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Lipoplatin (Liposomal cisplatin) is a nanoparticle of 110 nm average diameter composed of lipids and cisplatin.^[1] This new drug has successfully finished Phase I,^[2] Phase II,^[3] and Phase III human clinical trials.^[4] It has shown superiority to cisplatin in combination with paclitaxel as a chemotherapy regimen in non-small cell lung cancer (NSCLC) adenocarcinomas.

Mechanism of action

Lipoplatin evades immune surveillance thus escaping clearance from macrophages, circulates for long periods in body fluids after intravenous administration with a half-life of ~120 h, and extravasates through the compromised endothelium of the vasculature in tumors created during the process of neoangiogenesis Extravasation Figure. Thus, lipoplatin nanoparticles are concentrated to the primary tumor and metastases. Human studies have shown 40- to 200-fold higher platinum concentration compared to the adjacent normal tissue in specimens from human biopsies 20 post-infusion of the drug.^[5] Lipoplatin nanoparticles once inside the tumor cell mass can fuse with the cell membrane because of the presence of the fusogenic lipid DPPG in their lipid bilayer; an alternative mechanism proposed is that lipoplatin is taken by endocytosis by tumor cells as shown from lipoplatin containing fluorescent lipids and imaging of the tumor cells in culture thus treated with fluorescent microscopy. These processes occurring at the cell membrane level are promoted by the lipid shell of the nanoparticles (disguised as nutrients). The technology allows lipoplatin to empty its toxic payload (cisplatin) inside the cytoplasm to kill the tumor cell. The cell membrane is considered a significant barrier to transportation of the toxic molecules of cisplatin across and inside the tumor cell.

Trials

The European Medicines Agency (EMEA) gave lipoplatin orphan drug status in 2007 in an ongoing registrational Phase II/III study as a first line-treatment in pancreatic cancer.^[6] Under the trade name Nanoplatin, lipoplatin received EMEA consent in 2009 to be tested as a first-line treatment for non-squamous cell non-small-cell lung cancers (ns-NSCLC) that are mainly composed of adenocarcinomas. The results of a Phase III trial were published in October 2011.^[4] This study used lipoplatin in combination with paclitaxel to treat ns-NSCLC, comparing response rates and toxicities to a similar group of patients treated with cisplatin plus paclitaxel and demonstrated a statistically significant (‘’p’’-value = 0.036) increase in tumor response rate in the lipoplatin arm (59.22% of patients) versus the cisplatin arm (42.42% of patients). Most major toxicities of cisplatin, especially nephrotoxicity, were also reduced in the group of patients treated with lipoplatin and treatment did not require hospitalisation for lipoplatin patients. Median survival times were 10 months for the lipoplatin arm and 8 months for the cisplatin arm, with a ‘’p’’-value of 0.155. The median duration of response was 7 months for the lipoplatin arm and 6 months for the cisplatin arm. Although not statistically significant, these results suggest the potential for superior overall survival for lipoplatin compared to cisplatin, a hypothesis that is being tested in a larger trial. Furthermore, among the responders to lipoplatin a subgroup of patients demonstrated a substantially higher overall survival than a comparable subgroup of cisplatin responders. After 10 months, 30% of patients in the lipoplatin arm, as compared with just 16% of patients in the cisplatin arm, were without disease progression. By the end of the trial, there were 32 patients alive, 21 from the lipoplatin arm (20.39%) and 11 from the cisplatin arm (11.11%). Thus, after 18 months, the number of surviving patients was approximately double for lipoplatin versus cisplatin.^[4] The clinical development of lipoplatin in adenocarcinomas establishes this drug as the most active platinum drug with significantly lower side effects.

