Combination Cancer Therapy Research Articles

Hypoxia-alleviating hemoglobin nanoclusters for sensitizing chemo-photodynamic therapy of cervical cancer

Hypoxia-alleviating hemoglobin (Hb) nanoclusters (NCs) have been developed for sensitizing combined chemo-photodynamic therapy (chemo-PDT) of cervical cancer. Hb was conjugated with chlorin e6 and biotinylated polyethylene glycol and adsorbed with doxorubicin (DOX), resulting in the self-assembly of 220 nm diameter protein NCs. These oxygen-carrying NCs, namely DOX@HPBC, exhibited improved colloidal stability in the serum compared to that of native Hb and pH-responsive drug release favorable for cancer treatment. DOX@HPBC alleviated hypoxia by 64.8% in HeLa cells cultured under hypoxia and normalized the levels of related biomarkers, HIF-1α and MDR1, with enhanced cellular uptake via biotin–receptor interactions. Moreover, antitumor efficacy tests performed in HeLa monolayer and spheroid cultures revealed that DOX@HPBC possessed 3.8-fold improved therapeutic efficacy compared to DOX and chlorin e6 physical mixture, showing synergism between chemotherapy and PDT. DOX@HPBC-mediated chemo-PDT significantly suppressed tumor growth in heterotopic (96.6% reduction in tumor volume compared to no-intervention) and orthotopic (comparable uterus weight to the normal group) HeLa-xenografted mice with no significant toxicity. These results showed the hypoxia amelioration effect, which lowered HIF-1α and MDR1 levels in tumor tissues, and efficient DOX distribution to hypoxic regions of the tumor, suggesting that DOX@HPBC could be a promising chemo-PDT strategy for cervical cancer treatment.

Preclinical evaluation of pentagamavunone-1 as monotherapy and combination therapy for pancreatic cancer in multiple xenograft models

We previously reported that pentagamavunone-1 (PGV-1) effectively inhibited cell proliferation in many types of human tumors, including pancreatic cancer, by inducing M phase (prometaphase) arrest, senescence, and apoptosis with few side effects. However, a detailed evaluation of the effects of PGV-1 on pancreatic cancer cells in an in vivo setting has not yet been conducted. The present study investigated the potential efficacy of PGV-1 as both monotherapy and combination therapy for pancreatic cancer using multiple xenograft mouse assays. A cell-line derived xenograft model (CDX-M) with pancreatic cancer cell line and a patient-derived xenograft mouse model (PDX-M) using resected pancreatic cancer samples without neoadjuvant chemotherapy were established in both heterotopic and orthotopic manners. PGV-1 effectively suppressed tumor formation at the heterotopic and orthotopic sites in CDX-M than in untreated mice. Combination therapy with PGV-1 and gemcitabine more effectively suppressed tumor formation than monotherapy with PGV-1 or gemcitabine when administered after tumor formation. Monotherapy with PGV-1 or gemcitabine less effectively suppressed tumor formation in PDX-M than in CDX-M, whereas combination therapy with PGV-1 and gemcitabine more effectively suppressed tumor formation. PGV-1 as monotherapy and combination therapy with gemcitabine effectively inhibited tumor formation and has potential as an anticancer candidate for pancreatic cancer.

