Delving into the Latest Updates on Picoplatin with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

(SP-4-3)-Amminedichloro(2-methylpyridine)platinium, Picoplatin (INN/USAN/BAN), AMD 473

+ [8]

Target

DNA

Mechanism

DNA inhibitors(DNA inhibitors), DNA alkylating agents

Therapeutic Areas

NeoplasmsRespiratory DiseasesDigestive System Disorders+ [3]

Active Indication-

Inactive Indication

Advanced Malignant Solid NeoplasmBladder CancerBreast Cancer+ [8]

Originator Organization

AnorMED, Inc.

Active Organization-

Inactive Organization

Poniard Pharmaceuticals, Inc.

AnorMED, Inc.

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

RegulationOrphan Drug (US)

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Structure

Molecular FormulaC6H10Cl2N2Pt

InChIKeyIIMIOEBMYPRQGU-UHFFFAOYSA-L

CAS Registry181630-15-9

The goal of the current study is to improve the characteristics and bioavailability of the drug picoplatin (PPt) by encapsulating it in chitosan nanoparticles (CS NPs) which allows for the targeted delivery of cytotoxic cargo to cancerous tissue, reducing toxic side effects and raising the therapeutic index. When picoplatin was delivered into the CS, it was able to produce a complex with CS (PPt@CS NPs) that had an appropriate particle size of 275 ± 10 nm, a reasonably low PDI of 0.15 ± 0.05, and high stability (ζ = -22.1 ± 0.3 mV). Since almost all pharmaceuticals work by binding to specific proteins or DNA, the in vitro binding mechanism and affinity of bovine serum albumin (BSA), low molecular building units of nucleic acids (5-GMP), and Glutathione (GSH) (considering that cisplatin resistance could be due to a reaction between cisplatin and GSH) to PPt and PPt@CS NPs were examined using stopped-flow and other spectroscopic approaches. Through two reversible processes, a rapid second-order binding followed by a slower first-order isomerization reaction, and a static quenching mechanism, PPt and PPt@CS NPs bind to BSA with relative reactivity of around (PPt)/(PPt@CS NPs) = 1/2.5. The 5-GMP interaction studies demonstrated that, in addition to changing the binding mechanism, PPt's encapsulation in CS increases its rate of reaction through coordination affinity. PPt interacted with 5-GMP via two reversible processes, a rapid second-order binding to phosphate followed by a slower first-order migration to the N7 of pyrimidine moiety. PPt@CS NPs showed weaker binding to GSH compared to PPt and hence PPt@CS NPs exhibits a lower resistance factor. It was also found that the in vitro drug release of PPt@CS NPs in PBS at pH 7.4 was steady, releasing 30 % of the PPt in just 5 h. Nonetheless, 75 % of the release in a pH 5.4 solution containing 10 mM GSH-a solution that mimics the tumor microenvironment-shows that the PPt@CS NPs system is sensitive to GSH and specifically targets malignant tissue. The encapsulation of PPt in CS complex maintained its anticancer activity, as shown by an in vitro cell-survival assay on HepG2 cancer cell lines and also cleavage efficiency toward the minor groove of pBR322 DNA via the hydrolytic way. These findings collectively suggested that inclusion PPt in CS would be an effective strategy to formulate a novel picoplatin formulation intended for use as targeted anticancer treatment.

01 Jan 2023·Current pharmaceutical design

From Basics of Coordination Chemistry to Understanding Cisplatin-analogue Pt Drugs.

Article

Author: Yamamoto, Yuma ; Akitsu, Takashiro ; Tsvetkova, Dobrina ; Kostova, Irena ; Nakane, Daisuke

BACKGROUND:

Cisplatin, a platinum complex discovered by Rosenberg in 1969, has long been known as the first metal-based anticancer agent. Since then, various similar derivatives of cisplatin have been investigated for pharmacological activity, and the approved complexes have been applied as drugs.