Preliminary investigations suggest the potential for lipoplatin to be a suitable agent for targeting ovarian cancer in patients with aggressive cisplatin resistance.^[7]

References

^ Apps, Michael G.; Choi, Eugene H. Y.; Wheate, Nial J. (2015). "The state-of-play and future of platinum drugs". Endocrine-Related Cancer. 22 (4): R219–R233. doi:10.1530/ERC-15-0237. hdl:2123/24426. PMID 26113607.
^ Stathopoulos, G. P.; Boulikas, T.; Vougiouka, M.; Deliconstantinos, G.; Rigatos, S.; Darli, E.; Viliotou, V.; Stathopoulos, J. G. (2005). "Pharmacokinetics and adverse reactions of a new liposomal cisplatin (Lipoplatin): Phase I study". Oncol. Rep. 13 (4): 589–595. PMID 15756428.
^ Boulika, Teni (2009). "Clinical overview on Lipoplatin: A successful liposomal formulation of cisplatin". Expert Opin. Investig. Drugs. 18 (8): 1197–1218. doi:10.1517/13543780903114168.
^ ^a ^b ^c Stathopoulos, G. P.; Antoniou, D.; Dimitroulis, J.; Stathopoulos, J.; Marosis, K.; Michalopoulou, P. (2011). "Comparison of liposomal cisplatin versus cisplatin in non-squamous cell non-small-cell lung cancer". Cancer Chemother. Pharmacol. 68 (4): 945–950. doi:10.1007/s00280-011-1572-5. PMC 3180559. PMID 21301848.
^ Boulikas, Teni; Stathopoulos, Georgios P.; Volakakis, Nikolaos; Vougiouka, Maria (2005). "Systemic lipoplatin infusion results in preferential tumor uptake in human studies" (PDF). Anticancer Res. 25 (4): 3031–3039. PMID 16080562.
^ Committee for Orphan Medicinal Products (30 November 2007). "Public Summary of Positive Opinion for Orphan Designation of Cisplatin (Liposomal) for the Treatment of Pancreatic Cancer" (PDF). European Medicines Agency. Archived from the original (PDF) on 26 April 2012. Retrieved 25 March 2010.
^ Casagrande, Naike; Celegato, Marta; Borghese, Cinzia; Mongiat, Maurizio; Colombatti, Alfonso; Aldinucci, Donatella (2014). "Preclinical activity of the liposomal cisplatin lipoplatin in ovarian cancer". Clinical Cancer Research. 20 (21): 5496–5506. doi:10.1158/1078-0432.CCR-14-0713. PMID 25231401.

Sources

Boulikas T (2004) Low toxicity and anticancer activity of a novel liposomal cisplatin (Lipoplatin) in mouse xenografts. Oncol Rep 12: 3-12, 2004.

External links

[1] Apps, Michael G.; Choi, Eugene H. Y.; Wheate, Nial J. (2015). "The state-of-play and future of platinum drugs". Endocrine-Related Cancer. 22 (4): R219–R233. doi:10.1530/ERC-15-0237. hdl:2123/24426. PMID 26113607.

[ref_2-2] Stathopoulos, G. P.; Boulikas, T.; Vougiouka, M.; Deliconstantinos, G.; Rigatos, S.; Darli, E.; Viliotou, V.; Stathopoulos, J. G. (2005). "Pharmacokinetics and adverse reactions of a new liposomal cisplatin (Lipoplatin): Phase I study". Oncol. Rep. 13 (4): 589–595. PMID 15756428.

[ref_3-3] Boulika, Teni (2009). "Clinical overview on Lipoplatin: A successful liposomal formulation of cisplatin". Expert Opin. Investig. Drugs. 18 (8): 1197–1218. doi:10.1517/13543780903114168.

[Stathopoulos-4] Stathopoulos, G. P.; Antoniou, D.; Dimitroulis, J.; Stathopoulos, J.; Marosis, K.; Michalopoulou, P. (2011). "Comparison of liposomal cisplatin versus cisplatin in non-squamous cell non-small-cell lung cancer". Cancer Chemother. Pharmacol. 68 (4): 945–950. doi:10.1007/s00280-011-1572-5. PMC 3180559. PMID 21301848.

[ref_4-5] Boulikas, Teni; Stathopoulos, Georgios P.; Volakakis, Nikolaos; Vougiouka, Maria (2005). "Systemic lipoplatin infusion results in preferential tumor uptake in human studies" (PDF). Anticancer Res. 25 (4): 3031–3039. PMID 16080562.

[ref_5-6] Committee for Orphan Medicinal Products (30 November 2007). "Public Summary of Positive Opinion for Orphan Designation of Cisplatin (Liposomal) for the Treatment of Pancreatic Cancer" (PDF). European Medicines Agency. Archived from the original (PDF) on 26 April 2012. Retrieved 25 March 2010.