Effective breast cancer therapy based on palmitic acid-loaded PLGA nanoparticles

Although new strategies for breast cancer treatment have yielded promising results, most drugs can lead to serious side effects when applied systemically. Doxorubicin (DOX), currently the most effective chemotherapeutic drug to treat breast cancer, is poorly selective towards tumor cells and treatment often leads to the development of drug resistance. Recent studies have indicated that several fatty acids (FAs) have beneficial effects on inhibiting tumorigenesis. The saturated FA palmitic acid (PA) showed anti-tumor activities in several types of cancer, as well as effective repolarization of M2 macrophages towards the anti-tumorigenic M1 phenotype. However, water insolubility and cellular impermeability limit the use of PA in vivo. To overcome these limitations, here, we encapsulated PA into a poly(d,l-lactic co-glycolic acid) (PLGA) nanoparticle (NP) platform, alone and in combination with DOX, to explore PA's potential as mono or combinational breast cancer therapy. Our results showed that PLGA-PA-DOX NPs and PLGA-PA NPs significantly reduced the viability and migratory capacity of breast cancer cells in vitro. In vivo studies in mice bearing mammary tumors demonstrated that PLGA-PA-NPs were as effective in reducing primary tumor growth and metastasis as NPs loaded with DOX, PA and DOX, or free DOX. At the molecular level, PLGA-PA NPs reduced the expression of genes associated with multi-drug resistance and inhibition of apoptosis, and induced apoptosis via a caspase-3-independent pathway in breast cancer cells. In addition, immunohistochemical analysis of residual tumors showed a reduction in M2 macrophage content and infiltration of leukocytes after treatment of PLGA-PA NPs and PLGA-PA-DOX NPs, suggesting immunomodulatory properties of PA in the tumor microenvironment. In conclusion, the use of PA alone or in combination with DOX may represent a promising novel strategy for the treatment of breast cancer.

Model-Based Regional Control with Anomalous Diffusion of Multi-Drug Combined Cancer Therapy for Volume Predictions

Symmetry breaking in the anatomical lung is triggered by tumorigenesis and disrupted by delivering single or multiple drugs to stop the progression of the tumor and treat cancer. In this study, a prior model of combined drug therapy is augmented to introduce tissue heterogeneity when the drug is applied in multi-drug therapy of lung cancer. Patient-related drug resistance and synergy are investigated as a function of diffusion intensity as drug molecules reach the tumor site. The results indicate that diffusion of drug molecules plays an important role next to other factors such as patient sensitivity to the drug and drug synergy effects. We conclude that the minimal model provides meaningful predictions on tumor growth at the intermediate mesoscale level. With such models at hand, it is now possible to employ model-based control algorithms to optimize the dose profiles in terms of time and amount. In this paper, we present a theoretical framework for control employing networked game theory optimality. Specific situations are discussed in terms of finding optimality at Nash equilibrium in relation to patient response and drug synergy effects.

A copper nanocluster-based multifunctional nanoplatform for augmented chemo/chemodynamic/photodynamic combination therapy of breast cancer

With the development of nano drug delivery system, the treatment mode that can overcome the shortcomings of chemotherapy drugs and integrate combined therapy remains to be explored. Herein, a nano drug system was designed to achieve the combined effect of chemo/chemodynamic/photodynamic therapy on cancer. Specifically, copper clusters (CuNCs) were used as the carrier, hyaluronic acid (HA) and doxorubicin (DOX) were coupled on CuNCs and then and chlorin e6 (Ce6) was introduced to form the self-assembled HA-CuNCs@DC nanoparticles. In this system, the HA-CuNCs@DC was involved in the reaction to the acidic tumor microenvironment (TME)-release of DOX, which could not only inhibit tumor growth through chemotherapy, but enhance the generation of hydrogen peroxide. CuNCs carriers had the properties of Fenton-like activity to realize chemodynamic therapy (CDT) and oxidase-like activity to deplete intracellular glutathione (GSH). Additionally, the chemotherapy drug susceptibility increased owing to the GSH depletion and the outbreak of reactive oxygen species, indicating the enhanced CDT efficacy and amplified chemotherapy efficacy. It was also noteworthy that Ce6 could be activated by 660 nm light to produce abundant singlet oxygen for photodynamic therapy. Overall, our platform demonstrated excellent biosafety and tumor suppression capabilities. This multimodal theranostic strategy provided new insights into cancer therapy.

