Transferrin and Borneol-Enhanced Liposomes for Targeted Rapamycin Delivery in TBI

 With all this earlier research on rapamycin  for stroke I bet our incompetent stroke medical 'professionals' have done ABSOLUTELY NOTHING! Aren't you glad they are so fucking incompetent that your children and grandchildren won't recover from a stroke? It took me all of two minutes to Google Scholar for 'rapamycin for stroke' and find all this; and I'm obviously stroke-addled and know nothing!

Rapamycin in ischemic stroke: Old drug, new tricks? 2019

Rapamycin prevents cerebral stroke by modulating apoptosis and autophagy in penumbra in rats 2018

The effect of rapamycin treatment on cerebral ischemia: a systematic review and meta-analysis of animal model studies 2019

Rapamycin Treatment Improves Neuron Viability in an In Vitro Model of Stroke 2013 

The rationale of targeting mammalian target of rapamycin for ischemic stroke 2013

Rapamycin attenuates mitochondrial dysfunction via activation of mitophagy in experimental ischemic stroke 2014

Rapamycin up-regulation of autophagy reduces infarct size and improves outcomes in both permanent MCAL, and embolic MCAO, murine models of stroke 2014

The latest here:

Transferrin and Borneol-Enhanced Liposomes for Targeted Rapamycin Delivery in TBI

Authors Cai S, Yuan Z, Chen Y, Gong M, Lai J, Yan P, Mei Z

Received 29 July 2024

Accepted for publication 28 February 2025

Published 11 April 2025 Volume 2025:20 Pages 4503—4518

DOI https://doi.org/10.2147/IJN.S489165

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Kamakhya Misra

Download Article [PDF] 

Shihong Cai,^1,2,* Zhongwen Yuan,^1,* Yanfang Chen,³ Mingjie Gong,¹ Jianqi Lai,¹ Pengke Yan,¹ Zhengrong Mei<sup>1

1</sup>Department of Pharmacy, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, People’s Republic of China; ²Zhanjiang Healthcare Security Service Management Center, Zhanjiang, People’s Republic of China; ³Department of Pharmacy, Guangzhou Eighth People’s Hospital, Guangzhou Medical University, Guangzhou, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Pengke Yan, Email gysyypk@126.com Zhengrong Mei, Email meizhengrong@126.com

Background: The therapeutic potential of rapamycin (RAPA) for traumatic brain injury (TBI) is limited by its low bioavailability and poor penetration across the blood-brain barrier (BBB). We developed transferrin-modified rapamycin and borneol co-delivery liposomes (TF-RAPA/BO-LIP) to overcome these barriers, aiming to enhance both drug delivery to the brain and the treatment efficacy.
Methods: We employed the emulsion-solvent evaporation method to prepare TF-RAPA/BO-LIP and characterized their particle size, zeta potential, morphology, stability, and encapsulation efficiency. Pharmacokinetic studies were conducted in SD rats, and drug concentration was analyzed using LC-MS/MS. The brain-targeting capability and therapeutic efficacy were evaluated through in vitro cellular uptake studies, and in vivo in a TBI mouse model using both neurological and cognitive assessments.
Results: TF-RAPA/BO-LIP displayed optimal characteristics (95 nm particle size, > 90% encapsulation efficiency) and demonstrated enhanced stability. Pharmacokinetic analyses revealed reduced drug clearance and increased drug concentration-time curve area, indicating improved systemic and brain-specific drug bioavailability. Notably, TF-RAPA/BO-LIP achieved significantly higher RAPA accumulation in the brain tissue. Importantly, treatment with TF-RAPA/BO-LIP significantly ameliorated neurological deficits and improved spatial memory in TBI mice, as evidenced by behavioral tests.
Conclusion: Our study highlights TF-RAPA/BO-LIP as a promising strategy for delivering RAPA across the BBB, substantially enhancing its therapeutic efficacy for TBI. This novel liposomal system not only improves RAPA bioavailability but also offers significant neuroprotection, potentially transforming the clinical management of TBI.