[7] Casagrande, Naike; Celegato, Marta; Borghese, Cinzia; Mongiat, Maurizio; Colombatti, Alfonso; Aldinucci, Donatella (2014). "Preclinical activity of the liposomal cisplatin lipoplatin in ovarian cancer". Clinical Cancer Research. 20 (21): 5496–5506. doi:10.1158/1078-0432.CCR-14-0713. PMID 25231401.

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@@ Line 1: / Line 1: @@
-'''Lipoplatin''' (Liposomal cisplatin) is a [[nanoparticle]] of 110&nbsp;nm average diameter composed of [[lipid]]s and [[cisplatin]].<ref>{{cite journal | author = Apps, M. G., Choi, E. H. Y., Wheate, N. J. | year = 2015 | title = The state-of-play and future of platinum drugs | url = https://dx.doi.org/10.1530/ERC-15-0237 | journal = Endocrine-related Cancer | volume = 22 | issue = 4 | pages = 219–233 | pmid = 26113607 | doi = 10.1530/ERC-15-0237}}</ref> This new drug has successfully finished Phase I, Phase II and Phase III [[human clinical trials]].<ref name="ref_2">Stathopoulos GP, Boulikas T, Vougiouka M, Deliconstantinos G, Rigatos S, Darli E, Viliotou V, and Stathopoulos JG: Pharmacokinetics and adverse reactions of a new liposomal cisplatin (Lipoplatin): Phase I study Oncol Rep 13, 589-595 (2005).</ref><ref name="ref_3">Boulikas T. Clinical overview on Lipoplatin: a successful liposomal formulation of cisplatin. Expert Opin Investig Drugs. 2009 Aug;18(8):1197-218.</ref> It has shown superiority to cisplatin in combination with [[paclitaxel]] as a [[chemotherapy]] regimen in [[Non-small cell lung carcinoma|non-small cell lung cancer]] (NSCLC) [[adenocarcinoma]]s.
+'''Lipoplatin''' (Liposomal cisplatin) is a [[nanoparticle]] of 110&nbsp;nm average diameter composed of [[lipid]]s and [[cisplatin]].<ref>{{cite journal | last1 = Apps | first1 = Michael G. | last2 = Choi | first2 = Eugene H. Y. | last3 = Wheate | first3 = Nial J. |author-link3 = Nial J. Wheate | year = 2015 | title = The state-of-play and future of platinum drugs | doi-access = free | journal = [[Endocrine-Related Cancer]] | volume = 22 | issue = 4 | pages = R219–R233 | pmid = 26113607 | doi = 10.1530/ERC-15-0237| hdl = 2123/24426 | hdl-access = free }}</ref> This new drug has successfully finished Phase I,<ref name="ref_2">{{cite journal|last1 = Stathopoulos|first1 = G. P.|last2 = Boulikas|first2 = T.|last3 = Vougiouka|first3 = M.|last4 = Deliconstantinos|first4 = G.|last5 = Rigatos|first5 = S.|last6 = Darli|first6 = E.|last7 = Viliotou|first7 = V.|last8 = Stathopoulos|first8 = J. G.|title = Pharmacokinetics and adverse reactions of a new liposomal cisplatin (Lipoplatin): Phase I study|journal = [[Oncol. Rep.]]|volume = 13|issue = 4|pages = 589–595|year = 2005|pmid = 15756428}}</ref> Phase II,<ref name="ref_3">{{cite journal|journal = [[Expert Opin. Investig. Drugs]]|year = 2009|volume = 18|issue = 8|title = Clinical overview on Lipoplatin: A successful liposomal formulation of cisplatin|first = Teni|last = Boulika|pages = 1197–1218|doi = 10.1517/13543780903114168}}</ref> and Phase III [[human clinical trials]].<ref name = Stathopoulos/> It has shown superiority to cisplatin in combination with [[paclitaxel]] as a [[chemotherapy]] regimen in [[Non-small cell lung carcinoma|non-small cell lung cancer]] (NSCLC) [[adenocarcinoma]]s.
 ==Mechanism of action==
