Cancer nanomedicines were initially envisioned as magic bullets, travelling through the circulation to target tumours while sparing healthy tissues the toxicity of classic chemotherapy. While a limited number of nanomedicine therapies have resulted, the disappointing news is that major obstacles were overlooked in the nanoparticle's journey. However, some of these challenges may be turned into opportunities. Here, we discuss biological barriers to cancer nanomedicines and elaborate on two directions that the field is currently exploring to meet its initial expectations. The first strategy entails re-engineering cancer nanomedicines to prevent undesired interactions en route to the tumour. The second aims instead to leverage these obstacles into out-of-the-box diagnostic and therapeutic applications of nanomedicines, for cancer and beyond. Both paths require, among other developments, a deeper understanding of nano-bio interactions. We offer a forward look at how classic cancer nanomedicine may overcome its limitations while contributing to other areas of research.

Obstacles and opportunities in a forward vision for cancer nanomedicine.

A review on the efficacy and toxicity of different doxorubicin nanoparticles for targeted therapy in metastatic breast cancer.

Liposomes hold great potential as gene and drug delivery vehicles due to their biocompatibility and modular properties, coupled with the major advantage of attenuating the risk of systemic toxicity from the encapsulated therapeutic agent. Decades of research have been dedicated to studying and optimizing liposomal formulations for a variety of medical applications, ranging from cancer therapeutics to analgesics. Some effort has also been made to elucidate the toxicities and immune responses that these drug formulations may elicit. Notably, intravenously injected liposomes can interact with plasma proteins, leading to opsonization, thereby altering the healthy cells they come into contact with during circulation and removal. Additionally, due to the pharmacokinetics of liposomes in circulation, drugs can end up sequestered in organs of the mononuclear phagocyte system, affecting liver and spleen function. Importantly, liposomal agents can also stimulate or suppress the immune system depending on their physiochemical properties, such as size, lipid composition, pegylation, and surface charge. Despite the surge in the clinical use of liposomal agents since 1995, there are still several drawbacks that limit their range of applications. This review presents a focused analysis of these limitations, with an emphasis on toxicity to healthy tissues and unfavorable immune responses, to shed light on key considerations that should be factored into the design and clinical use of liposomal formulations.

https://www.mdpi.com/2079-4991/10/2/190/pdf

Immunological and Toxicological Considerations for the Design of Liposomes.

https://air.unimi.it/bitstream/2434/422095/2/Ferritin%20Nanocages_Manuscript_Mazzucchelli_Revised_Final.pdf

Ferritin nanocages: A biological platform for drug delivery, imaging and theranostics in cancer.

// Navid Koleini 1,2 and Elissavet Kardami 1,2,3 1 Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, Manitoba, Canada 2 Department of Physiology and Pathophysiology, Winnipeg, Manitoba, Canada 3 Department of Human Anatomy and Cell Sciences, University of Manitoba, Winnipeg, Manitoba, Canada Correspondence to: Elissavet Kardami, email: // Keywords : oncocardiology, anthracyclines, heart failure, impaired autophagy and mitophagy, lysosomal dysfunction Received : November 25, 2016 Accepted : March 17, 2017 Published : April 07, 2017 Abstract Doxorubicin (Dox) is a cytotoxic drug widely incorporated in various chemotherapy protocols. Severe side effects such as cardiotoxicity, however, limit Dox application. Mechanisms by which Dox promotes cardiac damage and cardiomyocyte cell death have been investigated extensively, but a definitive picture has yet to emerge. Autophagy, regarded generally as a protective mechanism that maintains cell viability by recycling unwanted and damaged cellular constituents, is nevertheless subject to dysregulation having detrimental effects for the cell. Autophagic cell death has been described, and has been proposed to contribute to Dox-cardiotoxicity. Additionally, mitophagy, autophagic removal of damaged mitochondria, is affected by Dox in a manner contributing to toxicity. Here we will review Dox-induced cardiotoxicity and cell death in the broad context of the autophagy and mitophagy processes.