Chemical characterization and antineoplastic effect of oligosaccharides from Cabernet Franc red wine in mammary tumor model in mice

The present study characterized oligosaccharide compounds (Oligo) in Cabernet Franc red wine and investigated its antineoplastic effects against mammary tumor cells in vivo and in vitro, isolated or in combination with chemotherapy. The Oligo fraction was characterized by nuclear magnetic resonance spectroscopy and mass spectrometry. The complex mixture of Oligo showed high amounts of oligoxyloglucuronans, oligorhamnogalacturonans, oligoarabinogalactans, and oligoglucans, such as trehalose and isomaltotriose. To investigate the antineoplastic effects of Oligo, Female Swiss mice were subcutaneously inoculated with Ehrlich tumor cells and then received vehicle (distilled water, p.o.), Oligo solution (9, 35, or 70 mg/kg, p.o.), or methotrexate (1.5 mg/kg, i.p.). The treatments were administered in a conventional (21-d) or chemopreventive (42-d) protocol. Oligo reduced the growth of Ehrlich tumors in both protocols and increased the effectiveness of methotrexate in controlling tumor growth. Oligo did not reduce the viability of MCF-7, MDA-MB-231, MDA-MB-436, and HB4a human breast cells that were cultured for 48 h, showing no cytotoxicity. Overall, Oligo exerted an in vivo antineoplastic effect and modulated immune blood cells, dependent on treatment time, and was not directly cytotoxic to tumor cells. Thus, Oligo may indirectly regulate tumor cell development and may be a promising drug for cancer therapy in combination with methotrexate.

Developing a Gallium(III) Agent Based on the Properties of the Tumor Microenvironment and Lactoferrin: Achieving Two-Agent Co-delivery and Multi-targeted Combination Therapy of Cancer.

To develop a next-generation anticancer metal-based drug, realize the multi-targeted combination therapy of protein drug and metal-based drug for cancer, solve their co-delivery challenges, and improve their in vivo targeting ability, we proposed to develop a multi-targeted anticancer metal-based agent exploiting the properties of the tumor microenvironment (TME) and of lactoferrin (LF). To this end, we optimized a series of gallium (Ga, III) isopropyl-2-pyridyl-ketone thiosemicarbazone compounds to obtain a Ga compound (C4) with remarkable cytotoxicity and then constructed a new LF-C4 nanoparticle (LF-C4 NP) delivery system. In vivo studies showed that LF-C4 NPs not only had a greater capacity for inhibiting tumor growth than LF or C4 alone but also solved the co-delivery problems of LF and C4 and improved their targeting ability. Furthermore, free C4 and LF-C4 NPs inhibited tumor growth through multiple synergistic actions on the TME: killing cancer cell, inhibiting tumor angiogenesis, and activating immune system.

A New Sono-Chemo Sensitizer Overcoming Tumor Hypoxia for Augmented Sono/Chemo-Dynamic Therapy and Robust Immune-Activating Response.

Novel sonosensitizers with intrinsic characteristics for tumor diagnosis, efficient therapy, and tumor microenvironment regulation are appealing in current sonodynamic therapy. Herein, a manganese (Mn)-layered double hydroxide-based defect-rich nanoplatform is presented as a new type of sono-chemo sensitizer, which allows ultrasound to efficiently trigger reactive oxygen species generation for enhanced sono/chemo-dynamic therapy. Moreover, such a nanoplatform is able to relieve tumor hypoxia and achieve augmented singlet oxygen production via catalyzing endogenous H2 O2 into O2 . On top of these actions, the released Mn2+ ions and immune-modulating agent significantly intensify immune activation and reverse the immunosuppressive tumor microenvironment to the immunocompetent one. Consequently, this nanoplatform exhibits excellent anti-tumor efficacy and effectively suppresses both primary and distant tumor growth, demonstrating a new strategy to functionalize nanoparticles as sono-chemo sensitizers for synergistic combination cancer therapy.

Prediction of Drug Synergism between Peptides and Antineoplastic Drugs Paclitaxel, 5-Fluorouracil, and Doxorubicin Using In Silico Approaches.