-Lipoplatin evades [[immune surveillance]] thus escaping clearance from [[macrophage]]s, circulates for long periods in [[body fluid]]s after intravenous administration with a [[half-life]] of ~120 h, and [[extravasate]]s through the compromised [[endothelium]] of the [[vasculature]] in [[tumor]]s created during the process of neoangiogenesis [https://web.archive.org/web/20120308061313/http://www.regulon.org/Technology_files/image004.png Extravasation Figure]. Thus, Lipoplatin nanoparticles are concentrated to the [[primary tumor]] and [[Metastasis|metastases]]. Human studies have shown 40- to 200-fold higher [[platinum]] concentration compared to the adjacent normal tissue in specimens from human [[Biopsy|biopsies]] 20h post-infusion of the drug.<ref name="ref_4">Boulikas T, Stathopoulos GP, Volakakis N and Vougiouka M. Systemic Lipoplatin infusion results in preferential tumor uptake in human studies. Anticancer Res, 25:3031-3040, 2005.</ref> Lipoplatin nanoparticles once inside the tumor cell mass can fuse with the cell membrane because of the presence of the fusogenic lipid DPPG in their lipid bilayer; an alternative mechanism proposed is that Lipoplatin is taken by endocytosis by tumor cells as shown from Lipoplatin containing fluorescent lipids and imaging of the tumor cells in culture thus treated with fluorescent microscopy. These processes occurring at the cell membrane level are promoted by the lipid shell of the nanoparticles (disguised as nutrients). The technology allows Lipoplatin to empty its toxic payload (cisplatin) inside the cytoplasm to kill the tumor cell. The cell membrane is considered a significant barrier to transportation of the toxic molecules of cisplatin across and inside the tumor cell.
+Lipoplatin evades [[immune surveillance]] thus escaping clearance from [[macrophage]]s, circulates for long periods in [[body fluid]]s after intravenous administration with a [[half-life]] of ~120&nbsp;h, and [[extravasate]]s through the compromised [[endothelium]] of the [[vasculature]] in [[tumor]]s created during the process of neo[[angiogenesis]] [https://web.archive.org/web/20120308061313/http://www.regulon.org/Technology_files/image004.png Extravasation Figure]. Thus, lipoplatin nanoparticles are concentrated to the [[primary tumor]] and [[Metastasis|metastases]]. Human studies have shown 40- to 200-fold higher [[platinum]] concentration compared to the adjacent normal tissue in specimens from human [[Biopsy|biopsies]] 20&nbsp; post-infusion of the drug.<ref name="ref_4">{{cite journal|last1 = Boulikas|first1= Teni|last2 = Stathopoulos|first2 = Georgios P.|last3 =  Volakakis|first3 = Nikolaos|last4 = Vougiouka|first4 = Maria|title = Systemic lipoplatin infusion results in preferential tumor uptake in human studies|journal = [[Anticancer Res.]]|volume = 25|issue = 4|pages = 3031–3039|year = 2005|pmid = 16080562|url = http://ar.iiarjournals.org/content/25/4/3031.full.pdf}}</ref> Lipoplatin nanoparticles once inside the tumor cell mass can fuse with the cell membrane because of the presence of the fusogenic lipid DPPG in their lipid bilayer; an alternative mechanism proposed is that lipoplatin is taken by endocytosis by tumor cells as shown from lipoplatin containing fluorescent lipids and imaging of the tumor cells in culture thus treated with fluorescent microscopy. These processes occurring at the cell membrane level are promoted by the lipid shell of the nanoparticles (disguised as nutrients). The technology allows lipoplatin to empty its toxic payload (cisplatin) inside the cytoplasm to kill the tumor cell. The cell membrane is considered a significant barrier to transportation of the toxic molecules of cisplatin across and inside the tumor cell.
 ==Trials==
-The [[European Medicines Agency]] (EMEA) gave lipoplatin [[orphan drug]] status in 2007 in an ongoing registrational Phase II/III study as a first line-treatment in [[pancreatic cancer]].<ref name="ref_5">{{cite web|url = http://www.ema.europa.eu/pdfs/human/comp/opinion/16785007en.pdf |title = Archived copy |accessdate = 2010-03-25 |deadurl = yes |archiveurl = https://web.archive.org/web/20100601090053/http://www.ema.europa.eu/pdfs/human/comp/opinion/16785007en.pdf |archivedate = 2010-06-01 |df= }}</ref> Under the trade name Nanoplatin, lipoplatin received EMEA consent in 2009 to be tested as a first-line treatment for [[non-squamous cell non-small-cell lung cancer]]s (ns-NSCLC) that are mainly composed of adenocarcinomas. The results of a Phase III trial were published in October 2011.