Research on Platelet Drug Delivery System

The main focus of drug carrier research today is to identify carriers that are both safe and effective for clinical treatment applications. As treatment strategies advance researchers regularly update drug delivery systems. Traditional drug delivery systems consist of liposomes and polymer micelles together with nanoparticles but despite their inclusion in clinical trials current versions still encounter limitations. Liposomes struggle to release hydrophobic drugs from their interior yet they encounter rapid clearance in blood circulation. Polyethylene glycol is applied to nanoparticle surfaces to improve their biocompatibility and stability. When multiple administrations occur polyethylene glycol gets recognized by the mononuclear phagocytic system as a foreign substance which activates the immune system and results in the fast clearance of the substance thus preventing the drug from reaching target cells. Traditional drug delivery systems cannot completely fulfill clinical requirements because of existing unresolved issues. It becomes crucial to investigate natural drug delivery systems when considering treatment methods for diseases. The blood circulation contains platelets as the second most abundant blood cell which perform multiple functions and present themselves as ideal drug carriers. The bone marrow megakaryocytes generate platelets that they release into the blood as cells without nuclei.

A healthy person has (150-400)×10⁶/mL platelets which make up around 5% of their total human cell count. Resting state platelets have a diameter that ranges from 2 to 5μm. When physiological conditions are stable platelets remain in circulation inside the blood for approximately 7 to 10 days. The anucleated platelets contain various types of content such as mitochondria and lysosomes along with dense granules and α granules. Upon activation platelets discharge internal granules and extracellular vesicles (EVs) which play key roles in thrombosis and hemostasis besides immune regulation thus has a reliable basis for drug delivery systems. An open canalicular system makes up roughly 1% of platelet volume which enables a two-way communication pathway between α granules and blood. This provides an innate channel and repository for transporting pharmaceuticals. Platelets naturally function as superior drug carriers because of the unique receptors on their surface. The CD47 protein on platelets binds with signal regulatory protein alpha (SIRPα) on macrophages which stops macrophages from clearing platelets through phagocytosis and extends the duration platelets circulate in blood. Glycoprotein 1b on platelet surfaces assists tissue regeneration and injury repair by attaching to von Willebrand factor (vWF) and collagen from damaged blood vessels and when activated P-selectin from platelets becomes externalized it binds to PSGL-1 or CD44 on tumor cells thereby forming a defensive wall against tumor cells. These processes can offer effective biological targeting for platelet delivery at specific sites or cells. Platelets take part in hemostasis and wound healing and they also contribute to immune inflammatory responses as well as tumorigenesis and metastasis besides the development of cardiovascular diseases. The platelet membrane surface displays multiple glycoproteins together with integrins and various antigens. When activated they release different organelles along with rich proteins and small RNAs through vesicles which enables these elements to connect with various cells. The unique properties of platelets including easy acquisition and strong targeting capabilities together with convenient release options and long circulation times make them ideal drug delivery carriers with weak cytotoxicity and high biosafety which enables their development into effective drug delivery systems. Platelet drug delivery systems will use platelets or their derivatives for creating specific drug carriers which can target matching cells to execute drug delivery functions and develop new treatment strategies. Current research directions for this drug system involve the following topics.

Platelets Directly Carry Drugs

Platelets can take up drugs into their cells via endocytosis. The traditional electroporation drug loading method suffers from complex procedures and delivers low packaging rates together with significant trauma. Scientists discovered that platelets can engulf bacteria which opens a new pathway for administering drugs non-invasively using platelets as carriers. Some studies have examined drug delivery systems using platelet endocytosis to absorb fluorescent beads and viral particles which get stored in platelet α-granules for subsequent release during platelet activation. During in vitro incubation researchers can administer interferon-γ-inducible protein 10 (IP10) inside platelets. Within the tumor microenvironment elevated levels of thrombin activate the IP10-platelet complex which releases its drug payload leading to substantial anti-tumor results.

The IP10-loaded platelets targeted and inhibited tumor cells in the B16F10 melanoma model and lessened immunosuppressive regulatory T cell activity through CD40L activation on platelet membranes which led to boosted anti-tumor immunity. When recombinant protein von Willebrand factor lyase (rADAMTS13) was co-incubated with platelets in vitro studies showed that rADAMTS13 gets stored inside platelet α-granules. ADAMTS13-/- mice experience decreased thrombosis rates in mesenteric arterioles after ferric chloride injury when they receive platelets loaded with rADAMTS13. Administering rADAMTS13-loaded platelets ex vivo into fresh whole blood or reconstituted whole blood substantially lowers thrombosis occurrence in arterial blood flow. The composition of recombinant whole blood includes both plasma from immune-mediated thrombotic thrombocytopenic purpura patients together with cellular elements from healthy people. Medical professionals collect fresh whole blood from patients who have thrombotic thrombocytopenic purpura (TTP). The research suggests that rADAMTS13 platelet infusion represents a promising novel therapy for arterial thrombosis and offers a new treatment approach for TTP patients.

