Current Topics in Medicinal Chemistry - Volume 20, Issue 27, 2020

Nanotechnology has revolutionized cancer treatment in both diagnosis and therapy. Since the initial application of nanoparticles (NPs) in cancer treatment, the main objective of nanotechnology was developing effective nanosystems with high selectivity and specificity for cancer treatment and diagnosis. To achieve this, different encapsulation and conjugation strategies along with surface functionalization techniques have been developed to synthesize anticancer drugs loaded NPs with effective targeting to specific tumor cells. The unique physicochemical attributes of NPs make them promising candidates for targeted drug delivery, localized therapies, sensing, and targeting at cellular levels. However, a nanosystem for localized and targeted cancer managements should overcome several biological barriers and biomedical challenges such as endothelial barriers, blood brain barrier, reticuloendothelial system, selective targeting, biocompatibility, acute/chronic toxicity, tumor-targeting efficacy. The NPs for in vivo applications encounter barriers at system, organ, and the cellular level. To overcome these barriers, different strategies during the synthesis and functionalization of NPs should be adapted. Pharmacokinetics and cellular uptake of NPs are largely associated with physicochemical attributes of NPs, morphology, hydrodynamic size, charge, and other surface properties. These properties can be adjusted during different phases of synthesis and functionalization of the NPs. This study reviews the advances in targeted cancer treatment and the parameters influencing the efficacies of NPs as therapeutics. Different strategies for overcoming the biological barriers at cellular, organ and system levels and biomedical challenges are discussed. Moreover, the applications of NPs in preclinical and clinical practice are reviewed.

Nanotechnology has recently provided exciting platforms in the field of anticancer research with promising potentials for improving drug delivery efficacy and treatment outcomes. Nanoparticles (NPs) possess different advantages over the micro and bulk therapeutic agents, including their capability to carry high payloads of drugs, with prolonged half-life, reduced toxicity of the drugs, and increased targeting efficiency. The wide variety of nanovectors, coupled with different conjugation and encapsulation methods available for different theranostic agents provide promising opportunities to fine-tune the pharmacological properties of these agents for more effective cancer treatment methods. This review discusses applications of NPs-assisted chemotherapy in preclinical and clinical settings and recent advances in design and synthesis of different nanocarriers for chemotherapeutic agents. Moreover, physicochemical properties of different nanocarriers, their impacts on different tumor targeting strategies and effective parameters for efficient targeted drug delivery are discussed. Finally, the current approved NPs-assisted chemotherapeutic agents for clinical applications and under different phases of clinical trials are discussed.

Background: Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that play a key role in both physiological and pathological tissue degradation. MMPs have reportedly shown great potentials in the degradation of the Extracellular Matrix (ECM), have shown great potentials in targeting bioactive and imaging agents in cancer treatment. MMPs could provoke Epithelial to Mesenchymal Transition (EMT) of cancer cells and manipulate their signaling, adhesion, migration and invasion to promote cancer cell aggressiveness. Therefore, targeting and particularly inhibiting MMPs within the tumor microenvironment is an effective strategy for cancer treatment. Based on this idea, different MMP inhibitors (MMPIs) have been developed to manipulate the tumor microenvironment towards conditions appropriate for the actions of antitumor agents. Studies are ongoing to improve the selectivity and specificity of MMPIs. Structural optimization has facilitated the discovery of selective inhibitors of the MMPs. However, so far no selective inhibitor for MMP-7 has been proposed. Aims: This study aims to comprehensively review the potentials and advances in applications of MMPs particularly MMP-7 in targeted cancer treatment approaches with the main focus on targeted drug delivery. Different targeting strategies for manipulating and inhibiting MMPs for the treatment of cancer are discussed. MMPs are upregulated at all stages of expression in cancers. Different MMP subtypes have shown significant targeting applicability at the genetic, protein, and activity levels in both physiological and pathophysiological conditions in a variety of cancers. The expression of MMPs significantly increases at advanced cancer stages, which can be used for controlled release in cancers in advance stages. Methods: Moreover, this study presents the synthesis and characteristics of a new and highly selective inhibitor against MMP-7 and discusses its applications in targeted drug delivery systems for therapeutics and diagnostics modalities. Results: Our findings showed that the structure of the inhibitor P3’ side chains play the crucial role in developing an optimized MMP-7 inhibitor with high selectivity and significant degradation activities against ECM. Conclusion: Optimized NDC can serve as a highly potent and selective inhibitor against MMP-7 following screening and optimization of the P3’ side chains, with a Ki of 38.6 nM and an inhibitory selectivity of 575 of MMP-7 over MMP-1.