<ref name = Stathopoulos>{{cite journal|journal = [[Cancer Chemother. Pharmacol.]]|volume = 68|issue = 4|pages = 945-950|title = Comparison of liposomal cisplatin versus cisplatin in non-squamous cell non-small-cell lung cancer|first1 = G. P.|last1 = Stathopoulos|first2 = D.|last2 = Antoniou|first3 = J.|last3 = Dimitroulis|first4 = J.|last4 = Stathopoulos|first5 = K.|last5 = Marosis|first6 = P.|last6 = Michalopoulou|year = 2011|doi = 10.1007/s00280-011-1572-5|doi-access = free|pmid = 21301848|pmc = 3180559}}</ref>  This study used lipoplatin in combination with [[paclitaxel]] to treat ns-NSCLC, comparing response rates and toxicities to a similar group of patients treated with cisplatin plus paclitaxel and demonstrated a statistically significant (‘’p’’-value = 0.036) increase in tumor response rate in the lipoplatin arm (59.22% of patients) versus the cisplatin arm (42.42% of patients). Most major toxicities of cisplatin, especially [[nephrotoxicity]], were also reduced in the group of patients treated with lipoplatin and treatment did not require hospitalisation for lipoplatin patients. Median survival times were 10 months for the lipoplatin arm and 8 months for the cisplatin arm, with a ‘’p’’-value of 0.155. The median duration of response was 7 months for the lipoplatin arm and 6 months for the cisplatin arm. Although not statistically significant, these results suggest the potential for superior overall survival for lipoplatin compared to cisplatin, a hypothesis that is being tested in a larger trial. Furthermore, among the responders to lipoplatin a subgroup of patients demonstrated a substantially higher overall survival than a comparable subgroup of cisplatin responders. After 10 months, 30% of patients in the lipoplatin arm, as compared with just 16% of patients in the cisplatin arm, were without disease progression. By the end of the trial, there were 32 patients alive, 21 from the lipoplatin arm (20.39%) and 11 from the cisplatin arm (11.11%). Thus, after 18 months, the number of surviving patients was approximately double for lipoplatin versus cisplatin.<ref name = Stathopoulos/> The clinical development of lipoplatin in adenocarcinomas establishes this drug as the most active platinum drug with significantly lower side effects.
+The [[European Medicines Agency]] (EMEA) gave lipoplatin [[orphan drug]] status in 2007 in an ongoing registrational Phase II/III study as a first line-treatment in [[pancreatic cancer]].<ref name="ref_5">{{cite web|title = Public Summary of Positive Opinion for Orphan Designation of Cisplatin (Liposomal) for the Treatment of Pancreatic Cancer|author = Committee for Orphan Medicinal Products|publisher = [[European Medicines Agency]]|url = http://www.emea.europa.eu/docs/en_GB/document_library/Orphan_designation/2009/10/WC500006089.pdf|date = 30 November 2007|access-date = 25 March 2010|archive-date = 26 April 2012|archive-url = https://web.archive.org/web/20120426182817/http://www.emea.europa.eu/docs/en_GB/document_library/Orphan_designation/2009/10/WC500006089.pdf|url-status = dead}}</ref> Under the trade name Nanoplatin, lipoplatin received EMEA consent in 2009 to be tested as a first-line treatment for non-squamous cell [[non-small-cell lung cancer]]s (ns-NSCLC) that are mainly composed of adenocarcinomas. The results of a Phase III trial were published in October 2011.<ref name = Stathopoulos>{{cite journal|journal = [[Cancer Chemother. Pharmacol.]]|volume = 68|issue = 4|pages = 945–950|title = Comparison of liposomal cisplatin versus cisplatin in non-squamous cell non-small-cell lung cancer|first1 = G. P.|last1 = Stathopoulos|first2 = D.|last2 = Antoniou|first3 = J.