Chemotherapy is the main treatment for most early-stage cancers; nevertheless, its efficacy is usually limited by drug resistance, toxicity, and tumor heterogeneity. Cell-penetrating peptides (CPPs) are small peptide sequences that can be used to increase the delivery rate of chemotherapeutic drugs to the tumor site, therefore contributing to overcoming these problems and enhancing the efficacy of chemotherapy. The drug combination is another promising strategy to overcome the aforementioned problems since the combined drugs can synergize through interconnected biological processes and target different pathways simultaneously. Here, we hypothesized that different peptides (P1-P4) could be used to enhance the delivery of chemotherapeutic agents into three different cancer cells (HT-29, MCF-7, and PC-3). In silico studies were performed to simulate the pharmacokinetic (PK) parameters of each peptide and antineoplastic agent to help predict synergistic interactions in vitro. These simulations predicted peptides P2-P4 to have higher bioavailability and lower Tmax, as well as the chemotherapeutic agent 5-fluorouracil (5-FU) to have enhanced permeability properties over other antineoplastic agents, with P3 having prominent accumulation in the colon. In vitro studies were then performed to evaluate the combination of each peptide with the chemotherapeutic agents as well as to assess the nature of drug interactions through the quantification of the Combination Index (CI). Our findings in MCF-7 and PC-3 cancer cells demonstrated that the combination of these peptides with paclitaxel (PTX) and doxorubicin (DOXO), respectively, is not advantageous over a single treatment with the chemotherapeutic agent. In the case of HT-29 colorectal cancer cells, the combination of P2-P4 with 5-FU resulted in synergistic cytotoxic effects, as predicted by the in silico simulations. Taken together, these findings demonstrate that these CPP6-conjugates can be used as adjuvant agents to increase the delivery of 5-FU into HT-29 colorectal cancer cells. Moreover, these results support the use of in silico approaches for the prediction of the interaction between drugs in combination therapy for cancer.

Nanoheterojunction-Mediated Thermoelectric Strategy for Cancer Surgical Adjuvant Treatment and β-Elemene Combination Therapy.

As an indispensable strategy for tumor treatment, surgery may cause two major challenges: tumor recurrence and wound infection. Here, a thermoelectric therapeutic strategy is provided as either an independent cancer therapy or surgical adjuvant treatment. Bi0.5 Sb1.5 Te3 (BST) and Bi2 Te2.8 Se0.2 (BTS) nanoplates composed of Z-scheme thermoelectric heterojunction (BST/BTS) are fabricated via a two-step hydrothermal processes. The contact between BST and BTS constructs an interfacial electric field due to Fermi energy level rearrangement, guiding electrons in the conductive band (CB) of BTS combine with the holes in the valance band (VB) of BST, leaving stronger reduction/oxidation potentials of electrons and holes in the CB of BST and the VB of BTS. Moreover, under a mild temperature gradient, another self-built-in electric field is formed facilitating the migration of electrons and holes to their surfaces. Based on the PEGylated BST/BTS heterojunction, a novel thermoelectric therapy platform is developed through intravenous injection of BST/BTS and external cooling of the tumors. This thermoelectric strategy is also proved effective for combination cancer therapy with β-elemene. Moreover, the combination of heterojunction and hydrogel is administrated on the wound after surgery, achieving efficient residual tumor treatment and antibacterial effects.

Immune-based combination therapy for esophageal cancer.

Esophageal cancer (EC) is an aggressive malignancy raising a healthcare concern worldwide. Standard treatment options include surgical resection, chemotherapy, radiation therapy, and targeted molecular therapy. The five-year survival rate for all stages of EC is approximately 20%, ranging from 5% to 47%, with a high recurrence rate and poor prognosis after treatment. Immunotherapy has shown better efficacy and tolerance than conventional therapies for several malignancies. Immunotherapy of EC, including immune checkpoint inhibitors, cancer vaccines, and adoptive cell therapy, has shown clinical advantages. In particular, monoclonal antibodies against PD-1 have a satisfactory role in combination therapy and are recommended for first- or second-line treatments. Here, we present a systematic summary and analysis of immunotherapy-based combination therapies for EC.

