Platin-M: Mitochondrial Targeting of Cisplatin to Treat Cancer
- *Abstract
-
Application
- Treatment of cancer
- Invitro studies show this may be particularly suited to thetreatment of neuroblastoma due to Platin-M’s ability to penetrate the brain
ProblemsAddressed (benefits/advantages)
- Treatment of cancers which are traditionallyresistant to cisplatin
- Highly active
- Targeted to mitochondrial DNA so it is possiblethat the drug may be more efficacious in lower quantities, which may also havean impact on potential side effects
TechnologySummary
Chemo-resistance ofcisplatin-based therapy is related to extensive repair of cisplatin-modifiedDNA in the nucleus by nucleotide excision repair (NER) machinery. Delivering cisplatin to the mitochondria toattack the mitochondrial genome lacking NER machinery can lead to a rationallydesigned therapy for metastatic, chemo-resistant cancers and might overcome theproblems associated with conventional cisplatin treatment.
To that end, a hydrophobicmitochondria-targeted cisplatin prodrug, Platin-M was constructed using astrain promoted alkyne azide cycloaddition chemistry. Efficient delivery of Platin-M using abiocompatible polymeric nanoparticle (NP) based on biodegradablepoly(lactic-co-glycolic acid) (PLGA)-block (b)-polyethyleneglycol (PEG)functionalized with a terminal triphenylphosphonium (TPP) cation which hasremarkable activity to target mitochondria of cells resulted in controlledrelease of cisplatin from Platin-M locally inside the mitochondrial matrix toattack mutated mitochondrial DNA (mtDNA) and exhibited otherwise resistantadvance cancer sensitive to cisplatin-based chemotherapy.
Identification of an optimizedtargeted-NP formulation with brain-penetrating properties allowed for deliveryof Platin-M inside the mitochondria of neuroblastoma cells, resulting inapproximately 18-fold more activity than cisplatin. The remarkable activity of Platin-M and itstargeting-NP in cisplatin was correlated with the hyperpolarization ofmitochondria in these cells and further supported the hypothesis viamitochondrial bioenergetics studies in the resistant cells. This unique approach to controlled deliveryof cisplatin in the form of a prodrug to the mitochondria to attack themitochondrial genome lacking NER machinery and in vivo distribution properties of the delivery vehicle in thebrain suggest previously undescribed routes for cisplatin-based therapy oftreatment of neuroblastoma.
Inventors
· Shanta Dhar, Ph.D.
Dr. Dhar’s research interests lie at the interface ofchemistry and biology with particular emphasis on nanocarrier-mediatedintracellular delivery of payloads for potential applications in variousdiseases.
- Sean Marrache, Graduate student
- Rakesh Pathak, Post-doctoral fellow
TechnologyDevelopment and IP Status
· Patentpending in US, Europe and Japan (PCT Publication WO 2015/157409)
· Discoveryand pre-clinical development stage
- *IP Issue Date
- None
- *IP Type
- Utility
- 國家
- Not Applicable (PCT App)
- 申請號碼
- WO 2015/157409
- 國家/地區
- 美國
