornea, and in tear fluids. Furthermore, liposomes can

#### **Figure 5.**

*Chemical structure of verteporfin (C41H42N4O8). Drawn using ChemDraw Professional 22.0 from PerkinElmer Informatics, Inc.*

enhance intraocular penetration and retard the drug's clearance, leading to a higher concentration in the vitreous humor and an increment in the drug's half-life [33].

Since verteporfin is a highly hydrophobic drug, encapsulation in liposomes can control its drug release and enhance its *in vivo* distribution upon intravenous injection [45].

The liposomal formulation was developed by Bausch & Lomb® and is currently marketed by the commercial name Visudyne®. Ophthalmologists consider this formulation a remarkable advance in vision sciences in view of its capability of reducing the magnitude of vision loss for at least 1 year, thus boosting the life quality of these patients [28].

Visudyne® is a light-activated nanomedicine and the first and only clinically approved photosensitizer, being applied in photodynamic therapy (PDT) to eliminate abnormal blood vessels in the eye's retina and choroid (**Figure 6**) [43, 45, 46]. Briefly, it accumulates in these vessels and, when exposed to red light in the presence of oxygen, produces highly reactive free oxygen radicals, which impose local damage to the endothelium and vessel blockage [45, 47, 48]. It has become a milestone in the ophthalmology field for the treatment of patients with subfoveal choroidal neovascularization derived either from age-related macular degeneration, secondary to pathological myopia or from ocular histoplasmosis syndrome [44, 45, 48].

The lipid bilayer of Visudyne® liposomal formulation is made of a synthetic saturated phospholipid DMPC (dimyristoylphosphatidylcholine) and egg yolk phosphatidylglycerol EGPC (comprised of unsaturated multiple species) in the 5:3 ratio [47, 49]. The encapsulation of verteporfin in liposomes was a resourceful way to deliver the drug intravenously, thereby evading the natural predisposition of hydrophobic molecules to self-aggregate in aqueous media [43].

## **4.2 A theranostic liposome of verteporfin**

More recently, in 2020, a group of Brazilian researchers designed a smart theranostic verteporfin-loaded lipid-polymer liposome for PTD. This study proposes the loading of the aforementioned verteporfin liposomes in a theranostic system. Shortly, it consists of lipid-polymer liposomes obtained from DPPC (1,2-dipalmitoylsn-glycero-3-phosphatidylcholine) coated with triblock copolymer Pluronic® F127 covalently functionalized with 5 [6]-carboxyfluorescein fluorescent probe. An

#### **Figure 6.**

*Comparison between a healthy eye and an eye with choroidal neovascularization, a condition observed in ocular histoplasmosis with the formation of abnormal blood vessels in retina and choroid. Created with BioRender.com.*

*Is Micro and Nanotechnology Helping Us Fight Histoplasmosis? DOI: http://dx.doi.org/10.5772/intechopen.110544*

**Figure 7.**

*Schematic representation of a theranostic system to load verteporfin liposomes. Created with BioRender.com.*

illustration of this delivery system is depicted in **Figure 7**. This innovative formulation yielded 100 nm vesicles, 0.15 polydispersity index, outstanding stability, and encapsulation efficiency higher than 90%. Despite these encouraging results, the designed system's efficiency was only proven in a glioblastoma cancer cell line, leaving its efficiency in ophthalmic diseases open for further future investigation [49].
