RNA granules and exosomes produced by tumour cells under various stresses in the microenvironment act as critical determinants of cell survival by promoting angiogenesis, cancer metastasis, chemoresistance, and immunosuppression. Meanwhile, developmental cancer/testis (CT) antigens that are normally sequestered in male germ cells of the testes, but which are overexpressed in malignant tumour cells, can function as tumour antigens triggering immune responses. As CT antigens are potential vaccine candidates for use in cancer immunotherapy, they could be targeted together with crosstalk between stress granules, exosomes, and immune cells for a synergistic effect. In this review, we describe the effects of exosomes and exosomal components presented to the recipient cells under different types of stresses on immune cells and cancer progression. Furthermore, we discuss their significance for cancer immunity, as well as the outlook for their future application.
We created and evaluated an enhanced topical delivery system featuring a combination of highly skin-permeable growth factors (GFs), quercetin (QCN), and oxygen; these synergistically accelerated re-epithelialization and granulation tissue formation of/in diabetic wounds by increasing the levels of GFs and antioxidants, and the oxygen partial pressure, at the wound site.To enhance the therapeutic effects of exogenous administration of GFs for the treatment of diabetic wounds, we prepared highly skin-permeable GF complexes comprised of epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), platelet-derived growth factor-A (PDGF-A), and basic fibroblast growth factor (bFGF), genetically attached, via the N-termini, to a low-molecular-weight protamine (LMWP) to form LMWP-EGF, LMWP-IGF-I, LMWP-PDGF-A, and LMWP-bFGF, respectively. Furthermore, quercetin (QCN)- and oxygen-carrying 1-bromoperfluorooctane (PFOB)-loaded nanoemulsions (QCN-NE and OXY-PFOB-NE) were developed to improve the topical delivery of QCN and oxygen, respectively. After confirming the enhanced penetration of LMWP-GFs, QCN-NE, and oxygen delivered from OXY-PFOB-NE across human epidermis, we evaluated the effects of combining LMWP-GFs, QCN-NE, and OXY-PFOB-NE on proliferation of keratinocytes and fibroblasts, and the chronic wound closure rate of a diabetic mouse model.The optimal ratios of LMWP-EGF, LMWP-IGF-I, LMWP-PDGF-A, LMWP-bFGF, QCN-NE, and OXY-PFOB-NE were 1, 1, 0.02, 0.02, 0.2, and 60, respectively. Moreover, a Carbopol hydrogel containing LMWP-GFs, QCN-NE, and OXY-PFOB-NE (LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL) significantly improved scratch-wound recovery of keratinocytes and fibroblasts in vitro compared to that afforded by hydrogels containing each component alone. LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL significantly accelerated wound-healing in a diabetic mouse model, decreasing wound size by 54 and 35% compared to the vehicle and LMWP-GFs, respectively.LMWP-GFs/QCN-NE/OXY-PFOB-NE-GEL synergistically accelerated the healing of chronic wounds, exerting both rapid and prolonged effects.
To prepare orally available oxaliplatin (OXA), nanocomplexes were formed by ionic conjugation of OXA with the deoxycholic acid derivative, Nalpha-deoxycholy-L-lysyl-methylester (DCK), as an oral absorption enhancer. We characterized the DCK-conjugated OXA nanocomplexes by differential scanning calorimetry, particle size determination, and morphological analysis. To evaluate the effects of DCK on the intestinal permeability of OXA, we assessed the solubilities and partition coefficients of OXA and the OXA/DCK nanocomplex, and then conducted in vitro artificial intestinal membrane and Caco-2 cell permeability studies. Finally, bioavailability in rats and tumor growth inhibition in the squamous cell carcinoma (SCC7) model after oral administration of the OXA/DCK nanocomplex were investigated compared to pure OXA. Analysis of the ionic complex formation of OXA with DCK revealed that OXA existed in an amorphous form within the complex, resulting in for- mation of nanocomp;exes (35.05 +/- 4.48 nm in diameter). The solubility of OXA in water was approximately 7.07 mg/mL, whereas the water solubility of OXA/DCK was approximately 2.04 mg/mL and its partition coefficient was approximately 1.2-fold higher than that of OXA. The in vitro intestinal membrane permeability of OXA was significantly enhanced by complex formation with DCK. An in vivo pharmacokinetic study revealed that the Cm value of the OXA/DCK nanocomplex was 3.18-fold higher than that of OXA (32.22 +/- 10.24 ng/mL), and the resulting oral bioavailability of the OXA/DCK nanocomplex was 39.3-fold more than that of OXA. Furthermore, the oral administration of OXA/DCK significantly inhibited tumor growth in SCC7-bearing mice, and maximally inhibited tumor volume by 54% compared to the control. These findings demonstrate the therapeutic potential of the OXA/DCK nanocomplex as an oral anti-cancer therapy because it improves the oral absorption of OXA, which may improve patient compliance and expand the therapeutic applications of OXA to the prevention of recurrence and metastasis.
