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Exosomes are nanoscale vesicles generated by cells for intercellular communication. Due to their composition, significant research has been conducted to transform these particles into specific delivery systems for various disease states. In this review, we discuss the common isolation and loading methods of exosomes, some of the major roles of exosomes in the tumor microenvironment, as well as discuss recent applications of exosomes as drug delivery vessels and the resulting clinical implications.

Background: Guggulsterone (pregna-4,17-diene-3,16-dione; C21H28O2) is an effective phytosterol isolated from the gum resin of the tree Commiphora wightii (Family Burseraceae) and is responsible for many of the properties of guggul. This plant is widely used as traditional medicine in Ayurveda and Unani system of medicine. It exhibits several pharmacological activities, such as anti-inflammatory, analgesic, antibacterial, anti-septic and anticancer. In this article, the activities of Guggulsterone against cancerous cells were determined and summarized.Methods: Using 7 databases (PubMed, PMC, Google Scholar, Science Direct, Scopus, Cochrane and Ctri.gov), the literature search was conducted since conception until June 2021. Extensive literature search yielded 55,280 studies from all the databases. A total of 40 articles were included in the systematic review and of them, 23 articles were included in the meta‐analysis.The cancerous cell lines used in the studies were for pancreatic cancer, hepatocellular carcinoma, head and neck squamous cell carcinoma, cholangiocarcinoma, oesophageal adenocarcinoma, prostrate cancer, colon cancer, breast cancer, gut derived adenocarcinoma, gastric cancer, colorectal cancer, bladder cancer, glioblastoma, histiocytic leukemia, acute myeloid leukemia and non-small cell lung cancer. The reliability of the selected studies was assessed using ToxRTool.Results: Based on this review, guggulsterone significantly affected pancreatic cancer (MiaPaCa-2, Panc-1, PC-Sw, CD18/HPAF, Capan1, PC-3), hepatocellular carcinoma (Hep3B, HepG2, PLC/PRF/5R), head and neck squamous cell carcinoma (SCC4, UM-22b, 1483), cholangiocarcinoma (HuCC-T1, RBE, Sk-ChA-1, Mz-ChA-1) and oesophageal adenocarcinoma (CP-18821, OE19), prostrate cancer (PC-3), colon cancer (HT-29), breast cancer (MCF7/DOX), gut derived adenocarcinoma (Bic-1), gastric cancer (SGC-7901), colorectal cancer (HCT116), bladder cancer (T24, TSGH8301), glioblastoma (A172, U87MG, T98G), histiocytic leukemia (U937), acute myeloid leukemia (HL60, U937) and non-small cell lung cancer (A549, H1975) by inducing apoptotic pathways, inhibiting cell proliferation, and regulating the expression of genes involved in apoptosis. Guggulsterone is known to have therapeutic and preventive effects on various categories of cancers. It can inhibit the progression of tumors and can even reduce their size by inducing apoptosis, exerting anti-angiogenic effects, and modulating various signaling cascades. In vitro studies reveal that Guggulsterone inhibits and suppresses the proliferation of an extensive range of cancer cells by decreasing intrinsic mitochondrial apoptosis, regulating NF-kB/STAT3/β-Catenin/PI3K/Akt/CHOP pathway, modulating the expression of associated genes/proteins, and inhibiting angiogenesis. Furthermore, Guggulsterone reduces the production of inflammatory markers, such as CDX2 and COX-2. The other mechanism of the Guggulsterone activity is the reversal of P-glycoprotein-mediated multidrug resistance. Twenty three studies were selected for meta-analysis following the PRISMA statements. Fixed effect model was used for reporting the odds ratio. The primary endpoint was percentage apoptosis. 11 of 23 studies reported the apoptotic effect at t = 24 h and pooled odds ratio was 3.984 (CI 3.263 to 4.865, p < 0.001). 12 studies used Guggulsterone for t > 24 h and the odds ratio was 11.171 (CI 9.148 to 13.643, 95% CI, p < 0.001). The sub-group analysis based on cancer type, Guggulsterone dose, and treatment effects. Significant alterations in the level of apoptotic markers were reported by Guggulsterone treatment.Conclusion: This study suggested that Guggulsterone has apoptotic effects against various cancer types. Further investigation of its pharmacological activity and mechanism of action should be conducted. In vivo experiments and clinical trials are required to confirm the anticancer activity.

Pancreatic cancer (PanCa) is one of the most fatal of all cancers and is ranked as the fourth most common cause of cancer related deaths among both men and women in the US. The management of PanCa, is exceptionally difficult due to the extremely poor response to available therapeutic modalities. Highly desmoplastic microenvironment in pancreatic tumor causes suboptimal drug delivery and increases chemo-resistance. Plumbagin (PL), a naturally occurring napthoquinone derived from the root of Plumbago zeylanica L., has showed potent cancer preventive and therapeutic activity against variety of cancers. However, the clinical translation of PL has been significantly hampered due to its toxicity and suboptimal bioavailability. To address these clinically relevant issues, we have developed and characterized a novel PL-loaded magnetic nanoparticle (MNP-PL) formulation. This MNP-PL formulation was prepared using Magnetic nanoparticles (MNPs) composed of an iron oxide core which has distinct advantages in i) bio/hemo-compatibility, ii) biodegradation, iii) higher drug loading capacity and iv) improved bioavailability. Our novel MNP-PL formulation provided average size of 125 nm in dynamic light scattering (DLS) and exhibited -9.42 to -10.79 mV zeta potential with an outstanding PL loading efficiency. We have evaluated anti-cancer potential of MNP-PL formulation in human PanCa cells (HPAF-II, AsPc1 and Panc-1). We first performed MTS and colony formation assays to determine the effects of free PL and MNP-PL formulation on growth of PanCa cells. In this experiment, cells were treated with various concentrations of free PL (1-15 μM) or MNP-PL (1-15 μM) for 24 hrs. Results exhibited efficient internalization of the MNP-PL formulation in a dose-dependent manner. As a result, the MNP-PL formulation showed four fold dose advantage over free PL. IC50 of free PL was recorded 10 μM which was significantly reduced to 2.5 μM in MNP-PL. MNP-PL also showed four fold inhibition in colony formation compared to free PL. MNP-PL treatment more efficiently inhibited oncogenic CXCL12/CXCR4 signaling pathway in both PanCa and patient derived stromal fibroblast cells. MNP-PL treatment also showed decreased expression of CXCR4 protein levels in PanCa cells. Moreover, MNP-PL treatment inhibited stromal derived factor 1 (SDF-1)/CXCL12 expression in stromal fibroblasts. These results suggest that our novel MNP-PL formulation has more anti-cancer potential than free PL against PanCa. In conclusion, MNP-PL formulation may reduce the toxicity and improve the bioavailability of free PL and could be used for the treatment of PanCa. Citation Format: Bilal B. Hafeez, Vivek K. Kashyap, Vijayakumar N. Boya, Aditya Ganju, Mohammad Sikander, Murali M. Yallapu, Meena Jaggi, Subhash C. Chauhan. Novel nanoparticle formulation of Plumbagin for pancreatic cancer treatment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2208.