|last3 = Dimitroulis|first4 = J.|last4 = Stathopoulos|first5 = K.|last5 = Marosis|first6 = P.|last6 = Michalopoulou|year = 2011|doi = 10.1007/s00280-011-1572-5|doi-access = free|pmid = 21301848|pmc = 3180559}}</ref>  This study used lipoplatin in combination with [[paclitaxel]] to treat ns-NSCLC, comparing response rates and toxicities to a similar group of patients treated with cisplatin plus paclitaxel and demonstrated a statistically significant (‘’p’’-value = 0.036) increase in tumor response rate in the lipoplatin arm (59.22% of patients) versus the cisplatin arm (42.42% of patients). Most major toxicities of cisplatin, especially [[nephrotoxicity]], were also reduced in the group of patients treated with lipoplatin and treatment did not require hospitalisation for lipoplatin patients. Median survival times were 10 months for the lipoplatin arm and 8 months for the cisplatin arm, with a ‘’p’’-value of 0.155. The median duration of response was 7 months for the lipoplatin arm and 6 months for the cisplatin arm. Although not statistically significant, these results suggest the potential for superior overall survival for lipoplatin compared to cisplatin, a hypothesis that is being tested in a larger trial. Furthermore, among the responders to lipoplatin a subgroup of patients demonstrated a substantially higher overall survival than a comparable subgroup of cisplatin responders. After 10 months, 30% of patients in the lipoplatin arm, as compared with just 16% of patients in the cisplatin arm, were without disease progression. By the end of the trial, there were 32 patients alive, 21 from the lipoplatin arm (20.39%) and 11 from the cisplatin arm (11.11%). Thus, after 18 months, the number of surviving patients was approximately double for lipoplatin versus cisplatin.<ref name = Stathopoulos/> The clinical development of lipoplatin in adenocarcinomas establishes this drug as the most active platinum drug with significantly lower side effects.
+Preliminary investigations suggest the potential for lipoplatin to be a suitable agent for targeting [[ovarian cancer]] in patients with aggressive cisplatin resistance.<ref>{{cite journal|journal = [[Clinical Cancer Research]]|title = Preclinical activity of the liposomal cisplatin lipoplatin in ovarian cancer|first1 = Naike|last1 = Casagrande|first2 = Marta|last2 = Celegato|first3 = Cinzia|last3 = Borghese|first4 = Maurizio|last4 = Mongiat|first5 = Alfonso|last5 = Colombatti|first6 = Donatella|last6 = Aldinucci|doi = 10.1158/1078-0432.CCR-14-0713|year = 2014|volume = 20|issue = 21|pages = 5496–5506|doi-access = free|pmid = 25231401}}</ref>
 ==References==
@@ Line 18: / Line 20: @@
 *http://www.lipoplatin.com
 *http://www.regulon.com
-*[http://meeting.ascopubs.org/cgi/content/abstract/25/18_suppl/18028 Lipoplatin plus gemcitabine versus cisplatin plus gemcitabine in NSCLC: Preliminary results of a phase III trial]
+*[https://archive.today/20130226011000/http://meeting.ascopubs.org/cgi/content/abstract/25/18_suppl/18028 Lipoplatin plus gemcitabine versus cisplatin plus gemcitabine in NSCLC: Preliminary results of a phase III trial]
-*[http://annonc.oxfordjournals.org/content/21/11/2227.long Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial]
+*[https://archive.today/20130415142736/http://annonc.oxfordjournals.org/content/21/11/2227.long Liposomal cisplatin combined with paclitaxel versus cisplatin and paclitaxel in non-small-cell lung cancer: a randomized phase III multicenter trial]
-*[http://regulon.org/publications/reviewarticles/2011%20stathopoulos-boulikas.pdf Lipoplatin Formulation Review Article]
+*[https://web.archive.org/web/20140202210033/http://regulon.org/publications/reviewarticles/2011%20stathopoulos-boulikas.pdf Lipoplatin Formulation Review Article]
 [[Category:Platinum-based antineoplastic agents]]