Perioperative chemotherapy with FLOT regimen in patients with resectable gastric or gastroesophageal junction adenocarcinoma (SIEWERT type I–III). Experience of the N. N. Blokhin russian cancer research center

To date, gastric cancer patients still have a poor prognosis. Current endoscopic or surgical treatment modalities are radical only for early gastric cancer (T1). Curability dramatically declines as tumor invasion progresses and lymph node metastasеs appear. In Europe and North America, the 5-year overall survival rate of patients with stage T2–4 cancer is 20 % [1]. Combination therapy for gastric cancer is being extensively studied to improve the treatment outcomes [2–6]. Currently, perioperative chemotherapy with FLOT regimen is the mainstay of resectable gastric cancer treatment in Europe. FLOT4-AIO randomized study has shown that the FLOT regimen was associated with significant increase in the median overall survival (50 versus 35 months), disease-free survival (18 versus 30 months) and R0 resection rate compared to ECF / ECХ regimen.In this work we evaluated the efficacy and toxicity of perioperative FLOT regimen in patients with gastric cancer and gastroesophageal junction cancer type I–III cT4aN0M0, cT1–4N + M0, using a prospective database of patients treated at the N. N. Blokhin Russian Cancer Research Center.

Combination therapy for cancer with IL-27 and anti-PD-1: A simplified mathematical model

Many experiential and clinical trials in cancer treatment show that a combination of immune checkpoint inhibitor with another agent can improve the tumor reduction. Anti Programmed death 1 (Anti-PD-1) is one of these immune checkpoint inhibitors that re-activate immune cells to inhibit tumor growth. In this work, we consider a combination treatment of anti-PD-1 and Interleukin-27 (IL-27). IL-27 has anti-cancer functions to promote the development of Th1 and CD8$^+$ T cells, but it also upregulates the expression of PD-1 and Programmed death ligand 1 (PD-L1) to inactivate these T cells. Thus, the functions of IL-27 in tumor growth is controversial. Hence, we create a simplified mathematical model to investigate whether IL-27 is pro-cancer or anti-cancer in the combination with anti-PD-1 and to what degree anti-PD-1 improves the efficacy of IL-27. Our synergy analysis for the combination treatment of IL-27 and anti-PD-1 shows that (i) ant-PD-1 can efficiently improve the treatment efficacy of IL-27; and (ii) there exists a monotone increasing function $F_c(G)$ depending on the treatment efficacy of anti-PD-1 $G$ such that IL-27 is an efficient anti-cancer agent when its dose is smaller than $F_c(G)$, whereas IL-27 is a pro-cancer agent when its dose is higher than $F_c(G)$. Our analysis also provides the existence and the local stability of the trivial, non-negative, and positive equilibria of the model. Combining with simulation, we discuss the effect of the IL-27 dosage on the equilibria and find that the T cells and IFN-$\gamma$ could vanish and tumor cells preserve, when the production rate of T cells by IL-27 is low or the dosage of IL-27 is low.

Prostate-specific antigen density as a predictor of recurrence-free survival following combined hormonal-radiation therapy of localized prostate cancer

Background. Prostate cancer is amongst one of the most prevalent cancers in men worldwide. Combined hormonal-radiation therapy has become a standard of care for localized prostate cancer definitive treatment. As many as 30 % of men are at risk for disease progression within 10 years following radical treatment.Aim. To assess the significance of prostate-specific antigen (PSA) density as a predictor of recurrence-free survival following combined hormonal-radiation therapy in patients with localized prostate cancer.Materials and methods. We conducted a retrospective study of 272 patients with clinically localized prostate cancer treatment results who received combined hormonal-radiation therapy between January 1996 and December 2016.Results. On the basis of our study, we confirmed high prognostic value of PSA density among patients with localized prostate cancer who received combined hormonal-radiation treatment. We utilized ROC-analysis in order to determine the threshold value of the PSA density index – 0.376 ng/ml/cm3, exceeding of which was associated with statistically significant reduction in the recurrence-free survival rate. The area under the curve was 0.711 (95 % confidence interval 0.653–0.764; p <0.0001). The risk of recurrence increased with rising of PSA density.Conclusion. PSA density has proven to be a reliable tool for assessing the risk of prostate cancer recurrence among patients with localized prostate cancer who have undergone combined hormonal-radiation therapy.

