EPR: Evidence and fallacy

Extracellular vesicles as drug delivery systems: lessons from the liposome field.

Odyssey of a cancer nanoparticle: from injection site to site of action.

Accumulating nanoparticles by EPR: A route of no return.

Three-dimensional in vitro cell systems are a promising alternative to animals to study cardiac biology and disease. We have generated three-dimensional in vitro models of the human heart (“cardiac spheroids”, CSs) by co-culturing human primary or iPSC-derived cardiomyocytes, endothelial cells and fibroblasts at ratios approximating those present in vivo. The cellular organisation, extracellular matrix and microvascular network mimic human heart tissue. These spheroids have been employed to investigate the dose-limiting cardiotoxicity of the common anti-cancer drug doxorubicin. Viability/cytotoxicity assays indicate dose-dependent cytotoxic effects, which are inhibited by the nitric oxide synthase (NOS) inhibitor L-NIO, and genetic inhibition of endothelial NOS, implicating peroxynitrous acid as a key damaging agent. These data indicate that CSs mimic important features of human heart morphology, biochemistry and pharmacology in vitro, offering a promising alternative to animals and standard cell cultures with regard to mechanistic insights and prediction of toxic effects in human heart tissue.

/pdf/cardiac-spheroids-as-promising-in-vitro-models-to-study-the-2y306yehh4.pdf

Cardiac spheroids as promising in vitro models to study the human heart microenvironment.

Background
The therapeutic success of chemotherapeutic agents is often limited by severe adverse effects. To reduce toxicity of these drugs, nanoscale particle-based drug delivery systems (DDS) are used. DDS accumulate to some extent in tumor tissues, but only a very small portion of a given dose reaches this target. Accumulation of DDS in tumor tissues is supposed to be much faster than in certain other tissues in which side effects occur ("Kinetic Targeting"). Once saturation in tumor tissue is achieved, most of the administered DDS still circulate in the plasma. The extracorporeal elimination of these circulating nanoparticles would probably reduce toxicity.

/pdf/kinetic-targeting-of-pegylated-liposomal-doxorubicin-a-new-43kuibpgj2.pdf

Kinetic Targeting of pegylated liposomal Doxorubicin: a new Approach to Reduce Toxicity during Chemotherapy (CARL-trial)

Neoadjuvant chemotherapy (NACT) is frequently used in patients with early breast cancer. Randomized controlled trials have demonstrated similar survival after NACT or adjuvant chemotherapy (ACT). However, certain subtypes may benefit more when NACT contains regimes leading to high rates of pathologic complete response (pCR) rates. In this study we analyzed data using the OncoBox research from 94,638 patients treated in 55 breast cancer centers to describe the current clinical practice of and outcomes after NACT under routine conditions. These data were compared to patients treated with ACT. 40% of all patients received chemotherapy. The use of NACT increased over time from 5% in 2007 up to 17.3% in 2016. The proportion of patients receiving NACT varied by subtype. It was low in patients with HR-positive/HER2-negative breast cancer (5.8%). However, 31.8% of patients with triple-negative, 31.9% with HR-negative/HER2-positive, and 26.5% with HR-positive/HER2-positive breast cancer received NACT. The rates of pCR were higher in patients with HR-positive/HER2-positive, HR-negative/HER2-positive and triple-negative tumors (36, 53 and 38%) compared to HR-positive/HER2-negative tumors (12%). PCR was achieved more often in HER2-positive and triple-negative tumors over time.This is the largest study on use and effects of NACT in German breast cancer centers. It demonstrates the increased use of NACT based on recommendations in current clinical guidelines. An improvement of pCR was shown in particular in HER2-positive and triple-negative breast cancer, which is consistent with data from randomized controlled trails. 

/pdf/current-clinical-practice-and-outcome-of-neoadjuvant-29xdr51q.pdf

Current clinical practice and outcome of neoadjuvant chemotherapy for early breast cancer: analysis of individual data from 94,638 patients treated in 55 breast cancer centers

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Kinetic Targeting of pegylated liposomal Doxorubicin: a new Approach to Reduce Toxicity during Chemotherapy (CARL-trial)

Current clinical practice and outcome of neoadjuvant chemotherapy for early breast cancer: analysis of individual data from 94,638 patients treated in 55 breast cancer centers