Safety Considerations of Cancer Nanomedicine-A Key Step toward Translation

Abstract

The rate of translational effort of nanomedicine requires strategic planning of nanosafety research in order to enable clinical trials and safe use of nanomedicine in patients. Herein, the experiences that have emerged based on the safety data of classic liposomal formulations in the space of oncology are discussed, along with a description of the new challenges that need to be addressed according to the rapid expansion of nanomedicine platform beyond liposomes. It is valuable to consider the combined use of predictive toxicological assessment supported by deliberate investigation on aspects such as absorption, distribution, metabolism, and excretion (ADME) and toxicokinetic profiles, the risk that may be introduced during nanomanufacture, unique nanomaterials properties, and nonobvious nanosafety endpoints, for example. These efforts will allow the generation of investigational new drug-enabling safety data that can be incorporated into a rational infrastructure for regulatory decision-making. Since the safety assessment relates to nanomaterials, the investigation should cover the important physicochemical properties of the material that may lead to hazards when the nanomedicine product is utilized in humans.

Keywords: clinical trials; nano safety; safe-by-design; translational nanomedicine.

Figure 1.

Comparative demonstration of free DOX and Doxil^®’s PK/biodistribution, targeted organ and safety features. (A) Appearance, cryoEM image and scheme of Doxil^® formulation. HSPC: hydrogenated soy phosphatidylcholine, Chol: cholesterol, DSPE-PEG_2K:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]. Reproduced with permission.^[21] Copyright 2012, Elsevier. (B) Pharmacokinetics (PK) profiles and main cardiotoxicity and palmar plantar erythrodysesthesia (PPE) effects/mechanism of doxorubicin and Doxil^® formulation. Reproduced with permission. ^{[21, 23, 34, 37]} Copyright 2012, Elsevier. Copyright 2003, Springer Nature. Copyright 2017, Elsevier. Copyright 2013, Springer Nature. (C) Clinical adverse effect profile of pegylated liposomal doxorubicin. Reproduced with permission.^[24] Copyright 2008, Elsevier. (D) Scheme and clinical adverse effect profile of liposomal irinotecan Onivyde^®. Reproduced with permission. ^{[48, 60]} Copyright 2014, Elsevier. Copyright 2016, Elsevier. (E) Scheme and clinical adverse effect profile of cytarabine and daunorubicin co-delivery liposome Vyxeos^®. Reproduced with permission.^{[64, 71]} Copyright 2018, Future Medicine Ltd. Copyright 2018, American Society of Clinical Oncology.

Figure 1.

Comparative demonstration of free DOX and Doxil^®’s PK/biodistribution, targeted organ and safety features. (A) Appearance, cryoEM image and scheme of Doxil^® formulation. HSPC: hydrogenated soy phosphatidylcholine, Chol: cholesterol, DSPE-PEG_2K:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]. Reproduced with permission.^[21] Copyright 2012, Elsevier. (B) Pharmacokinetics (PK) profiles and main cardiotoxicity and palmar plantar erythrodysesthesia (PPE) effects/mechanism of doxorubicin and Doxil^® formulation. Reproduced with permission. ^{[21, 23, 34, 37]} Copyright 2012, Elsevier. Copyright 2003, Springer Nature. Copyright 2017, Elsevier. Copyright 2013, Springer Nature. (C) Clinical adverse effect profile of pegylated liposomal doxorubicin. Reproduced with permission.^[24] Copyright 2008, Elsevier. (D) Scheme and clinical adverse effect profile of liposomal irinotecan Onivyde^®. Reproduced with permission. ^{[48, 60]} Copyright 2014, Elsevier. Copyright 2016, Elsevier. (E) Scheme and clinical adverse effect profile of cytarabine and daunorubicin co-delivery liposome Vyxeos^®. Reproduced with permission.^{[64, 71]} Copyright 2018, Future Medicine Ltd. Copyright 2018, American Society of Clinical Oncology.

Figure 1.

Comparative demonstration of free DOX and Doxil^®’s PK/biodistribution, targeted organ and safety features. (A) Appearance, cryoEM image and scheme of Doxil^® formulation. HSPC: hydrogenated soy phosphatidylcholine, Chol: cholesterol, DSPE-PEG_2K:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]. Reproduced with permission.^[21] Copyright 2012, Elsevier. (B) Pharmacokinetics (PK) profiles and main cardiotoxicity and palmar plantar erythrodysesthesia (PPE) effects/mechanism of doxorubicin and Doxil^® formulation. Reproduced with permission. ^{[21, 23, 34, 37]} Copyright 2012, Elsevier. Copyright 2003, Springer Nature. Copyright 2017, Elsevier. Copyright 2013, Springer Nature. (C) Clinical adverse effect profile of pegylated liposomal doxorubicin. Reproduced with permission.^[24] Copyright 2008, Elsevier. (D) Scheme and clinical adverse effect profile of liposomal irinotecan Onivyde^®. Reproduced with permission. ^{[48, 60]} Copyright 2014, Elsevier. Copyright 2016, Elsevier. (E) Scheme and clinical adverse effect profile of cytarabine and daunorubicin co-delivery liposome Vyxeos^®. Reproduced with permission.^{[64, 71]} Copyright 2018, Future Medicine Ltd. Copyright 2018, American Society of Clinical Oncology.

Figure 1.

