18 research outputs found
Ultrasound-directed enzyme-prodrug therapy (UDEPT) using self-immolative doxorubicin derivatives
Background: Enzyme-activatable prodrugs are extensively employed in oncology and beyond. Because enzyme concentrations and their (sub)cellular compartmentalization are highly heterogeneous in different tumor types and patients, we propose ultrasound-directed enzyme-prodrug therapy (UDEPT) as a means to increase enzyme access and availability for prodrug activation locally. Methods: We synthesized β-glucuronidase-sensitive self-immolative doxorubicin prodrugs with different spacer lengths between the active drug moiety and the capping group. We evaluated drug conversion, uptake and cytotoxicity in the presence and absence of the activating enzyme β-glucuronidase. To trigger the cell release of β-glucuronidase, we used high-intensity focused ultrasound to aid in the conversion of the prodrugs into their active counterparts. Results: More efficient enzymatic activation was observed for self-immolative prodrugs with more than one aromatic unit in the spacer. In the absence of β-glucuronidase, the prodrugs showed significantly reduced cellular uptake and cytotoxicity compared to the parent drug. High-intensity focused ultrasound-induced mechanical destruction of cancer cells resulted in release of intact β-glucuronidase, which activated the prodrugs, restored their cytotoxicity and induced immunogenic cell death. Conclusion: These findings shed new light on prodrug design and activation, and they contribute to novel UDEPT-based mechanochemical combination therapies for the treatment of cancer
Hygiene in der Praxis
Glucocorticoids (GC) are known for their potent immunosuppressive and anti-inflammatory properties. As a consequence, they have been extensively used for the treatment of many different diseases. Prolonged and/or high-dose GC therapy, however, generally comes with severe side effects, resulting not only from their very diverse mechanism(s) of action, but also from their relatively poor biodistribution. Drug delivery systems, and in particular liposomes, have been extensively used to enhance the biodistribution and the target site accumulation of GC, and to thereby improve the balance between their efficacy and their toxicity. Many different types of liposomes have been employed, and both local and systemic treatments have been evaluated. We here summarize the progress made in the use of liposomal GC formulations for the treatment of asthma, rheumatoid arthritis, multiple sclerosis and cancer, and we show that the targeted delivery of GC to pathological sites holds significant clinical potential
Liposomal corticosteroids for the treatment of inflammatory disorders and cancer
Glucocorticoids (GC) are known for their potent immunosuppressive and anti-inflammatory properties. As a consequence, they have been extensively used for the treatment of many different diseases. Prolonged and/or high-dose GC therapy, however, generally comes with severe side effects, resulting not only from their very diverse mechanism(s) of action, but also from their relatively poor biodistribution. Drug delivery systems, and in particular liposomes, have been extensively used to enhance the biodistribution and the target site accumulation of GC, and to thereby improve the balance between their efficacy and their toxicity. Many different types of liposomes have been employed, and both local and systemic treatments have been evaluated. We here summarize the progress made in the use of liposomal GC formulations for the treatment of asthma, rheumatoid arthritis, multiple sclerosis and cancer, and we show that the targeted delivery of GC to pathological sites holds significant clinical potential
Influence of cholesterol inclusion on the doxorubicin release characteristics of lysolipid-based thermosensitive liposomes
Fast hyperthermia (i.e. 39-42 °C) triggered doxorubicin release from lysolipid-containing thermosensitive liposomes (LTSL) in the tumor vasculature has been demonstrated to result in considerable enhancement of bioavailable drug levels in heated tumor tissue in preclinical tumor models. However, there is also significant leakage of doxorubicin already at 37 °C in the bloodstream, making these LTSL less efficient and increasing the risk for systemic toxicity. In conventional liposomes, cholesterol is incorporated in the bilayer to increase the stability of the liposomes. Here, we investigate the effect of cholesterol inclusion on the doxorubicin release characteristics of LTSL at 37 °C and hyperthermic temperatures. For this purpose, three LTSL formulations with 0, 5 and 10 mol% cholesterol were prepared. Inclusion of cholesterol reduced the undesired doxorubicin leakage at 37 °C in Hepes-buffered saline (HBS) as well as in fetal bovine serum (FBS). The incorporation of cholesterol in the LTSL bilayers did not influence the hyperthermia-triggered release property of the LTSL. These results were supported by DSC measurements. Therefore, in conclusion, our data indicate that cholesterol inclusion in LTSL offers a simple solution to the problem of significant leakage of doxorubicin from LTSL already at 37 °C in the bloodstream
Hyperthermia-Induced Drug Delivery from Thermosensitive Liposomes Encapsulated in an Injectable Hydrogel for Local Chemotherapy
A novel drug delivery system, enabling an in situ, thermally triggered drug release is described, consisting of an injectable thermoresponsive chitosan hydrogel containing doxorubicin-loaded thermosensitive liposomes. The design, fabrication, characterization, and an assessment of in vitro bioactivity of this formulation is detailed. Combining on-demand drug delivery with in situ gelation results in a promising candidate for local chemotherap
Characteristics of temperature senstitive liposomes (TSL) loaded with DOX and [Gd(HPDO3A)(H<sub>2</sub>O)].
<p>Characteristics of temperature senstitive liposomes (TSL) loaded with DOX and [Gd(HPDO3A)(H<sub>2</sub>O)].</p
Temperature triggered release of DOX from TSL.
<p>Temperature triggered release of DOX from TSL (DPPC:MSPC:DSPE-PEG2.000 86:10:4) in 20 mM HEPES buffer pH 7.4 (A) or 50% fetal bovine serum (B) at 37 and 42°C. Temperature triggered DOX release from TSL-Ba-ms in 20 mM HEPES buffer pH 7.4 (C) and 50% FBS (D) at 37 and 42°C.</p
T<sub>1</sub>-maps and T<sub>1</sub>-wt images of intratumoral injected TSL-Ba-ms and Ho-ms in a tumor in the auricle of a New Zealand White rabbit.
<p>T<sub>1</sub>-maps (A-C) and T<sub>1</sub>-wt images (D-E) of a tumor in the auricle of a New Zealand White rabbit before (A,D) and after (B) intratumoral co-injection of TSL-Ba-ms and Ho-ms. Finally, the tumor was heated in the range between 42 and 46°C for 15 minutes (C,E).</p
Experimental setup for the preparation of alginate microspheres.
<p><b>(A) Schematic representation of the experimental setup.</b> An alginate solution (3% w/v in 20 mM HEPES buffer pH 7.4 containing 8 NaCl/L) is transferred into a syringe and introduced in the spraying system via a syringe pump (1.5 mL/min) which are connected via a plastic tube. Alginate droplets are formed by passing nitrogen gas (0.8 Bar) through the nozzle. The droplets are collected in a crosslinking solution (containing 100 mM barium chloride or holmium chloride). Photos of experimental setup (B) and nozzle (C).</p