molecules Review Nanoformulations for Delivery of Pentacyclic Triterpenoids in Anticancer Therapies Anna Kaps *, Paweł Gwiazdo ´nand Ewa Chodurek Department of Biopharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Poland, 8 Jedno´sciStr., 41-208 Sosnowiec, Poland; [email protected] (P.G.); [email protected] (E.C.) * Correspondence: [email protected]; Tel.: +48-323641247 Abstract: The search for safe and effective anticancer therapies is one of the major challenges of the 21st century. The ineffective treatment of cancers, classified as civilization diseases, contributes to a decreased quality of life, health loss, and premature mortality in oncological patients. Many natural phytochemicals have anticancer potential. Pentacyclic triterpenoids, characterized by six- and five-membered ring structures, are one of the largest class of natural metabolites sourced from the plant kingdom. Among the known natural triterpenoids, we can distinguish lupane-, oleanane- , and ursane-types. Pentacyclic triterpenoids are known to have many biological activities, e.g., anti-inflammatory, antibacterial, hepatoprotective, immunomodulatory, antioxidant, and anticancer properties. Unfortunately, they are also characterized by poor water solubility and, hence, low bioavailability. These pharmacological properties may be improved by both introducing some modifications to their native structures and developing novel delivery systems based on the latest nanotechnological achievements. The development of nanocarrier-delivery systems is aimed at increasing the transport capacity of bioactive compounds by enhancing their solubility, bioavail- Citation: Kaps, A.; Gwiazdo´n,P.; ability, stability in vivo and ensuring tumor-targeting while their toxicity and risk of side effects are Chodurek, E. Nanoformulations for significantly reduced. Nanocarriers may vary in sizes, constituents, shapes, and surface properties, Delivery of Pentacyclic Triterpenoids all of which affect the ultimate efficacy and safety of a given anticancer therapy, as presented in this in Anticancer Therapies. Molecules review. The presented results demonstrate the high antitumor potential of systems for delivery of 2021, 26, 1764. https://doi.org/ pentacyclic triterpenoids. 10.3390/molecules26061764 Keywords: pentacyclic triterpenoids; drug delivery systems; nanoformulations; nanocarriers; anti- Academic Editors: Robert Kubina and cancer activity; civilization diseases Agata Kabała-Dzik Received: 24 February 2021 Accepted: 17 March 2021 1. Introduction Published: 21 March 2021 Natural substances have been used in medicine for ages [1]. They may be useful Publisher’s Note: MDPI stays neutral in many civilization disorders like diabetes, obesity, and cardiovascular and neoplastic with regard to jurisdictional claims in diseases [2,3]. Cancers are often characterized by an unknown etiology, high genetic published maps and institutional affil- instability, high histological heterogeneity, lack of specific biomarkers, and high local iations. aggressiveness or spreading, all of which are usually challenging for modern medicine [4]. Despite the development in pharmacological sciences and the discovery of novel drugs for specific types of cancer, there are many factors that limit the possibility of their use. Toxicity to normal cells, the development of drug resistance, or a too short circulation in the body all ultimately add to the conclusion that cancer is one of the most common causes Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. of death worldwide [5]. This article is an open access article The strategies of anticancer therapies are most often based on the elimination of distributed under the terms and cancer cells by inhibiting their proliferation and on inducing the apoptosis process. It is conditions of the Creative Commons extremely important that these properties should be limited to cancer without affecting Attribution (CC BY) license (https:// normal cells. In recent years, there has been a growing interest in plant-sourced compounds creativecommons.org/licenses/by/ that possess desired biological and pharmacological activities [6]. Pentacyclic triterpenoids, 4.0/). classified as phytochemicals, are secondary plant metabolites. They are most commonly Molecules 2021, 26, 1764. https://doi.org/10.3390/molecules26061764 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 22 Molecules 2021, 26, 1764 that possess desired biological and pharmacological activities [6]. Pentacyclic triterpe-2 of 19 noids, classified as phytochemicals, are secondary plant metabolites. They are most com- monly found in the peel of fruits, leaves, and the bark of plants (e.g., the peel of apples, foundleaves inof theeucalyptus, peel of fruits, and birch leaves, bark). and theTheir bark physiological of plants (e.g., role the is peelto protect of apples, against leaves the ofharmful eucalyptus, effects and of microorganisms birch bark). Their and physiological insects. Plants role with is to a protectparticularly against high the content harmful of effectspentacyclic of microorganisms triterpenoids andcould insects. be used Plants in withthe medical a particularly treatment high called content ‘phytotherapy.’ of pentacyclic triterpenoidsThe pentacyclic could triterpenoids be used in the can medical be classified treatment into called three ‘phytotherapy.’main groups: lupane The pentacyclic (betulin, triterpenoidsbetulinic acid, can and be lupeol), classified oleanane into three (olean mainolic groups: acid, lupanemaslinic (betulin, acid, erythrodiol, betulinic acid, and and β- lupeol),amyrin) oleananeand ursane (oleanolic (ursolic acid, uvaol, maslinic and acid, α-amyrin) erythrodiol, [7]. Their and chemicalβ-amyrin) structures and ursane con- (ursolicsist of five- acid, and/or uvaol, six-member and α-amyrin)ed carbon [7]. Their rings chemical [8]. The structures range of biological consist of five-properties and/or of six-memberedtriterpenoids includes carbon rings anticancer, [8]. The rangeantiangiogenic, of biological anti-inflammatory, properties of triterpenoids antiviral, includes antioxi- anticancer,dant, antidiabetic, antiangiogenic, antihyperlipidemic, anti-inflammatory, antibacterial, antiviral, hepatoprotective, antioxidant, antidiabetic, and cardioprotec- antihy- perlipidemic,tive activities, antibacterial, among others. hepatoprotective, Therefore, most and triterpenoids cardioprotective are highly activities, biologically among others. active Therefore,with a low most toxicity triterpenoids that indicates are highly the possibility biologically to use active them with as aan low alternative toxicity thatto traditional indicates thechemotherapeutics possibility to use [9,10]. them as an alternative to traditional chemotherapeutics [9,10]. 2.2. BiologicalBiological ActivitiesActivities ofof PentacyclicPentacyclic TriterpenoidsTriterpenoids 2.1.2.1. Lupane-TypeLupane-Type TriterpenoidsTriterpenoids BetulinBetulin (BT;(BT; lup-20(29)-ene-3lup-20(29)-ene-3ββ,28-diol;,28-diol; FigureFigure1 1a)a) also also known known as as a a betulin betulin alcohol alcohol or or betulinol,betulinol, isis one one of of the the most most studied studied and and best characterizedbest characterized pentacyclic pentacyclic lupane-type lupane-type triter- penoids.triterpenoids. The highest The highest concentration concentration of BT of (up BT to (up 80%) to 80%) is found is found in birch in birch bark extractsbark extracts [11]. BT[11]. has BT two has hydroxyl,two hydroxyl, at C3 at and C3 C28,and C28, and oneand isopropenyl,one isopropenyl, at C19, at C1 functional9, functional groups. groups. Its extensiveIts extensive chemical chemical structure structure is ais very a very good good substrate substrate for for numerous numerous modifications. modifications.This This enablesenables thethe synthesissynthesis ofof appropriateappropriate derivativesderivatives withwith thethe desireddesired characteristicscharacteristics [ 12[12].]. FigureFigure 1.1. ChemicalChemical structuresstructures ofof betulin betulin ( a(a),), betulinic betulinic acid acid ( b(b),), oleanolic oleanolic acid acid (c (),c), and and ursolic ursolic acid acid (d ). (d). The most common betulin derivative is betulinic acid (BA; 3β-hydroxy-lup-20(29)-en- 28-oicThe acid; most Figure common1b). Among betulin the derivative lupane-type is betulinic triterpenoids, acid (BA; BA is3β the-hydroxy-lup-20(29)- most biologically activeen-28-oic [11 ].acid; Unlike Figure normal 1b). Among cells, BA the impairs lupane-t theype antioxidant triterpenoids, defense BA is system, the most produces biologi- reactivecally active oxygen [11]. speciesUnlike normal (ROS), andcells, increases BA impairs cytotoxicity the antioxidant in cancer defense cells. system, It can induce produces the cellreactive cycle oxygen arrest and species apoptosis (ROS), of and neoplastic increases cells. cyto Thesetoxicity properties in cancer can cells. be usedIt can as induce markers the for anticancer activity assessment (Figure2). Molecules 2021, 26, x FOR PEER REVIEW 3 of 22 Molecules 2021, 26, 1764 cell cycle arrest and apoptosis of neoplastic cells. These properties can be used as markers 3 of 19 for anticancer activity assessment (Figure 2). Figure 2. Markers for anticancer activity assessment. ROS: reactive oxygen species. Figure 2. Markers for anticancer activity assessment. ROS: reactive oxygen species. BA regulates the expression of genes related to the apoptotic process and increases