Biomedical nanotechnology is an evolving field having enormous potential to positively impact the health care system. Important biomedical applications of nanotechnology that may have potential ...clinical applications include targeted drug delivery, detection/diagnosis and imaging. Basic understanding of how nanomaterials, the building blocks of nanotechnology, interact with the cells and their biological consequences are beginning to evolve. Noble metal nanoparticles such as gold, silver and platinum are particularly interesting due to their size and shape dependent unique optoelectronic properties. These noble metal nanoparticles, particularly of gold, have elicited a lot of interest for important biomedical applications because of their ease of synthesis, characterization and surface functionalization. Furthermore, recent investigations are demonstrating another promising application of these nanomaterials as self-therapeutics. To realize the potential promise of these unique inorganic nanomaterials for future clinical translation, it is of utmost importance to understand a few critical parameters; (i) how these nanomaterials interact with the cells at the molecular level; (ii) how their biodistribution and pharmacokinetics influenced by their surface and routes of administration; (iii) mechanism of their detoxification and clearance and (iv) their therapeutic efficacy in appropriate disease model. Thus in this critical review, we will discuss the various clinical applications of gold, silver and platinum nanoparticles with relevance to above parameters. We will also mention various routes of synthesis of these noble metal nanoparticles. However, before we discuss present research, we will also look into the past. We need to understand the discoveries made before us in order to further our knowledge and technological development (318 references).
Nanotechnology is an evolving field with enormous potential for biomedical applications. The growing interest to use inorganic nanoparticles in medicine is due to the unique size- and shape-dependent ...optoelectronic properties. Herein, we will focus on gold, silver and platinum nanoparticles, discussing recent developments for therapeutic applications with regard to cancer in terms of nanoparticles being used as a delivery vehicle as well as therapeutic agents. We will also discuss some of the key challenges to be addressed in future studies.
Immune checkpoint inhibitors targeting PD-1 have shown clinical benefit in adults with cancer, but data on these drugs in children are scarce. We did a phase 1–2 study of nivolumab, a PD-1 blocking ...monoclonal antibody, to determine its safety, pharmacokinetics, and antitumour activity in children and young adults with recurrent or refractory non-CNS solid tumours or lymphoma.
We did a multicentre, open-label, single-arm, dose-confirmation and dose-expansion, phase 1–2 trial in 23 hospitals in the USA. Eligible patients for part A (dose-confirmation phase) of the study were aged 1–18 years with solid tumours with measurable or evaluable disease (by Response Evaluation Criteria in Solid Tumors RECIST version 1.1) regardless of histology. Eligible patients for part B (dose-expansion phase) were aged 1–30 years with measurable disease (by RECIST criteria) in the following disease cohorts: rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, neuroblastoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and melanoma. Patients in part A and were given nivolumab 3 mg/kg intravenously over 60 min on days 1 and 15 of a 28-day cycle in a rolling 6 study design with de-escalation upon dose-limiting toxicities to establish the recommended phase 2 dose. Patients in part B were given the recommended phase 2 dose. The primary outcomes were the tolerability, systemic exposure, maximum tolerated dose, and the antitumour activity of nivolumab at the adult recommended dose in children and young adults. This trial is registered with ClinicalTrials.gov, NCT02304458, with follow-up ongoing and is closed to new participants.
85 patients were enrolled between Feb 22, 2015, and Dec 31, 2018, and 75 patients were fully evaluable for toxicity. Median follow-up was 30 days (IQR 27–83). In part A, 13 patients were enrolled and 12 were evaluable for toxicity. There were no dose de-escalations or dose-limiting toxicities and nivolumab 3 mg/kg was confirmed as the paediatric recommended phase 2. 72 patients were enrolled in part B and 63 were evaluable for toxicity. Five (7%) patients in part B had dose-limiting toxicities. The most common overall toxicity was anaemia (35 47% of 75 patients; five patients had grade 3 or grade 4) and non-haematological toxicity was fatigue (28 37% patients; none had grade 3 or grade 4). Responses were observed in patients with lymphoma (three 30% of ten with Hodgkin lymphoma and one 10% of ten with non-Hodgkin lymphoma; all responders had PD-L1 expression). Objective responses were not observed in other tumour types.
Nivolumab was safe and well tolerated in children and young adults and showed clinical activity in lymphoma. Nivolumab showed no significant single-agent activity in the common paediatric solid tumours. This study defines the recommended phase 2 dose and establishes a favourable safety profile for nivolumab in children and young adults, which can serve as the basis for its potential study in combinatorial regimens for childhood cancer.
Bristol-Myers Squibb, Children's Oncology Group, National Institutes of Health, Cookies for Kids Cancer Foundation.