Ultrathin Porous Nitrogen-Doped Carbon-Coated CuSe Heterostructures for Combination Cancer Therapy of Photothermal Therapy, Photocatalytic Therapy, and Logic-Gated Chemotherapy.

The construction of nanoplatforms for the multimodal cancer therapy still remains an enormous challenge. Ultrathin porous nitrogen-doped carbon coated stoichiometric copper selenide heterostructures (CuSe/NC) are prepared using a facile and green one-pot hydrothermal method. Interestingly, CuSe/NC itself can achieve both photothermal therapy (PTT) and photocatalytic therapy (PCT) under irradiation of a single near-infrared (NIR) light (808 nm), which is convenient and safe for clinical applications. Importantly, the triple-enhanced NIR light-activated PCT, including O2-independent free radicals, Fenton-like reaction, and glutathione (GSH) depletion, breaks through the limitations of hypoxia and overexpressed GSH in cancer cells. Furthermore, CuSe/NC is loaded with doxorubicin (DOX) via metal coordination and then decorates with DNA to construct the CuSe/NC-DOX-DNA nanoplatform. Surprisingly, the facile nanoplatform has an advanced biocomputing capability of an "AND" Boolean logic gate with the smart "AND" logic controlled release of DOX upon combined stimuli of pH and GSH for precise cancer chemotherapy. The synergistic mechanism of proton-mediated ligand exchange between DOX and GSH is proposed for the "AND" logic controlled drug release from CuSe/NC-DOX-DNA. In vitro and in vivo studies demonstrate that CuSe/NC-DOX-DNA has excellent anticancer efficacy and negligible toxicity. This innovative nanoplatform with multienhanced anticancer efficacy provides a paradigm for combination cancer therapy of PTT, PCT, and chemotherapy.

Tailoring carrier-free nanocombo of small-molecule prodrug for combinational cancer therapy.

The outcomes of monotherapy could not satisfy clinical cancer treatment owing to the challenges of tumor heterogeneity, multi-drug resistance, tumor metastasis and relapse. In response, the significance of combinational cancer therapy has been highlighted. Traditional combinational schemes usually utilize "free" drug for multi drug administration, independently. The diverse pharmacokinetics and biodistribution greatly hinder the antitumor effects and cause systematic toxicity. To tackle the hinderance, various nanoparticulate drug delivery systems (Nano-DDSs) have been developed. However, conventional Nano-DDSs encapsulate drugs into carrier materials through noncovalent interactions, resulting in low drug loading, fixed multi drug encapsulation ratio, chemical instability and carrier-associated toxicity. Recently, carrier-free nanocombos based on self-assembling small-molecule prodrugs (SPNCs) have emerged as a versatile Nano-DDSs for multiple drug delivery. Benefited by the self-assembly capability, SPNCs could be facilely fabricated with distinct merits of ultra-high drug loading, adjustable drug ratio and negligible carrier-associated toxicity. Herein, we summarize the latest trends of SPNCs. First, a basic review on self-assembling small-molecule prodrugs is presented. Additionally, facile techniques to prepare SPNCs are introduced. Furthermore, advanced combinational therapies based on SPNCs are spotlighted with special emphasis on synergistic mechanisms. Finally, future prospects and challenges are discussed.