OBJECTIVES:

The aims of the current study are: 1) to summarize the advantages and dose-limiting effects of the approved and unapproved chemotherapy platinum cytostatics, 2) to develop new strategies for the development of platinum anticancer drugs, and 3) to clarify the important factors for the mechanism of action of platinum complexes.

METHODS:

A search was conducted in the literature databases, and the obtained information was summarized and analyzed.

RESULTS:

Myelosuppression is the main dose-limiting effect and the reason for the disapproval of platinum complexes, such as picoplatin, enloplatin, miboplatin, sebriplatin, zeniplatin, spiroplatin, iproplatin, and ormaplatin. From the basic point of view of inorganic coordination chemistry, such as theoretical calculations, crystal structures of model complexes, docking structures with nucleic acid molecules, spectroscopy, and biological aspects, the importance of physicochemical properties of inorganic platinum complexes for their mechanism of action has been indicated. Spectroscopic methods, such as FTIR, NMR, X-ray crystal structure analysis, and fluorescence microscopy, are important for the investigation of the conformational changes in the binding of platinum complexes and DNA.

CONCLUSION:

In the development of platinum complexes, strong anti-cancer drug activity, low toxicity, and resistance can be obtained by the application of polynuclear platinum agents, complexes with targeted activity, and nanoparticle formulations. Electronic structure, stereochemical, and thermodynamic properties are essential for understanding the reaction mechanism of platinum complexes.

22 Nov 2022·ACS omega

Thermosensitive Liposomes Encapsulating Nedaplatin and Picoplatin Demonstrate Enhanced Cytotoxicity against Breast Cancer Cells

Article

Author: Shoeib, Tamer ; Fahmy, Sherif Ashraf ; El-Said Azzazy, Hassan Mohamed ; Dayyih, Alice Abu ; Preis, Eduard ; Bakowsky, Udo ; Alawak, Mohamed

Thermosensitive liposomes (TSL) have been used for localized temperature-responsive release of chemotherapeutics into solid cancers, with a minimum of one invention currently in clinical trials (phase III). In this study, TSL was designed using a lipid blend comprising 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene glycol)-2000] (DSPE-PEG-2000) (molar ratio of 88:9:2.8:0.2). Either nedaplatin (ND) or p-sulfonatocalix[4]arene-nedaplatin was encapsulated in the aqueous inner layer of TSL to form (ND-TSL) or p-SC4-ND-TSL, respectively. The hydrophobic platinum-based drug picoplatin (P) was loaded into the external lipid bilayer of the TSL to develop P-TSL. The three nanosystems were studied in terms of size, PDI, surface charge, and on-shelf stability. Moreover, the entrapment efficiency (EE%) and release % at 37 and 40 °C were evaluated. In a 30 min in vitro release study, the maximum release of ND, p-SC4-ND, and picoplatin at 40 °C reached 74, 79, and 75%, respectively, compared to approximately 10% at 37 °C. This demonstrated temperature-triggered drug release from the TSL in all three developed systems. The designed TSL exhibited significant in vitro anticancer activity at 40 °C when tested on human mammary gland/breast adenocarcinoma cells (MDA-MB-231). The cytotoxicity of ND-TSL, p-SC4-ND-TSL, and P-TSL at 40 °C was approximately twice those observed at 37 °C. This study suggests that TSL is a promising nanoplatform for the temperature-triggered release of platinum-based drugs into cancer cells.

