Increasing the concentration of unsaturated phospholipids ensures that the lipid bilayer is permeable, whereas saturated phospholipids make the barrier impermeable. By controlling the lipid composition and length of the fatty acid chains, liposomal nanocarriers can be engineered to respond to temperature and/or pH, allowing the controlled release of the active ingredient under physiological conditions that are specific to the disease site. The cellular uptake of liposomes can be also tuned by the lipid composition, which influences the overall surface charge.Neutral liposomes tend to remain in circulation longer and do not readily interact with cells, promoting the release of active ingredients in the extracellular space. This strategy is used by DaunoXome , Marqibo , and Onivyde .Whereas positively charged liposomes readily interact with the negative charge on the cell surface via electrostatic forces, neutral liposomes are prone to faster clearance. However, conventional liposomes of all types are rapidly eliminated from the bloodstream due to opsonization and uptake by Kupffer cells in the liver and spleen, which limits their bio-availability.This has been addressed by conjugating hydrophilic polymers to the liposome surface, such as polyethylene glycol in the case of Doxil, the first clinically approved liposome.Depending on the liposome formulation, PEGylation has been shown to increase the half-life of the active ingredient from 2 h to 24 h in rodents and up to 45 h in humans, resulting in a 4–16-fold higher concentration at the target site.

However, PEGylation can inhibit the interaction between liposomes and the cell surface,wholesale grow bags preventing fusion and uptake. Furthermore, passive targeting is limited by the heterogeneity of the EPR effect both within the tumor environment and when comparing different types of cancer.Low-molecular-weight molecules such as folate, as well as peptides and monoclonal antibodies or their fragments, have been incorporated onto the surface of liposomes to achieve targeted delivery.Liposomes also have the versatility to deliver multiple active ingredients simultaneously at a suitable molar ratio to maximize their synergistic interactions. The liposomal nanocarrier Vyxeos is thus far the only approved formulation that delivers more than one active ingredient, namely cytarabine and daunorubicin .The first liposome formulation was approved in 1995, and since then 10 further products have been approved by the FDA/EMA for clinical use, mostly for combination cancer therapy . Exceptionally, AmBisome is indicated for fungal infections,Curosurf is indicated for respiratory distress syndrome, and Visudyne is indicated for macular degeneration. The most recent addition is Onpattro, the first siRNA delivery formulation, approved in 2018 by the FDA.Onpattro encapsulates a transthyretin-directed siRNA for the treatment of amyloidosis. Additional liposomal nanocarriers are undergoing clinical trials against a wide range of diseases, including ocular and topical applications . Although many of the new formulations are cancer therapies, the landscape of current trials highlights the potential of nanomedicine across the field.

For example, liposomal alprostadil is a potent vasodilator that increases peripheral blood flow, inhibits platelet aggregation, and induces bronchodilation ; liposomal cyclosporine A is also being investigated as an inhaled delivery formulation for the treatment of bronchiolitis obliterans syndrome.Another example targeting cardiovascular disease consists of sodium alendronate encapsulated in liposomes of distearoylphosphatidylglycerol, 1,2-distearoyl-sn-glycero-3-phosphocholine, and cholesterol. Phase II testing is underway for the treatment of de novo stenotic lesions in native coronary arteries in patients undergoing percutaneous coronary intervention with implantation of a bare metal stent . Furthermore, a topical gel nanoliposome formulation of vitamin B12 is undergoing clinical trials to treat moderate atopic dermatitis , and liposomal latanoprost is being tested as a means to lower intraocular pressure in patients with open-angle glaucoma and ocular hypertension. Liposomal meglumine antimoniate and liposomal paromomycin are being investigated for the treatment of anthroponotic cutaneous leishmaniasis caused by Leishmania tropica in both humans and dogs. Novel liposomal nanocarriers are also undergoing veterinary trials .In 2006, a phase I trial of doxorubicin encapsulated into temperature-sensitive liposomes was carried out in companion dogs suffering from spontaneous tumors.Injection of the nanocarrier followed by the induction of tumor hyperthermia caused 100% of the drug cargo to be released within 20 s at 41.3 °C. Of the 21 dogs enrolled in the study, 18 showed a decrease in tumor volume, including 12 with a decrease of more than 50%. Liposomal doxorubicin in combination with palliative radiotherapy improved the clinical outcome of cats with soft tissue sarcomas.Clodronate encapsulated in liposomes was able to eliminate malignant histocytosis in dogs.Liposomeen capsulated amphotericin B demonstrated high efficacy in dogs infected with the blastomyces fungus while reducing the adverse effects often associated with amphotericin B.Liposomes have also been used to facilitate the absorption of hydrophobic active ingredients via the cuticles of plants and insects.