Elevated intraocular pressure is the only treatable risk factor for glaucoma, an eye disease that is the leading cause of irreversible blindness worldwide. We have identified cromakalim prodrug 1 ...(CKLP1), a novel water-soluble ATP-sensitive potassium channel opener, as a new ocular hypotensive agent. To evaluate the pharmacokinetic and safety profile of CKLP1 and its parent compound levcromakalim, Dutch-belted pigmented rabbits were treated intravenously (0.25 mg/kg) or topically (10 mM; 4.1 mg/ml) with CKLP1. Body fluids (blood, aqueous and vitreous humor) were collected at multiple time points and evaluated for the presence of CKLP1 and levcromakalim using a liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) based assay. Histology of tissues isolated from Dutch-belted pigmented rabbits treated once daily for 90 days was evaluated in a masked manner by a certified veterinary pathologist. The estimated plasma parameters following intravenous administration of 0.25 mg/kg of CKLP1 showed CKLP1 had a terminal half-life of 61.8 ± 55.2 min, Tmax of 19.8 ± 23.0 min and Cmax of 1968.5 ± 831.0 ng/ml. Levcromakalim had a plasma terminal half-life of 85.0 ± 37.0 min, Tmax of 61.0 ± 32.0 min and Cmax of 10.6 ± 1.2 ng/ml. Topical CKLP1 treatment in the eye showed low levels (<0.3 ng/mL) of levcromakalim in aqueous and vitreous humor, and trace amounts of CKLP1 and levcromakalim in the plasma. No observable histological changes were noted in selected tissues that were examined following topical application of CKLP1 for 90 consecutive days. These results suggest that CKPL1 is converted to levcromakalim in the eye and likely to some extent in the systemic circulation.
Over the last few decades, the study of nanotechnology has grown exponentially. Nanotechnology bridges science, engineering and technology; it continues to expand in definition as well as practice. ...One sub-set of nanotechnology is bionanotechnology, this will be the focus of this review. Currently, bionanotechnology is being studied and exploited for utility within medicinal imaging, diagnosis and therapy in regard to cancer. Cancer is a world-wide health problem and the implication rate as well as the death rate increase year to year. However promising work is being done with gold nanoparticles for detection, diagnosis and targeted drug delivery therapy. Gold nanoparticles can be synthesized in various shapes and sizes, which directly correlates to the color; they can also be manipulated to carry various antibody, protein, plasmid, DNA or small molecule drug. Herein we summarize some of the very influential research being done in the field of Cancer Nanotechnology with an emphasis on gold nanoparticles.
Altered tumor microenvironment (TME) arising from a bidirectional crosstalk between the pancreatic cancer cells (PCCs) and the pancreatic stellate cells (PSCs) is implicated in the dismal prognosis ...in pancreatic ductal adenocarcinoma (PDAC), yet effective strategies to disrupt the crosstalk is lacking. Here, we demonstrate that gold nanoparticles (AuNPs) inhibit proliferation and migration of both PCCs and PSCs by disrupting the bidirectional communication via alteration of the cell secretome. Analyzing the key proteins identified from a functional network of AuNP-altered secretome in PCCs and PSCs, we demonstrate that AuNPs impair secretions of major hub node proteins in both cell types and transform activated PSCs toward a lipid-rich quiescent phenotype. By reducing activation of PSCs, AuNPs inhibit matrix deposition, enhance angiogenesis, and inhibit tumor growth in an orthotopic co-implantation model in vivo. Auto- and heteroregulations of secretory growth factors/cytokines are disrupted by AuNPs resulting in reprogramming of the TME. By utilizing a kinase dead mutant of IRE1-α, we demonstrate that AuNPs alter the cellular secretome through the ER-stress-regulated IRE1-dependent decay pathway (RIDD) and identify endostatin and matrix metalloproteinase 9 as putative RIDD targets. Thus, AuNPs could potentially be utilized as a tool to effectively interrogate bidirectional communications in the tumor microenvironment, reprogram it, and inhibit tumor growth by its therapeutic function.
Alisertib is an oral Aurora A kinase inhibitor with preclinical activity in neuroblastoma. Irinotecan and temozolomide have activity in patients with advanced neuroblastoma. The goal of this phase I ...study was to determine the maximum tolerated dose (MTD) of alisertib with irinotecan and temozolomide in this population.
Patients age 1 to 30 years with relapsed or refractory neuroblastoma were eligible. Patients received alisertib tablets at dose levels of 45, 60, and 80 mg/m(2) per day on days 1 to 7 along with irinotecan 50 mg/m(2) intravenously and temozolomide 100 mg/m(2) orally on days 1 to 5. Dose escalation of alisertib followed the rolling six design. Samples for pharmacokinetic and pharmacogenomic testing were obtained.