Extracellular vesicles (EVs) are membrane vesicles (MVs) playing important roles in various cellular and molecular functions in cell-to-cell signaling and transmitting molecular signals to adjacent as well as distant cells. The preserved cell membrane characteristics in MVs derived from live cells, give them great potential in biological applications. EVs are nanoscale particulates secreted from living cells and play crucial roles in several important cellular functions both in physiological and pathological states. EVs are the main elements in intercellular communication in which they serve as carriers for various endogenous cargo molecules, such as RNAs, proteins, carbohydrates, and lipids. High tissue tropism capacity that can be conveniently mediated by surface molecules, such as integrins and glycans, is a unique feature of EVs that makes them interesting candidates for targeted drug delivery systems. The cell-derived giant MVs have been exploited as vehicles for delivery of various anticancer agents and imaging probes and for implementing combinational phototherapy for targeted cancer treatment. Giant MVs can efficiently encapsulate therapeutic drugs and deliver them to target cells through the membrane fusion process to synergize photodynamic/photothermal treatment under light exposure. EVs can load diagnostic or therapeutic agents using different encapsulation or conjugation methods. Moreover, to prolong the blood circulation and enhance the targeting of the loaded agents, a variety of modification strategies can be exploited. This paper reviews the EVs-based drug delivery strategies in cancer therapy. Biological, pharmacokinetics and physicochemical characteristics, isolation techniques, engineering, and drug loading strategies of EVs are discussed. The recent preclinical and clinical progresses in applications of EVs and oncolytic virus therapy based on EVs, the clinical challenges and perspectives are discussed.

Background: Surgery remains the front-line therapeutic strategy to treat early hepatocellular carcinoma (HCC). However, the 5-year recurrence rates of HCC patients are high. 10- Hydroxycamptothecin (10-HCPT) is a known anti-HCC agent but its poor solubility and bioavailability have limited its clinical use. Objective: In this study, we developed a novel nanoliposome encapsulated 10-hydroxycamptothecin modified with glycyrrhetinic acid (GA) and TAT peptide (GA/TAT-HCPT-LP) for the treatment of HCC. Dual modified GA and TAT can enhance tumor targeting and tumor penetration. Methods: The GA/TAT-HCPT-LP NPs were synthesized using the thin-film dispersion method. GA/TAT-HCPT-LP were characterized for particle size, zeta potential and morphology. Drug release from the GA/TAT-HCPT-LP liposomes was measured by dialysis. Cell-uptake was assessed by microscopy and flow cytometry. Cell proliferation, migration and apoptosis were measured to evaluate in vitro antitumor activity of GA/TAT-HCPT-LP via CCK-8 assays, Transwell assays, and flow cytometry, respectively. The in vivo distribution of GA/TAT-HCPT-LP was evaluated in HCC animal models. Tumor- bearing mouse models were used to assess the in vivo therapeutic efficacy of GA/TAT-HCPT-LP. Results: The mean particle size and mean zeta potential of GA/TAT-HCPT-LP were 135.55 ± 2.76 nm and -4.57 ± 0.23 mV, respectively. Transmission electron micrographs (TEM) showed that the GA/TAT-HCPT-LP had a near spherical shape and a double-membrane structure. GA/TAT-HCPT-LP led to slow and continuous drug release, and could bind to HepG2 cells more readily than other groups. Compared to control groups, treatment with GA/TAT-HCPT-LP had a significantly large effect on inhibiting cell proliferation, tumor cell migration and cell apoptosis. In vivo assays showed that GA/TATHCPT- LP selectively accumulated in tumor tissue with obvious antitumor efficacy. Conclusion: In conclusion, the synthesized GA/TAT-HCPT-LP could effectively target tumor cells and enhance cell penetration, highlighting its potential for hepatocellular cancer therapy.

Background: Metal nanomaterials are widely used in various fields, including targeted therapy and diagnosis. They are extensively used in targeted drug delivery and local treatments. However, the toxicity associated with these materials could lead to severe adverse health effects. Methods: In this study, we investigated the relationships between the toxicity and structures of metal nanoparticles by using theoretical calculations and quantitative structure-activity relationships. Twenty four physicochemical descriptors and toxicity data of 23 types of metal nanoparticles were selected as samples, and a multiple linear regression model was established to obtain a toxicity prediction equation with 5 descriptors with an R2 of 0.910. Structures of copper nanoparticles were designed based on the model, and the structure with low toxicity was searched. The multiple nonlinear regression model was used to further improve the prediction accuracy. Results: The R2 values were 0.995 in the training set and 0.988 in the test set, which indicated that the prediction accuracy improved. Based on the result of multiple linear regression, we designed copper nanoparticles with low toxicity. Conclusion: The study confirmed that the quantitative structure-activity relationship was a reasonable method for predicting the toxicity and designing the structures with low toxicity of metal nanoparticles.