/pdf/autophagy-and-mitophagy-in-the-context-of-doxorubicin-ab6mih44tx.pdf

Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity

Background 
Various trials have compared the efficacy and toxicity of liposomal doxorubicin-based chemotherapy with the conventional formulation of doxorubicin although arriving at inconsistent conclusions. To derive a conclusive assessment of the efficacy and cardiotoxicity associated with chemotherapy, we performed a meta-analysis by combining data from all eligible randomized controlled trials.
Methods 
We used the PubMed database to identify relevant studies published through December 28, 2014. Eligible studies included randomized controlled trials directly comparing the efficacy and cardiotoxicity of liposomal doxorubicin-based chemotherapy with conventional doxorubicin in advanced breast cancer with adequate data. Odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (CIs) were used to assess the efficacy and cardiotoxicity in a fixed-effects or random-effects model.
Results 
Ten randomized controlled trials containing efficacy and data from a total of 2,889 advanced breast cancer patients were included in this report. Liposomal doxorubicin-based chemotherapy was associated with a significant reduction in the risk of cardiotoxicity (OR = 0.46, 95% CI 0.23 to 0.92, p = 0.03) and a significant improvement in the overall response rate (ORR) (OR = 1.25, 95% CI 1.02 to 1.52, p=0.03) compared with conventional doxorubicin. An apparent improvement in progression-free survival (PFS) for patients treated with liposomal doxorubicin-based chemotherapy was noted; however, this difference was not significant (HR = 1.14, 95% CI 0.96 to 1.34, p = 0.12). In terms of overall survival (OS), no significant difference between the two chemotherapy regimens was noted (HR = 1.00, 95% CI 0.91 to 1.10, p = 0.93).
Conclusion 
The results of this meta-analysis suggest that liposomal doxorubicin-based chemotherapy is associated with a significant improvement in the ORR and a significant reduction in the risk of cardiotoxicity.

/pdf/efficacy-and-cardiotoxicity-of-liposomal-doxorubicin-based-1i9jjob4r9.pdf

Efficacy and Cardiotoxicity of Liposomal Doxorubicin-Based Chemotherapy in Advanced Breast Cancer: A Meta-Analysis of Ten Randomized Controlled Trials.

Next-generation sequencing technology allows simultaneous analysis of multiple susceptibility genes for clinical cancer genetics. In this study, multiplex genetic testing was conducted in a Chinese family with multiple cases of cancer to determine the variations in cancer predisposition genes. The family comprises a mother and her five daughters, of whom the mother and the eldest daughter have cancer and the secondary daughter died of cancer. We conducted multiplex genetic testing of 90 cancer susceptibility genes using the peripheral blood DNA of the mother and all five daughters. WRN frameshift mutation is considered a potential pathogenic variation according to the guidelines of the American College of Medical Genetics. A novel WRN frameshift mutation (p.N1370Tfs*23) was identified in the three cancer patients and in the youngest unaffected daughter. Other rare non-synonymous germline mutations were also detected in DICER and ELAC2. Functional mutations in WRN cause Werner syndrome, a human autosomal recessive disease characterized by premature aging and associated with genetic instability and increased cancer risk. Our results suggest that the WRN frameshift mutation is important in the surveillance of other members of this family, especially the youngest daughter, but the pathogenicity of the novel WRN frameshift mutation needs to be investigated further. Given its extensive use in clinical genetic screening, multiplex genetic testing is a promising tool in clinical cancer surveillance.

/pdf/a-novel-wrn-frameshift-mutation-identified-by-multiplex-sc9tmp9c9c.pdf

A Novel WRN Frameshift Mutation Identified by Multiplex Genetic Testing in a Family with Multiple Cases of Cancer

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Efficacy and Cardiotoxicity of Liposomal Doxorubicin-Based Chemotherapy in Advanced Breast Cancer: A Meta-Analysis of Ten Randomized Controlled Trials.

A Novel WRN Frameshift Mutation Identified by Multiplex Genetic Testing in a Family with Multiple Cases of Cancer