Silica-coated flexible liposomes as a nanohybrid delivery system for enhanced oral bioavailability of curcumin

So when are our doctors going to put 2 and 2 together and give curcumin to us as a neuroprotective in the first days as listed here:
http://oc1dean.blogspot.com/2011/03/tumeric-and-stroke-rehab.html
The delivery article here:
http://www.dovepress.com/article_11689.t14230688
Abstract: We investigated flexible liposomes as a potential oral drug delivery system. However, enhanced membrane fluidity and structural deformability may necessitate liposomal surface modification when facing the harsh environment of the gastrointestinal tract. In the present study, silica-coated flexible liposomes loaded with curcumin (CUR-SLs) having poor water solubility as a model drug were prepared by a thin-film method with homogenization, followed by the formation of a silica shell by the sol-gel process. We systematically investigated the physical properties, drug release behavior, pharmacodynamics, and bioavailability of CUR-SLs. CUR-SLs had a mean diameter of 157 nm and a polydispersity index of 0.14, while the apparent entrapment efficiency was 90.62%. Compared with curcumin-loaded flexible liposomes (CUR-FLs) without silica-coatings, CUR-SLs had significantly higher stability against artificial gastric fluid and showed more sustained drug release in artificial intestinal fluid as determined by in vitro release assays. The bioavailability of CUR-SLs and CUR-FLs was 7.76- and 2.35-fold higher, respectively, than that of curcumin suspensions. Silica coating markedly improved the stability of flexible liposomes, and CUR-SLs exhibited a 3.31-fold increase in bioavailability compared with CUR-FLs, indicating that silica-coated flexible liposomes may be employed as a potential carrier to deliver drugs with poor water solubility via the oral route with improved bioavailability.

Bilirubin is an antioxidant of possible physiological importance

To give some more context to my earlier post.
http://www.sciencemag.org/content/235/4792/1043.short

Abstract

Bilirubin, the end product of heme catabolism in mammals, is generally regarded as a potentially cytotoxic, lipid-soluble waste product that needs to be excreted. However, it is here that bilirubin, at micromolar concentrations in vitro, efficiently scavenges peroxyl radicals generated chemically in either homogeneous solution or multilamellar liposomes. The antioxidant activity of bilirubin increases as the experimental concentration of oxygen is decreased from 20% (that of normal air) to 2% (physiologically relevant concentration). Furthermore, under 2% oxygen, in liposomes, bilirubin suppresses the oxidation more than alpha-tocopherol, which is regarded as the best antioxidant of lipid peroxidation. The data support the idea of a "beneficial" role for bilirubin as a physiological, chain-breaking antioxidant.

WNT/ BETA-CATENIN SIGNALING IS EVIDENT POST-STROKE AND ENHANCES ENDOGENOUS NEUROGENESIS WHEN UPREGULATED

I wish someone would try this out in humans with a protocol.
http://kenes.com/brain2011/abstracts/pdf/597.pdf
Objectives: Wnt/ beta-catenin signaling is essential for maintaining endogenous neurogenesis
in the adult brain1and enhancing post-stroke neurogenesis has been shown to be beneficial for
recovery2-4. Having established that Wnt/ beta-catenin signaling is present within one of the two adult neurogenic niches: the subventricular zone, SVZ, we examined the dynamics of the
signaling pathway following transient middle cerebral artery occlusion, MCAO. We also
investigated the effect of upregulating the pathway on the endogenous post-stroke
neurogenesis, by employing a novel Wnt-3a liposomal preparation.
Methods: - Young adult male Axin 2 reporter mice for Wnt/ beta-catenin signaling were
subjected to 25 min MCAO and cohorts of 4 mice were sacrificed at 1 day, 3 days, 7 days and
14 days post-stroke. Immunohistochemistry was employed to visualize the cell types
demonstrating Wnt/ beta-catenin signaling. Optical density values of images taken at each time
point were compared using ImageJ in order to evaluate pathway activation levels.
- Wnt-3a liposomes were freshly made 5 and injected intra-parenchymally at 1, 3, 7 and 14 days
post-stroke in two 1.5 ul boluses at 3mm and 1.5 mm depth (1.2 mm laterally, 0.6 mm anterior
of bregma).
- DAB staining and stereology were employed to quantify the number of Doublecortin, DCX,
positive newborn neurons at 1 month after MCAO.
Results: - Wnt/ beta catenin signaling was evident in GFAP, Nestin and Doublecortin cells
present at the SVZ in both naïve and post-stroke animals, as well as in mature NeuN positive
neurons within the cortex and striatum. In post-MCAO animals it was also present in GFAP
positive astrocytes at the penumbra.
- We observed an oscillation in the upregulation pattern of Wnt/ beta-catenin signaling after
stroke, which we are confirming with larger cohorts.
- Wnt-3a liposomes exhibited a potent ability to activate the Wnt/ beta-catenin pathway both in
vivo (5 fold greater than baseline) and in vitro (comparable to recombinant Wnt-3a protein) and
significantly increased the number of Doublecortin positive newborn neurons (up to 20 fold
compared to PBS alone) when injected at 3 and 7 days post -stroke.
Conclusions: Here we show that the Wnt/ beta-catenin signaling pathway is active within the
adult brain and upregulated following stroke. Activation of the pathway, in a novel liposomemediated way, significantly enhances endogenous neurogenesis post-stroke.