Twenty-three patients enrolled, and 22 were eligible and evaluable for dose escalation. A total of 244 courses were administered. The MTD for alisertib was 60 mg/m(2), with mandatory myeloid growth factor support and cephalosporin prophylaxis for diarrhea. Thrombocytopenia and neutropenia of any grade were seen in the majority of courses (84% and 69%, respectively). Diarrhea in 55% of courses and nausea in 54% of courses were the most common nonhematologic toxicities. The overall response rate was 31.8%, with a 50% response rate observed at the MTD. The median number of courses per patient was eight (range, two to 32). Progression-free survival rate at 2 years was 52.4%. Pharmacokinetic testing did not show evidence of drug-drug interaction between irinotecan and alisertib.
Alisertib 60 mg/m(2) per dose for 7 days is tolerable with a standard irinotecan and temozolomide backbone and has promising response and progression-free survival rates. A phase II trial of this regimen is ongoing.
Pancreatic cancer is the fourth leading cause of cancer related deaths in America. Monoclonal antibodies are a viable treatment option for inhibiting cancer growth. Tumor specific drug delivery could ...be achieved utilizing these monoclonal antibodies as targeting agents. This type of designer therapeutic is evolving and with the use of gold nanoparticles it is a promising approach to selectively deliver chemotherapeutics to malignant cells. Gold nanoparticles (GNPs) are showing extreme promise in current medicinal research. GNPs have been shown to non-invasively kill tumor cells by hyperthermia using radiofrequency. They have also been implemented as early detection agents due to their unique X-ray contrast properties; success was revealed with clear delineation of blood capillaries in a preclinical model by CT (computer tomography). The fundamental parameters for intelligent design of nanoconjugates are on the forefront. The goal of this study is to define the necessary design parameters to successfully target pancreatic cancer cells.
The nanoconjugates described in this study were characterized with various physico-chemical techniques. We demonstrate that the number of cetuximab molecules (targeting agent) on a GNP, the hydrodynamic size of the nanoconjugates, available reactive surface area and the ability of the nanoconjugates to sequester EGFR (epidermal growth factor receptor), all play critical roles in effectively targeting tumor cells in vitro and in vivo in an orthotopic model of pancreatic cancer.
Our results suggest the specific targeting of tumor cells depends on a number of crucial components 1) targeting agent to nanoparticle ratio 2) availability of reactive surface area on the nanoparticle 3) ability of the nanoconjugate to bind the target and 4) hydrodynamic diameter of the nanoconjugate. We believe this study will help define the design parameters for formulating better strategies for specifically targeting tumors with nanoparticle conjugates.
Adavosertib (AZD1775), an inhibitor of WEE1 kinase, potentiates replicative stress induced by oncogenes or chemotherapy. Antitumor activity of adavosertib has been demonstrated in preclinical models ...of pediatric cancer. This phase I trial was performed to define dose-limiting toxicities (DLT), recommended phase II dose (RP2D), and pharmacokinetics of adavosertib in combination with irinotecan in children and adolescents with relapsed or refractory solid tumors or primary central nervous system tumors.
Using a 3+3 escalation design, five dose cohorts of the combination of adavosertib and irinotecan (50/70; 65/70; 65/90; 85/90; 110/90 mg/m
/day) delivered on days 1-5 of a 21-day cycle were studied. Pharmacokinetics and analysis of peripheral blood γH2AX was performed.
Thirty-seven patients were enrolled; 27 were evaluable. The median (range) age was 14 (2-20) years. Twenty-five (93%) received prior chemotherapy (median, three regimens) and 21 (78%) received prior radiotherapy. Eleven patients had a primary central nervous system (CNS) malignancy. Common toxicities were hematologic and gastrointestinal. Two patients receiving adavosertib (110 mg/m
) in combination with irinotecan (90 mg/m
) experienced dose-limiting grade 3 dehydration. A patient with Ewing sarcoma had a confirmed partial response and 2 patients (ependymoma and neuroblastoma) had prolonged stable disease (≥ 6 cycles). Pharmacokinetics of adavosertib were variable but generally dose proportional and clearance was lower in younger patients.
Adavosertib (85 mg/m
) in combination with irinotecan (90 mg/m
) administered orally for 5 days was the MTD in children and adolescents with solid and CNS tumors.
In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; ...evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes.
We conducted a two-stage phase II trial of alisertib tablets (60 mg/m
/dose × 7 days), irinotecan (50 mg/m
/dose i.v. × 5 days), and temozolomide (100 mg/m
/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m
using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts.
Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m
had significantly higher median
and exposure compared with tablets at 60 mg/m
. Higher alisertib trough concentration was associated with first cycle DLT, whereas
amplification was associated with inferior PFS.
This combination shows antitumor activity, particularly in patients with
nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.
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