Plant Resin Delivery by Nanovectors as an Emerging Approach to Boost Solubility, Permeability and Bioavailability

Introduction

Plant resins are complex blends of secondary constituents, mainly characterized by nonvolatile terpenoids (di- or triterpenes; rarely both) in combination with other constituents, mainly represented by essential oils (mono- and sesquiterpenes, denominated oleoresins), gums (polyterpenes, denominated gum resins), oil and gum (named oleogum resins) and polyphenols (phenylpropanoids, lignans, flavonoids, denominated balsams). Very frequently, oleogum resins are pleasantly fragrant, owing to the presence of the essential or volatile oil in some quantity [1].
Resins are synthesized in specified subcellular structures and can be produced spontaneously or due to stress (wound, pathogen attack). Their physiological role is probably to protect the plant from insects, fungi or other infections, or to close wounds. Resins principally constituted of terpenoids are internally formed, while resins containing polyphenols are produced on the surface. Due to this specific composition, resins are generally insoluble in water but soluble in alcohol, oil, chloroform, and ether [2]. Resins and resinous extracts of plant origin have been regarded as an important plant resource in traditional medicine and represent the oldest plant-based products, used by humans for thousands of years in various applications, principally for their antimicrobial, anti-inflammatory, antispasmodic, analgesic, and digestive properties. Their effects and applications in traditional medicine are widely described in Egyptian, Roman, Greek, Chinese and Oriental literature and include frankincense, myrrh, Dragon’s blood and ferulae resins, among the most widely used [3,4,5].

In the early 20th century, resins were still used in therapy; indeed, “Mastisol”, used for wound healing, was developed using mastic, styrax, methyl salicylate and alcohol [6]. The Merck’s Annual Report in 1913 referred to Mastisol as a resinous preparation containing 5% of mastic (terebinth 15 g, mastic 12 g, resin (any) 25 g, resin alb. 8.0 g, alcohol 90% 180 g) recommended as a wound dressing [7]. In the same period, Dr. Norman Moore of the Royal College of Physicians suggested another formulation based on resins: 20 g mastic, 50 g benzol, 20 drops linseed oil, 10 g colophony and 7 g Venice turpentine [8]. Finally, the formulation is also reported in Medicamenta, an Italian theoretical-practical guide for medical doctors and pharmacists [9]. Indeed, resins and their fractions, including EOs and isolated constituents, due to their lipid nature, are generally insoluble in water and petroleum ether, but soluble in alcohol, chloroform, and ether, and are quite soluble in acetone and fixed and volatile oils [4,5]. Their hydrophobic nature represents a major issue when resins are used as medicinal products because their low solubility limits their pharmacokinetics and biodistribution, representing a major challenge in the field of drug delivery. This limit can be overcome by their formulation in nanoparticles, improving their efficacy, specificity and targeting ability, and possibly obtaining a controlled and sustained drug release. In addition, nanovectors protect their cargo from degradation in the biological media, improve bioavailability, and optimize the cellular uptake [10,11]. The aim of this review was to give an overview on the published data on nanovectors loaded with resins or their fractions or isolated constituents.

Nanocarriers Are Smart Delivery Systems in Nanomedicine

Nanocarriers have shown great promise as drug deliverers and have been extensively investigated in the past few decades as transport modules for drugs. These colloidal drug carrier systems typically have submicron particle sizes, generally from a few to 250 nm [10], but many studies describe larger particles (up to 500 nm in diameter) [11]. Size, shape, surface charge, and surface chemistry have a fundamental role in the optimization of intracellular delivery of drugs and the pharmacokinetic and pharmacodynamics parameters of the drugs [10]. Commonly used nanocarriers include organic (natural or synthetic) and inorganic materials, or even hybrid nanodelivery systems. Different types of nanomaterials can be used to formulate nanocarriers, which are capable of being loaded with hydrophobic and/or hydrophilic drugs [11]. The inclusion of the drug in the nanocarriers has many advantages in terms of biopharmaceutical properties with respect to the naked drug. Indeed, nanoencapsulation of the drug enhances drug stability and solubility, with a consequent enhanced absorption, and decreases elimination and metabolism of drugs, resulting in an increased bioavailability and reduced therapeutic dose and toxicity. Other advantages of nanodrug delivery systems could be targeted drug delivery and drug-controlled release, minimizing systemic side effects compared to free drugs [10,11].