Comparative demonstration of free DOX and Doxil^®’s PK/biodistribution, targeted organ and safety features. (A) Appearance, cryoEM image and scheme of Doxil^® formulation. HSPC: hydrogenated soy phosphatidylcholine, Chol: cholesterol, DSPE-PEG_2K:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]. Reproduced with permission.^[21] Copyright 2012, Elsevier. (B) Pharmacokinetics (PK) profiles and main cardiotoxicity and palmar plantar erythrodysesthesia (PPE) effects/mechanism of doxorubicin and Doxil^® formulation. Reproduced with permission. ^{[21, 23, 34, 37]} Copyright 2012, Elsevier. Copyright 2003, Springer Nature. Copyright 2017, Elsevier. Copyright 2013, Springer Nature. (C) Clinical adverse effect profile of pegylated liposomal doxorubicin. Reproduced with permission.^[24] Copyright 2008, Elsevier. (D) Scheme and clinical adverse effect profile of liposomal irinotecan Onivyde^®. Reproduced with permission. ^{[48, 60]} Copyright 2014, Elsevier. Copyright 2016, Elsevier. (E) Scheme and clinical adverse effect profile of cytarabine and daunorubicin co-delivery liposome Vyxeos^®. Reproduced with permission.^{[64, 71]} Copyright 2018, Future Medicine Ltd. Copyright 2018, American Society of Clinical Oncology.

Figure 1.

Comparative demonstration of free DOX and Doxil^®’s PK/biodistribution, targeted organ and safety features. (A) Appearance, cryoEM image and scheme of Doxil^® formulation. HSPC: hydrogenated soy phosphatidylcholine, Chol: cholesterol, DSPE-PEG_2K:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]. Reproduced with permission.^[21] Copyright 2012, Elsevier. (B) Pharmacokinetics (PK) profiles and main cardiotoxicity and palmar plantar erythrodysesthesia (PPE) effects/mechanism of doxorubicin and Doxil^® formulation. Reproduced with permission. ^{[21, 23, 34, 37]} Copyright 2012, Elsevier. Copyright 2003, Springer Nature. Copyright 2017, Elsevier. Copyright 2013, Springer Nature. (C) Clinical adverse effect profile of pegylated liposomal doxorubicin. Reproduced with permission.^[24] Copyright 2008, Elsevier. (D) Scheme and clinical adverse effect profile of liposomal irinotecan Onivyde^®. Reproduced with permission. ^{[48, 60]} Copyright 2014, Elsevier. Copyright 2016, Elsevier. (E) Scheme and clinical adverse effect profile of cytarabine and daunorubicin co-delivery liposome Vyxeos^®. Reproduced with permission.^{[64, 71]} Copyright 2018, Future Medicine Ltd. Copyright 2018, American Society of Clinical Oncology.

Figure 2.

Overall blueprint of safety assessment of nanomedicine. Therapeutic nanomaterials of various chemical compositions demand comprehensive characterization, such as size, morphology, charge, surface area, porosity, crystal structure, API concentration, release profiles, etc. It is necessary to consider HTS assays and response readouts in cells to obtain mechanistic toxicity insight with a view to plan and prioritize the animal assessments for the IND filing. The in vivo toxicity assessment should be designed and implemented with necessary consideration on ADME, toxicokinetics, administration routes, and acute vs chronic toxicity, which may not be fully covered in the in vitro assays. The output of these assays needs to be analyzed to facilitate the decision-making with respect to the technology translation. If necessary, a safe-by-design approach could be helpful to improve nanomedicine’s safety features. The preclinical data can be used to as a reference for the clinical safety assessment, i.e. patient adverse event report and management, for the efficacious and safe use of nanomedicine in patients.

Figure 3.

Mechanistic injury responses that are frequently involved in nanomaterials. This includes dissolution and release of toxic metal ions from metal or metal oxide nanoparticles, cationic injury to surface membrane and organelles, frustrated phagocytosis and inflammasome activation by long aspect ratio nanomaterials, reactive surface that may lead to membrane disruption, and bio-transformation response in rare earth nanoparticles.

Figure 4.

Critical research aspects that are required to strengthen nanomedicine nanosafety investigation.

Figure 5.

Safety assessment of Auroshell nanoparticles, an example for inorganic biomedical nanomaterials. (A) Scheme of the silica/gold core-shell structure of Auroshell nanoparticle. (B) Preclinical International Organization for Standardization (ISO) toxicological testing performed for Auroshell particles. (C) Mass balance data of mice receiving a single injection of Auroshell particles and sacrificed at the time points indicated. Gold content was detected by Neutron activation analysis (NAA). Reproduced with permission.^[154] Copyright 2012, SAGE Publishing.

Figure 6.

Development of silicasome drug nanocarrier to address irinotecan safety and efficacy for pancreatic and colon cancer treatment. (A) In the setting of PDAC, while FOLFIRINOX is more potent than GEM, this regimen is far more toxic, in which irinotecan contributes in a major way to its toxicity on the bone marrow and the GIT. (B) Scheme and unique characteristics of silicasome nanocarrier. (C) Successful scale-up development of silicasome for translational study. (D) Use of highly stringent orthotopic cancer models to study PK, efficacy and safety features of silicasome nanocarrier. Irinotecan delivery by silicasome led to a major improvement of efficacy and safety over free drug and commercial liposomes for PDAC and colon cancer. In order to study irinotecan’s toxicity in diffident formulations, liver, sternal bone marrow, and intestinal tissues were collected from the mice. Histological examination of these organs showed reduced hepatocyte necrosis and GIT apoptosis. Panel D highlights the H&E staining result of bone marrow. While animals treated with free drug or commercial liposomes generated strong effects on bone marrow damage (i.e. evidenced by ~30% of the space being filled by hematopoietic cells), there was no major reduction in silicasome treated mice. This correlates to peripheral blood neutropenia in patients receiving either free drug or Onivyde_®. No neutropenia was observed in mice receiving irinotecan silicasome. Reproduced with permission.^{[155, 164]} Copyright 2017, American Society for Clinical Investigation. All other figures. Copyright 2019, American Chemical Society.