Oral insulin therapy has great potential benefits over conventional therapy for diabetic patients as well as mimicking the physiological fate of insulin. Here we evaluated the characteristics of insulin and deoxycholate-based synthetic N(alpha)-deoxycholyl-L-lysyl-methylester (DCK) complex, and diabetes correction in pancreatectomized canines after oral administration. After the insulin/DCK complexation was made, the insulin's folding structure, stability against digestive enzymes, lipophilicity and permeability to Caco-2 monolayer were evaluated in vitro. Diabetic canines were kept under fasting conditions, and Eudragit-coated gelatin capsules containing insulin or insulin/DCK powder were singly or triply administered. Evaluation of glucodynamics, pharmacokinetics, oral glucose tolerance test (OGTT) and reproducibility were carried out. After complexation with DCK, the folding structure of insulin did not become denatured and the resistance against digestive enzymes was powerfully improved. The lipophilicity and permeability of insulin/DCK (coupling ratio up to 1:10) were also highly increased. The insulin/DCK complex, administered orally into diabetic canines at the doses of 21, 42, and 81 IU/kg, reduced the plasma glucose levels by about 28%, 44% and 67%, respectively, while the plasma insulin concentrations increased. During OGTT, insulin/DCK nearly maintained the normoglycemic state in the diabetic canines, whereas the hyperglycemic state of placebo-treated controls was not corrected. During oral administration of insulin/DCK, it repetitively showed similar therapeutic efficacy in diabetic canines for 3 days. The therapeutic efficacy of insulin/DCK was exhibited in its digestive enzyme resistance, deoxycholate-based lipophilicity for enhancing permeability and intact insulin delivery without chemical modification, providing potential oral therapeutic remedy as an alternative to injectable insulin medication.
Tumor heterogeneity and evolutionary complexity may underlie treatment failure in spite of the development of many targeted agents. We suggest a novel strategy termed induced phenotype targeted therapy (IPTT) to simplify complicated targets because of tumor heterogeneity and overcome tumor evolutionary complexity.We designed a caspase-3 specific activatable prodrug, DEVD-S-DOX, containing doxorubicin linked to a peptide moiety (DEVD) cleavable by caspase-3 upon apoptosis. To induce apoptosis locally in the tumor, we used a gamma knife, which can irradiate a very small, defined target area. The in vivo antitumor activity of the caspase-3-specific activatable prodrug combined with radiation was investigated in C3H/HeN tumor-bearing mice (n = 5 per group) and analyzed with the Student's t test or Mann-Whitney U test. All statistical tests were two-sided. We confirmed the basic principle using a caspase-sensitive nanoprobe (Apo-NP).A single exposure of radiation was able to induce apoptosis in a small, defined region of the tumor, resulting in expression of caspase-3. Caspase-3 cleaved DEVD and activated the prodrug. The released free DOX further activated DEVD-S-DOX by exerting cytotoxic effects on neighboring tumor or supporting cells, which repetitively induced the expression of caspase-3 and the activation of DEVD-S-DOX. This sequential and repetitive process propagated the induction of apoptosis. This novel therapeutic strategy showed not only high efficacy in inhibiting tumor growth (14-day tumor volume [mm(3)] vs radiation alone: 848.21 ± 143.24 vs 2511.50 ± 441.89, P < .01) but also low toxicity to normal cells and tissues.Such a phenotype induction strategy represents a conceptually novel approach to overcome tumor heterogeneity and complexity as well as to substantially improve current conventional chemoradiotherapy with fewer sequelae and side effects.
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