Classification of the nanocarriers is mainly based on the nature of the nanocarriers and includes polymer-based systems, lipid-based systems, inorganic systems and hybrid systems (Figure 1). Polymeric nanocarriers are composed of natural, semisynthetic or synthetic polymers (Figure 1). Their selection is established by the characteristics of the drugs to be encapsulated and by their performances in terms of biodegradability and biocompatibility [12]. Natural and synthetic polymers have been used for the formulations of resin-based nanoparticles and nanocapsules (Figure 1). Polymeric micelles have also been used as resin-loaded nanovectors. They consist of block copolymers made of hydrophobic and hydrophilic units, which can spontaneously associate in an aqueous solution, originating the micelle at a certain concentration (critical micellar concentration, CMC) [13] (Figure 1).

Lipid-based nanocarriers are widely used for the loading of resins, their fractions or isolated constituents. They include vesicles, nanoparticles and nanoemulsions (Figure 1b). Nanoemulsions and microemulsions are both nanosized emulsions, constituted of an oil phase and an aqueous phase [14]. Microemulsions are biphasic, isotropic, homogeneous and thermodynamically stable. Nanemulsions are thermodynamically unstable, even they show long-term stability when compared to macroemulsions [15]. In some cases, nanoemulsions and microemulsions have a low viscosity, leading to little retention time and spreadability, which can be overcome by developing nanoemulgel and microemulgel using a suitable gelling agent. There are many advantages of the nanoemulgel with respect to nanoemulsion and microemulsion, principally extraordinary drug loading capacity, improved viscosity, retention time and spreadability, little skin irritation and enhanced thermodynamic stability [16]. These microemulsions are very interesting as nanovectors for EO because they can decrease their volatility and increase both the water solubility and stability of EO in the presence of oxygen, light and humidity [17].

Vesiscles are also used to load resins, fractions of resins or single constituents. They are characterized by a bilayer structure spontaneously formed by natural or synthetic phospholipids or non-ionic surfactants, respectively denominated by liposomes and niosomes (Figure 1). They are very versatile nanocarriers because they can encapsulate both hydrophilic and hydrophobic drugs, respectively, in the aqueous compartment and the lipophilic bilayer. The principal advantage of these nanocarriers is their tremendous biocompatibility and safety [18]. Cholesterol can be replaced by other natural constituents such as saponins, which can impart to the bilayer a characteristic architecture, resulting in enhanced drug loading and drug skin penetration [19]. These nanovescicles can be also formulated in thermosensitive gels, which are of particular interest because the gel is formed in situ due to a sol–gel phase transition near body temperature, optimizing the prolonged release of the loaded drugs [20]. Finally, proniosomes are pre-vesicular formulations which can overcome the limitations of niosomes and general vesicular systems. The gel texture of proniosomes can be converted into the niosomes immediately upon hydration, simply in situ by absorbing water from the skin [21].

Lipid nanoparticles (Figure 1) have a lipid core consisting of solid or solid-plus-liquid lipids, and include natural and synthetic components and surfactants, mainly represented by polysorbates, phospholipids and bile salts. Lipid nanoparticles possess great biocompatibility, extraordinary biodegradability, and high safety, and they are more stable than vesicles. Another advantage is the easy and cheap industrial upscaling [22]. To limit the extrusion phenomena and optimize the entrapment efficiency of drugs, the blend of liquid and solid lipids at room temperature is strongly recommended to form the matrix [23].

Since their isolation, cyclodextrins (CDs) have been recognized for their applications in drug delivery [24,25]. Nanosponges based on CDs can be produced by reacting the CD unit with an appropriate crosslinking agent. These sponges have an astonishing ability to encapsulate drugs due to the three-dimensional networks with spherical shape [26].

Among the inorganic particles, mesoporous bioactive glass nanoparticles (MPGs) represent a smart class of nanoparticles and have been used for loading extracts from resins. Indeed, bioactive glasses (BGs) have been known for 50 years, made of SiO2–Na2O–CaO–P2O5 systems, greatly recognized as new biomaterials for regenerating bone. MPGs have high biocompatibility and quick bioactive response, representing useful nanoparticles for regenerative medicine [27,28].

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Excipients mentioned in the study: Tween 80 and Labrasol, Capmul MCM C8, Hydroxypropyl-β-cyclodextrin (HPβ-CD), Compritol 888 ATO

Truzzi, E.; Vanti, G.; Grifoni, L.; Maretti, E.; Leo, E.; Bilia, A.R. Plant Resin Delivery by Nanovectors as an Emerging Approach to Boost Solubility, Permeability and Bioavailability. Pharmaceutics 2025, 17, 53. https://doi.org/10.3390/pharmaceutics17010053

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