liposome pictures

From the Nikon's annual Small World Photomicrography Competition.
It was great to see what may become one of the useful transport mechanisms for helping drugs crossing the blood-brain barrier. I talked about it earlier here - http://oc1dean.blogspot.com/2011/05/what-are-liposomes-good-for-in-stroke.html
and here - http://oc1dean.blogspot.com/2011/05/liposome-encapsulated-hemoglobin.html

pictures here - http://www.nikonsmallworld.com/gallery/search/all/liposome

What are liposomes good for in stroke rehab?

def.

An artificial microscopic vesicle consisting of an aqueous core enclosed in one or more phospholipid layers, used to convey vaccines, drugs, enzymes, or other substances to target cells or organs.

I think this is basically a nanoparticle to be able to deliver drugs thru the blood-brain barrier and I already talked about it here:

http://oc1dean.blogspot.com/2010/12/nanoparticles-and-stroke-rehab.html

But I really like the fact that companies already produce liposomes and could probably attach any type of drug to them. This makes the entry to testing new therapies much easier.

http://www.encapsula.com/?gclid=CLKtj4HlyqgCFQQbKgod9SN0tQ

http://www.nanoliposomals.com/

Don't self-medicate, your doctor is for that.

And with this easy way to try new drugs/ideas your own doctor could do clinical trials. I explain one way this is done here:
http://oc1dean.blogspot.com/2011/04/faster-better-cheaper-clinical-trial.html
So ask your doctor what is stopping them from doing a trial, I have given enough examples to follow up on if they can't think of anything. In fact propose to them a trial of your choosing

Liposome-encapsulated hemoglobin ameliorates ischemic stroke

A bit too scientific for me, but I liked the result of reducing the infarction. So I wonder if the full article mentions how long after onset it would be useful.
http://www.ncbi.nlm.nih.gov/pubmed/19910538
Abstract
An artificial oxygen carrier, liposome-encapsulated hemoglobin (LEH), protective in a rodent stroke model, was quantitatively evaluated in monkeys. Serial positron emission tomography studies using the steady-state (15)O-gas inhalation method were performed to quantify O(2) metabolism, which was compared based on the infarction extent and immunohistochemical evaluation in 19 monkeys undergoing middle cerebral artery occlusion (3 h), infusion of various LEH doses (n = 11), empty liposome (n = 4), or saline (n = 4) 5 min after the onset of ischemia, and reperfusion for 5 h. There was no significant difference in O(2) metabolism until 3 h after reperfusion, when the cerebral metabolic rate of O(2) (CMRO(2)) was significantly less suppressed in the cortex [mild suppression in CMRO(2) (71-100%) of preischemic ipsilateral control as in the ischemic penumbra: 64.7 +/- 14.3% in empty liposome versus 32.4 +/- 7.9% in LEH (2 ml/kg) treatment, P < 0.05] but not in basal ganglia. Immunohistochemical studies showed a reciprocal expression of microtubular-associated protein II expression in the cortex and LEH deposition in basal ganglia, suggesting the LEH perfusion, but not deposition, afforded the protection. Dose-response studies revealed that as little as 0.4 ml/kg LEH (24 mg/kg hemoglobin) was effective in preserving CMRO(2), whereas 2 and 10 ml/kg were protective in significantly reducing the area of infarction as well, by 66 and 56%, respectively, compared with animals receiving saline. CMRO(2) and histological integrity were better preserved early after 3-h occlusion and reperfusion of the middle cerebral artery of monkeys receiving LEH early after onset of ischemia.