100 Deals associated with Picoplatin

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External Link

KEGG	Wiki	ATC	Drug Bank
D08968	Picoplatin	-	DB04874

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Small Cell Lung Cancer	Phase 3	AR	Poniard Pharmaceuticals, Inc.	01 Apr 2007
Small Cell Lung Cancer	Phase 3	BY	Poniard Pharmaceuticals, Inc.	01 Apr 2007
Small Cell Lung Cancer	Phase 3	BA	Poniard Pharmaceuticals, Inc.	01 Apr 2007
Small Cell Lung Cancer	Phase 3	BG	Poniard Pharmaceuticals, Inc.	01 Apr 2007
Small Cell Lung Cancer	Phase 3	CL	Poniard Pharmaceuticals, Inc.	01 Apr 2007
Small Cell Lung Cancer	Phase 3	HR	Poniard Pharmaceuticals, Inc.	01 Apr 2007
Small Cell Lung Cancer	Phase 3	HU	Poniard Pharmaceuticals, Inc.	01 Apr 2007
Small Cell Lung Cancer	Phase 3	IN	Poniard Pharmaceuticals, Inc.	01 Apr 2007
Small Cell Lung Cancer	Phase 3	LV	Poniard Pharmaceuticals, Inc.	01 Apr 2007
Small Cell Lung Cancer	Phase 3	ME	Poniard Pharmaceuticals, Inc.	01 Apr 2007

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


SPEAR (ASCO2010)	Phase 3	Small Cell Lung Cancer	401	Picoplatin + BSC	qwavikngbv(sdazyvpvzu) = wualztycau qewmeofcgi (ibdwjslohj, CI 19 - 25) View more	Positive	20 May 2010
				picoplatin (BSC)	qwavikngbv(sdazyvpvzu) = raihrwiuny qewmeofcgi (ibdwjslohj, CI 16 - 24) View more
ASCO2009	Phase 2	Colorectal Cancer First line	101	Picoplatin	(xhtssalxkk) = Neurotoxicity was less frequent and less severe in the FOLPI arm compared to the FOLFOX arm vwlmwiryyf (qunvozdevd )	-	20 May 2009
				modified FOLFOX-6 (FOLFOX)
ASCO2009	Phase 2	Metastatic castration-resistant prostate cancer First line	32	Picoplatin + Docetaxel + Prednisone	jvlsavjvbx(vslafrgirv) = cqapqjeczw ooofvzshfn (tctpitkoyj )	-	20 May 2009
AACR2009	Phase 1	Advanced Malignant Solid Neoplasm	-	IV picoplatin	vbbvvlcpsu(qwpqcgfrdn) = wljjgzakqe wyqanaybop (mfetmkcfze, 23) View more	-	01 May 2009
				Oral picoplatin	vbbvvlcpsu(qwpqcgfrdn) = prczqxbehd wyqanaybop (mfetmkcfze, 28) View more
AACR2009	Phase 1	Colorectal Cancer	73	Pico every 4 wks	vjtfttdtok(efphrzfvzw) = wbkawbulaz xlxqndzdab (ngunpmtgog )	-	01 May 2009
				Pico every 2 wks	wzmauttjon(zjkrascxxf) = jzsnggbzjy vswzvjtwry (koqnlzhyuc )
ASCO2008	Phase 2	Colorectal Cancer First line	59	Picoplatin + 5-fluorouracil + leucovorin (FOLPI)	vfghzjkizj(fxembobfvg) = knjfoylhav gybmpvxkxx (civeooakus )	-	20 May 2008
ASCO2008	Phase 2	Metastatic castration-resistant prostate cancer	30	Picoplatin with docetaxel + prednisone	clsqznwadt(kgyegsrzea) = flwrlvqxzn tpxqojbsmf (axiberzool ) View more	-	20 May 2008
ASCO2008	Phase 1	Advanced Malignant Solid Neoplasm	-	Picoplatin	azunuszsxa(iiwtvdeauu) = gvmtzlshjm gdmwnaiucv (nwwwrtmrxt )	-	20 May 2008
ASCO2007	Phase 1	Metastatic castration-resistant prostate cancer	16	Picoplatin + Docetaxel + Prednisone	szxejlglsh(ntwibbhwwc) = kbdqbieziy ofzqcighlq (pphtjsqqga ) View more	-	20 Jun 2007
ASCO2007	Phase 1	Metastatic Colorectal Carcinoma	23	Picoplatin every 2 weeks	zxoomxnfdv(xxzkfoxzci) = lwyqfkpcij hiwysydgwq (wteboyuvhg )	-	20 Jun 2007
				Picoplatin every 4 weeks	zxoomxnfdv(xxzkfoxzci) = lodqphkfjv hiwysydgwq (wteboyuvhg )