Engineering Platelet Drug Loading

Platelet particles can encapsulate therapeutic drugs while platelet surface modifications can also load. Through the expression of programmed death-ligand 1 (PDL1) tumor cells induce T cell exhaustion and immunosuppression. Through genetic modification of anucleate platelets into megakaryocytes researchers can generate mature platelets with programmed death protein 1 (PD-1) that release T cells to reestablish immune function. To create engineered platelets scientists load platelets that display PD-1 on their surface with a low dose of cyclophosphamide (CP). Large quantities of activated platelets and their vesicles gather in surgical wounds from tumors. When PD-1 molecules on platelets interact with anti-PD-1 on tumor cells they release drugs that eliminate regulatory T cells while boosting CD8+ T cell functions which helps decrease tumor recurrence and metastasis after surgery. Certain researchers joined hematopoietic stem cells (HSC) with platelets modified with anti-PD-1 antibodies (aPD-1) and delivered them back into mice with leukemia through intravenous injection. The HSC-platelet-aPD-1 conjugate reached the bone marrow to release aPD-1 locally which boosted the anti-leukemia immune response by increasing active T cells and extending mice survival time which resulted in significant suppression of leukemia growth and recurrence. Scientists have designed a motor-shaped platelet micromotor through asymmetric urease fixation on natural platelets. The biological functions of platelets are preserved in platelet micromotors with their ability to target cancer cells and pathogens. Biofuels enable motor-shaped platelet micromotors to achieve directed propulsion. As platelets circulate in the blood the micromotors activate asymmetrical reactions to breakdown urea and ammonia while producing carbon dioxide which propels doxorubicin-loaded platelets toward targeted delivery sites. Surface engineering of platelets has led to significant advancements in cancer therapy approaches.

Platelet Membrane-Coated Biomimetic Nanoparticles for Drug Delivery

Platelet membrane-coated nanoparticles have good application value. Nanotechnology developments have resulted in nanoparticles becoming common tools for tumor treatment. Uncoated drug-loaded nanoparticles (NPs) have limitations because they are quickly targeted and destroyed by the mononuclear phagocytic system which leads to their swift removal from the body. Cell membrane-coated nanoparticle delivery systems manage to avoid immune detection, extend circulation duration with minimal toxicity while reducing non-targeted distribution thus establishing themselves as superior therapeutic carriers. The nanoscale particles coated with platelet membranes possess a blood circulation half-life of 30 hours in living organisms while they display specific surface receptors including CD47 protein from platelet membranes which helps extend their survival time by minimizing macrophage absorption. In vivo infusion of platelet membrane-coated nanoparticles carrying doxorubicin into a guidewire friction-induced aortic valve stenosis model showed a reduction in aortic valve calcification. Scientists developed rapamycin-loaded polyethylene glycol nanoparticles surrounded by platelet membranes which show effectiveness against atherosclerosis. The surface of Staphylococcus aureus along with infection sites can be targeted by platelet membrane-coated nanoparticles that have been prepared. The mouse Staphylococcus aureus pneumonia model shows better anti-infection results with platelet membrane-coated nanoparticles than free vancomycin while not exhibiting any clear toxicity. Researchers have examined coated nanoparticles across different tumor types including human breast cancer and primary metastatic cancer along with liver cancer. Research on platelet membrane-coated nanoparticles shows potential in cancer therapy as well as cardiovascular disease treatment with broad application possibilities. Drug-loaded platelet extracellular vesicles (PEVs) obtain the parent platelet cell membrane’s integrins and receptors which makes them viable candidates for targeted drug delivery systems. Nano-sized vesicles called PEVs originate from natural cells and transport diverse contents from parent cells including nucleic acids as well as proteins and lipids. Activated platelet secretion produces most of the plasma vesicles which represent between 70% and 90% of plasma derivatives. Platelet-derived extracellular vesicles (PEVs) carry multiple platelet membrane glycoproteins including GPIIbIIIa (CD41/CD61 or integrin αIIb/β3), GPIa (CD49b/CD29), GPIb (CD42b), P-selectin (CD62P), PECAM-1/CD31 and GP53 (CD63) which makes them effective as drug carriers. The platelets underwent stimulation with thrombin after being incubated with doxorubicin followed by centrifugation to acquire PEVs containing doxorubicin. The suppression of cell growth in lung cancer, breast cancer and colon cancer cells achieved through co-culture exhibited 7 to 23 times greater effectiveness than liposome delivery after PEVs were stored at −80℃. The PEVs received a load of cytokine release inhibitors which included MCC950 along with NLRP3 inflammasome inhibitors. MCC950-PEVs administered intravenously significantly decreased atherosclerotic plaque formation while also reducing local inflammation and blocking macrophage and T cell proliferation within the plaque area.