Natural compounds-based nanomedicines for cancer treatment: Future directions and challenges

Abstract

Several efforts have been extensively accomplished for the amelioration of the cancer treatments using different types of new drugs and less invasives therapies in comparison with the traditional therapeutic modalities, which are widely associated with numerous drawbacks, such as drug resistance, non-selectivity and high costs, restraining their clinical response. The application of natural compounds for the prevention and treatment of different cancer cells has attracted significant attention from the pharmaceuticals and scientific communities over the past decades. Although the use of nanotechnology in cancer therapy is still in the preliminary stages, the application of nanotherapeutics has demonstrated to decrease the various limitations related to the use of natural compounds, such as physical/chemical instability, poor aqueous solubility, and low bioavailability. Despite the nanotechnology has emerged as a promise to improve the bioavailability of the natural compounds, there are still limited clinical trials performed for their application with various challenges required for the pre-clinical and clinical trials, such as production at an industrial level, assurance of nanotherapeutics long-term stability, physiological barriers and safety and regulatory issues. This review highlights the most recent advances in the nanocarriers for natural compounds secreted from plants, bacteria, fungi, and marine organisms, as well as their role on cell signaling pathways for anticancer treatments. Additionally, the clinical status and the main challenges regarding the natural compounds loaded in nanocarriers for clinical applications were also discussed.

Keywords: Biological compounds; Cancer cells; Clinical trials; Drug delivery and targeting; Nanocarriers.

Fig. 1

Types of structural forms of polymeric NPs: A Schematic depiction illustrating the structure of nanocapsules and nanospheres. B Various options for drug association with nanospheres and nanocapsules [41, 43]. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)

Fig. 2

Process of formation of a polymeric micelle [56]. This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (https://creativecommons.org/licenses/by/4.0/)

Fig. 3

Schematic illustration of pH-sensitive mechanisms for effective tumor-targeted drug delivery, generating enhanced cellular uptake, and facilitating intracellular drug release [55, 57]. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/)

Fig. 4

Diagram of a dendrimer structure and dendrimer synthesis. A General illustration of a dendrimer composed by a central core, radiating branch units defining the number of generations, and surface terminals. B Dendrimer synthesis via divergent and convergent approaches [61]. This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Fig. 5

Different types of NLCs: A Type I: imperfect, B Type II: multiple and C Type III: amorphous [84]. This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Fig. 6

General liposome structure and classification based on layer number and size [92]. This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Fig. 7

An illustration depicting the releases of a specific type of EV, namely an exosome [112]. The image presents several examples of bioactive compounds that can be incorporated in these EVs for delivery and diverse therapeutic applications. This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (https://creativecommons.org/licenses/by/4.0/)

Fig. 8

Differences between a healthy and endothelium surrounding a mature tumor. While endothelial cells of healthy tissues present are tightly joined while the tumor is still immature, the tumor vessel's structure contains wide fenestration that allows an EPR of NPs in the tumor interstitium. Adapted with permission [115]. Copyright 2015, Elsevier

Fig. 9

NPs from the blood circulation into the tumor interstitium by the EPR effect (a) or transcytosis (b), which can be subcategorized as intracellular vesicles-mediated (1), vesiculo-vacuolar organelles (VVOs)-mediated (2) or fenestrae-mediated (3) pathways. Reproduced with permission [130]. Copyright 2022, Elsevier B.V

Fig. 10

The active targeting of AuNPs using anti-PSMA antibodies has demonstrated higher penetration into the tumor site than non-functionalized AuNPs. A Dual-modality computed tomography (CT) and x-ray fluorescence CT (XFCT) transverse slices of 2 mice receiving passive and active targeting GNPs administrated IV demonstrated that the active targeting presented a maximum concentration 3 times higher than that of passive-targeting GNPs. B The H&E and silver staining demonstrated that GNPs (stained black; red arrows) presented a higher accumulation in the tumor site when they were functionalized with anti-PSMA antibodies, being possible to observe clusters of GNPs. Adapted with permission [137]. Copyright 2021, Elsevier B.V

Fig. 11

Histological photomicrograph of transverse lung sections: A control mice presented normal alveoli architecture with thin interalveolar septa constituted of simple squamous epithelial cells and normal interstitial tissues and alveolar sacs; B mice treated with urethane presented alveolar adenoma, cellular alterations (cells tend to be round, with stained cytoplasm, poor defined borders) and mildly differentiated squamous cell carcinoma; C mice treated with urethane also presented a defined alveolar adenoma demarcated from surrounding parenchyma as well as a mass of inflammatory cells infiltration, with damaging potential for the lung tissue; D mice treated with urethane and BBR displayed a partial alleviation of lung tissue degradation, with mild aggregations areas; E Mice treated with urethane and BBR-loaded chitosan NPs presented a significant reduction of the lung tissue degradation Reproduced with permission [259]. Copyright 2022, Elsevier B.V

