ABSTRACT
Survival rates in pancreatic cancer have remained largely unchanged over the past four decades with less than 5% of patients surviving five years following initial diagnosis. FOLFIRINOX chemotherapy, a combination of folinic acid, 5-fluoruracil, irinotecan and oxaliplatin, has shown the greatest survival benefit for patients with advanced disease but is only indicated for those with good physical performance status due to its extreme off-target toxicity. Ultrasound targeted microbubble destruction (UTMD) has emerged as an effective strategy for the targeted delivery of drug payloads to solid tumours and involves using low intensity ultrasound to disrupt (burst) MBs in the tumour vasculature, releasing encapsulated or attached drugs in a targeted manner. In this manuscript, we describe the preparation of a microbubble-liposome complex (IRMB-OxLipo) carrying two of the three cytotoxic drugs present in the FOLFIRINOX combination, namely irinotecan and oxaliplatin. Efficacy of the IRMB-OxLipo complex following UTMD was determined in Panc-01 3D spheroid and BxPC-3 human xenograft murine models of pancreatic cancer. The results revealed that tumours treated with the IRMB-OxLipo complex and ultrasound were 136% smaller than tumours treated with the same concentration of irinotecan/oxaliplatin but delivered in a conventional manner, i.e. as a non-complexed mixture. This suggests that UTMD facilitates a more effective delivery of irinotecan/oxaliplatin improving the overall effectiveness of this drug combination and to the best of our knowledge, is the first reported example of a microbubble-liposome complex used to deliver these two chemotherapies.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Irinotecan/pharmacology , Lipids/chemistry , Oxaliplatin/pharmacology , Pancreatic Neoplasms/drug therapy , Ultrasonics , Animals , Antineoplastic Combined Chemotherapy Protocols/chemistry , Cell Line, Tumor , Drug Compounding , Female , Irinotecan/chemistry , Liposomes , Mice, Inbred BALB C , Mice, SCID , Microbubbles , Oxaliplatin/chemistry , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Tumor Burden/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Malignant melanoma is an aggressive skin cancer with poor survival outcomes for patients diagnosed at an advanced stage. While targeted serine/threonine-protein kinase B-Raf (BRAF) and immune checkpoint inhibitors have improved survival outcomes for a proportion of these patients, response rates remain variable. There is a need, therefore, for more effective treatments to bolster the options available for melanoma patients. In this manuscript, we covalently attached Rose Bengal (RB) to the amphipathic peptide (AMP) C(KLAKLAK)2 and determined the effectiveness of the resulting RB-C(KLAKLAK)2 conjugate as a photodynamic therapy (PDT) sensitizer. RB-C(KLAKLAK)2-mediated PDT treatment of subcutaneous B16-F10-Luc2 tumors in C57 mice resulted in lesions that were 479% smaller at the end of the study than animals treated with RB-mediated PDT. The synergistic effect between RB and C(KLAKLAK)2 has been attributed to the AMP sensitizing cells to reactive oxygen species (ROS), making them more susceptible to ROS-induced oxidative stress.
Subject(s)
Antineoplastic Agents/therapeutic use , Melanoma/drug therapy , Peptides/therapeutic use , Photosensitizing Agents/therapeutic use , Rose Bengal/analogs & derivatives , Rose Bengal/therapeutic use , Amino Acid Sequence , Animals , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Cell Line, Tumor , Humans , Mice, SCID , Necrosis/chemically induced , Peptides/chemical synthesis , Photochemotherapy/methods , Photosensitizing Agents/chemical synthesis , Reactive Oxygen Species/metabolismABSTRACT
PURPOSE: The increase in online purchasing of medications raises safety concerns regarding teratogenic drugs. The use of the teratogenic drug 'isotretinoin' for women of childbearing age requires strict adherence to the Pregnancy Prevention Programme (PPP), a risk minimisation measure imposed on prescribers and users. We sought to determine how readily consumers can purchase isotretinoin online and the associated safety procedures and information. METHODS: A descriptive cross-sectional survey was conducted of 50 e-pharmacies identified from commonly used search engines. E-pharmacy characteristics and isotretinoin PPP specific criteria were evaluated. Purchases of isotretinoin from seven e-pharmacies not bearing authentication logos and not requiring a prescription were assessed for PPP policy adherence, purchasing procedures and compound quality. RESULTS: Forty-three (86%) of the e-pharmacies did not have an authentication seal/logo. Isotretinoin could be purchased from 42 sites without a valid prescription. Information on isotretinoin causing birth defects was lacking in 25 of the 50 sites, on not taking isotretinoin in pregnancy in 24 sites and not taking isotretinoin if planning or at risk of a pregnancy in 33 sites. Of the eight attempted purchases, seven arrived, all without any patient information leaflet. All were verified as isotretinoin. CONCLUSION: The Internet provides a loophole for purchasing of medications known to cause congenital abnormalities, which needs to be addressed by medicines regulatory agencies worldwide. The current PPP for isotretinoin may be failing to protect mothers and babies from preventable harm-clinicians need to be aware of this, and the public needs to be educated about the potential risks.