However, because they are so expensive to produce, agricultural applications are likely to be restricted for the foreseeable future. For example, Doxil costs $1313 for 5 mg , whereas newer formulations are even more expensive, such as Marquibo and Onpattro . Even so, a few studies have investigated the liposomal delivery of pesticides such as entofenprox.An alternative and less expensive solution may be the use of liposomes comprising plant-derived lipids . This was proposed for the delivery of Fe and Mg totomato plants, and 33% of the encapsulated metal was able to penetrate leaves and enter plant cells compared to 1% of the free active ingredient.Polymeric bio-materials are easy to produce at low cost and have therefore been developed and tested as inert shells to promote the accumulation and controlled release of active ingredients at a given target site. Natural polymers have been derived from chitosan, sodium alginate, collagen, heparin, and silk, whereas many different synthetic polymers have been tested, including, polyacrylate , PEG, polycaprolactone , polylactic acid , polyglycolic acid , polylactic-co-glycolic acid , polyesters and polyurethanes. Natural and synthetic polymers can be biocompatible and biodegradable, and their physicochemical properties are inherently flexible and can be tuned to control mechanical and physiological behavior.For clinical and veterinary applications, the nanocarrier shell must comprise linear or branched polymers with a molecular weight in the range 0.4–40 kDa to increase the circulation time of the active ingredient while ultimately ensuring renal elimination.PLGA is particularly promising as a nanocarrier material because the PLA-to-PGA ratio can be adjusted to control the rate of degradation, and thus the release rate of the active ingredient. Using this concept, Eligard was approved by the FDA in 2002 to deliver leuprolide acetate to prostate cancer cells .PLGA nanocarriers are also being tested in the veterinary field for the delivery of temozolomide to canine brain tumors . The only other polymeric nanocarrier approved by the FDA is Welchol, an allylamine polymer that encapsulates colesevelam hydrochloride to lower the levels of sugar and low-density lipoproteins circulating in adults suffering from type 2 diabetes and high cholesterol.Although the development pipeline for polymeric drug delivery systems is moving rapidly,grow bags for gardening there is a puzzling lack of approvals. A possible explanation is that most polymeric drug delivery systems do not improve efficacy but rather enhance safety, and thus do not achieve significant improvements over liposomal formulations or the free drug at a lower dose. Dendrimers are a special class of highly-branched polymeric nanocarriers with organized tree-like structures and a low polydispersity, ranging in size from 5 to 500 kDa.They comprise a central core that radiates a series of repeated branching units , terminating with chemical groups available for functionalization. The active ingredient can be encapsulated in the core micelle via hydrophobic/electrostatic interactions, or conjugated to the surface. The greater the number of branches, the more reactive terminal groups can be coupled with the active ingredient. Branches exposed on the surface can also be functionalized to increase tissue specificity.Most of the dendrimers used as nanocarriers are synthesized from hydrophilic polyamidoamine or polypropylene imine units, which are not recognized by the immune system. Poly-L-lysine dendrimers are positively charged, and are therefore ideal for the delivery of nucleic acids. Other dendrimers are being developed from PEG, polyglycerol, polyglycerol-co-succinic acid, poly-2,2-bispropionic acid, melamine, and triazine.Only two dendrimer-based nanocarriers are currently undergoing clinical trials . The first consists of N-acetyl cysteine covalently coupled to a metabolically-stable inactive hydroxyl dendrimer, and has been administered to healthy volunteers to determine its safety, tolerability, and pharmacokinetics. The second is a poly-L-lysine dendrimer that encapsulates nitro-imidazole-methyl-1,2,3-triazol-methyl-di-[2-pycolyl]amine bound to a rhenium isotope , and is currently under investigation for the treatment of liver cancer. Many other polymeric nanocarriers are undergoing clinical trials . CriPec is a polymeric nanocarrier, 30–100 nm in diameter and of uncertain composition , which encapsulates docetaxel and is shielded by PEG.