Fig. 12

In vivo and ex vivo of mice after treatment with DMSO, GE11, Evo, Evo-NPs, GE11-Evo-NPs, and C225. A In vivo and B ex vivo bioluminescence images of lung, liver, and kidney metastases in the mice and follow H&E staining of metastasis tumor in the selected organs indicates the antimetastatic potential of GE11 NPs loaded with EVO. Reproduced with permission [277]. Copyright 2019, Royal Society of Chemistry. DMSO: Dimethyl sulfoxide; Evo: evodiamine; NPs: nanoparticles

Fig. 13

Nanomicelles loaded with celastrol have presented antitumor properties, reducing the tumor growth (A) and the neovascularization (B) in SO-Rb50 tumor-bearing mice. Adapted with permission [287]. Copyright 2019, Taylor & Francis Online ~ . H&E: Hematoxylin and Eosin

Fig. 14

Tumor tissue immunofluorescence staining of CD3 + and CD8 + T cells. It is possible to observe that Rh2@HMnO2-AM group have the largest distribution of CD3 + and CD8 + T compared to the other treatments, followed by the Rh2@HMnO2, Rh2, HMnO2-AM, and PBS groups. Adapted with permission [291]. Copyright 2022, Elsevier.; AM: alendronate/K7M2 cancer cell membranes; HMnO₂: hollow manganese dioxide; NPs: nanoparticles

Fig. 15

The encapsulation of TP into galactosylated-chitosan NPs decreased the hepatic, renal and male reproductive toxicity of this plant compound, as it is possible to observe comparing the histopathological images of liver, kidney, testis, and epididymis of mice treated low and high doses of TP (1 and 2.5 mg/kg, respectively) and Triptolide NPs (6.76 to 16.90 mg/kg, respectively). Overall, the encapsulation of TP into the galactosylated-chitosan NPs reduced the anomalous alterations the glomerulus and renal tubes, the cell swelling, vacuolar degeneration and necrosis in liver tissue, the damage in seminiferous tubules, with necrotic germ cells and deficient spermatogenesis. Adapted with permission [297]. Copyright 2019, Elsevier B.V. NPs: nanoparticles; TP: triptolide

Fig. 16

In vivo biodistribution studies of the several loaded nanoparticles produced using a fluorescent dye (DiR): A In vivo fluorescence images of 4T1 breast tumor-bearing BALB/c mice at different timepoints, in which it was possible to observe that while NPs functionalized with HA presented fluorescence at the tumor site at 24 h post administration, which lasted until the experiment ended, the fluorescent signal of the non-functionalized NPs appeared at 28 h after administration and the signal was much weaker; B Ex vivo fluorescence images of tumors and organs emphasising that the intratumoral delivery of the functionalized NPs was much higher and extensive than the non-functionalized NPs, although a relevant NPs accumulation was visible for both groups. Reprinted with permission [300]. Copyright 2020, Elsevier B.V. HA: hyaluronic acid; NPs: nanoparticles

Fig. 17

Images (20 × magnification) of A549 3D spheroids treated with single or multiple doses of Res and CD-Res NPs and further stained with fluorescent filters: green fluorescent protein (imaging calcein AM) for live cells; and red fluorescent protein (imaging EthD-III), for dead cells. It was possible to observe that, for both single- and multiple- doses, the spheroids treated with CD-Res NPs presented an increased intensity of red fluorescent protein (higher number of dead cells) compared to control and both concentrations of Res. Reproduced with permission [304]. Copyright 2020, ElsevierB.V. CD: cyclodextrin; NPs: nanoparticles; Res: resveratrol

Fig. 18

Intracellular behavior of Cur and Cur-MSNs in Hela cells. A Cur poor solubility prevents its cell internalization (red fluorescence), while its internalization into MSNs increased its internalization after 4 h of incubation. B Therefore, the generation of reactive oxygen species (ROS) in Hela cells incubation after incubation with Cur-MSNs was increased compared with free Cur, especially when combined with irradiation (430 nm, 20 mW cm.⁻²). Reproduced with permission [311]. Copyright 2020, RSC Publishing. Cur: Curcumin; MSNs: mesoporous silica NPs; NPs: nanoparticles

Fig. 19

A431 spheroids PDT treated with ethosomes and lipid-coated chitosan NPs loaded with ferrous CHL before and after treatment. Reproduced with permission [348]. Copyright 2019, Elsevier B.V

Fig. 20

Confocal laser scanning microscopic images of SKOV3 cells after treatment of the nanosystem loaded with coumarin-6-loaded. Red signal stems from MitoTracker™ Deep Red (MTDR)-staining mitochondria. The yellow signal observed in the merged channels indicates an overlapping of FITC and MTDR channels from the NPs and mitochondria, respectively, suggesting that triphenylphosphonium acted as a mitochondrial targeting ligand. Reprinted with permission [355]. Copyright, Elsevier B.V

Fig. 21

Biosynthesis of AgNPs. The plant extracts, collected by heating, contained several reducing agents, used for AgNPs biofabrication. Reproduced with permission [359]. Copyright 2022, Elsevier B.V

Fig. 22

Analysis of all publications. A Trends in annual publications. B Co-citation network analysis of publications. C Chronological timeline of key articles in herbal nanoparticle research [392]. This is an open access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (https://creativecommons.org/licenses/by/4.0/)