PP038 Drug repurposing and gemcitabine-based combination therapy for pancreatic cancer

PP038 Drug repurposing and gemcitabine-based combination therapy for pancreatic cancer

Dual-Drug Nanosystem: Etoposide Prodrug and Cisplatin Coloaded Nanostructured Lipid Carriers for Lung Cancer Therapy.

Cisplatin (CDDP) and etoposide (Etp) are recommended first-line therapy for lung cancer. Nanostructured lipid carriers (NLCs) are engineered to deliver drugs for lung cancer treatment. In the present study, NLCs were applied to coload an Etp prodrug (EtpP) and CDDP. The Etp prodrug was synthesized by linking the phenolic hydroxyl group of Etp with polyethylene glycol (PEG). EtpP and CDDP coencapsulated NLCs (EtpP-CDDP NLCs) were prepared using film ultrasound. Cytotoxicity of drugs and drug-containing NLCs was assessed by evaluating cell viability using MTT assays. In vivo antitumor efficiency of EtpP-CDDP NLCs was evaluated on lung cancer-bearing xenografts. EtpP-CDDP NLCs showed a uniformly spherical morphology with a size of 176.8±4.9 nm and -potential of -31.9±3.2 mV. Cellular uptake efficiency of EtpP-CDDP NLCs was 57.4%±3.9% on A549/DDP cells. EtpP-CDDP NLCs exhibited more sustained plasma retention, the highest drug distribution in tumors, and the highest tumor-inhibition rates in lung tumor-bearing mice. EtpP-CDDP NLCs improved tumor-cell uptake, cytotoxicity, and tumor-inhibition efficiency, and could be used as a promising drug-delivery system for lung cancer combination therapy.

Potential of histone deacetylase inhibitors for the therapy of ovarian cancer.

Malignant ovarian tumors bear the highest mortality rate among all gynecological cancers. Both late tumor diagnosis and tolerance to available chemotherapy increase patient mortality. Accumulating evidence demonstrates that histone modifications play a key role in cancerization and progression. Histone deacetylases is associated with chromatin condensed structure and transcriptional repression and play a role in chromatin remodeling and epigenetics. Histone deacetylases are promising targets for therapeutic interventions intended to reverse aberrant epigenetic associated with cancer. Therefore, histone deacetylases inhibitors could be used as anti-cancer drugs. Preclinical studies have shown promising outcomes of histone deacetylases inhibitors in ovarian cancer while clinical trials have had mixed results and limited success as monotherapy. Therefore, combination therapy with different anticancer drugs for synergistic effects and newly selective histone deacetylases inhibitors development for lower toxicity are hot issues now. In this review, we summarize the latest studies on the classification and mechanisms of action of histone deacetylase and the clinical application of their inhibitors as monotherapy or combination therapy in ovarian cancer.

Polylactic acid based polymeric nanoparticle mediated co-delivery of navitoclax and decitabine for cancer therapy

Combination chemotherapy with systemic administration of drugs in their free form can be challenging due to non-synchronized pharmacokinetics and sub-optimal tumor accumulation. The present study investigates a PLA-based block copolymeric nanocarrier for the co-delivery of navitoclax and decitabine (NAV/DCB NPs) for combination cancer therapy. NAV/DCB NPs exhibited potent in vitro synergistic cytotoxicity in both acute myeloid leukemia and breast cancer cell lines. Biodistribution studies of NAV/DCB NPs in tumor bearing mice, showed significant drug accumulation in tumor tissue and detectable quantities in plasma even after 48 h. Good hemocompatibility with reduced in vivo platelet toxicity indicated that encapsulation in PLA-based nanocarrier helped ameliorate navitoclax associated thrombocytopenia. In vivo biological activity of NAV/DCB NPs evaluated in xenograft AML and syngeneic breast cancer model, demonstrated potent tumor growth inhibition efficacy. PLA-based NAV/DCB dual NPs present a novel, safe and effective nanoformulation for combination cancer therapy in both solid tumors and hematologic malignancies.