It is being tested for the treatment of solid tumors and platinum-resistant ovarian cancer. PEOX is a branched polymer shell composed of polyethyloxazoline, encapsulating paclitaxel for the treatment of solid tumors. PEOX circumvents the need to solubilize paclitaxel with Kolliphor EL , a toxic solvent that requires the co-administration of antihistamines to prevent an immune response.32 IMX-110 is a polymeric nanoshell encapsulating curcumin and doxorubicin for the treatment of solid tumors. Following its release in the tumor environment, curcumin targets and inhibits the activation of the transcription factors STAT3 and NF-κB, which prevents apoptotic tumor resistance and enhances the efficacy of doxorubicin.Another example is eRapa, the protein kinase inhibitor rapamycin encapsulated in polymethyl methacrylate, which is undergoing clinical testing for the treatment of prostate cancer.A novel nanocarrier for the delivery of cisplatin to canine brain tumors has been developed using hyaluronic acid, a linear polymer of alternating D-glucuronic acid and N-acetyl-D-glucosamine residues. Hyaluronic acid is a component of the extracellular matrix and is degraded by hyaluronidase, an enzyme over expressed in the glioma microenvironment.Therefore, the nanocarrier accumulates in the tumor environment, where its degradation causes the local release of cisplatin to minimize systemic toxicity. One novel formulation that did not progress beyond clinical trials is BIND-014, a PLAPEG co-polymer displaying a ligand targeting the extracellular domain of the prostate specific membrane antigen. Early studies in rats indicated that BIND-014 could delay tumor growth by preferentially delivering docetaxel to prostate cancer xenografts, limiting the accumulation of this drug in the liver and bone marrow.BIND-014 was applied in several clinical trials for the treatment of prostate cancer, non-small-cell lung cancer, cervical cancer, and head and neck cancer.Unfortunately, the trials did not demonstrate sufficient efficacy, with an objective response of only 10% in the head and neck cancer cohort. Pfizer acquired BIND Therapeutics for $40 million in 2016 but no further clinical trials have been reported. Various synthetic and natural biodegradable polymers have also been synthesized for the delivery of agrochemicals. The formulations have been prepared using emulsion or double emulsion strategies, as well as layer-by-layer deposition, nanoprecipitation, and solvent evaporation.Such formulations include nanospheres and nanocapsules . These nanocarriers have been prepared from PEG, PCL, PAL, chitosan, or sodium alginate,and have been used to deliver diverse pesticides, including ametryn,atrazine,acephate,emanectin benzoate,garlic essential oil,imidacloprid,lansiumamide B,methomyl, paraquat,and simazine. However, these formulations are currently at an early developmental stage and are still being tested in vitro as well as in field trials. Polymers have also been used to prepare other forms of active ingredient delivery system, such as hydrogels,polymer–drug conjugates,108 and seed coatings.Hydrogels are crosslinked hydrophilic polymers with a high water retention capacity. A reservoir of the active ingredient may be present at the core of the hydrogel, or it may be uniformly dispersed. The controlled release of the active ingredient is achieved by regulating the physical properties of the hydrogel matrix, such as its porosity and swelling capacity. Environmental stimuli such as temperature, pH, ionic strength, and enzyme activity are often use to control the rate of polymer degradation to achieve the slow and sustained release of the active ingredient. Examples include the FDA-approved intracanalicular implant Dextenza, a dexamethasone-loaded PEG hydrogel for the treatment of ocular pain following ophthalmic surgery,as well as hydrogel compositions containing dextran, PAL, propylene glycol, hyaluronic acid, or carboxymethyl cellulose.Although not technically a nanocarrier application, active ingredients are often conjugated to PEG in a process known as PEGylation, which increases the hydrophilicity and hydrodynamic radius of small-molecule drugs and proteins, thus improving their solubility, masking them from the immune system, slowing their renal clearance, and increasing their circulation half-life while retaining their bio-activity.Adagen, a PEGylated adenosine deaminase, was the first PEGylated formulation used in the clinic to treat severe combined immunodeficiency disease. Since then, more PEGylated drugs have been approved by the FDA/EMA and the majority are indicated for cancer, hepatitis C, or hemophilia .