Biodegradable nanoparticles for cytosolic delivery of therapeutics☆

Abstract

Many therapeutics require efficient cytosolic delivery either because the receptors for those drugs are located in the cytosol or their site of action is an intracellular organelle that requires transport through the cytosolic compartment. To achieve efficient cytosolic delivery of therapeutics, different nanomaterials have been developed that consider the diverse physicochemical nature of therapeutics (macromolecule to small molecule; water soluble to water insoluble) and various membrane associated and intracellular barriers that these systems need to overcome to efficiently deliver and retain therapeutics in the cytoplasmic compartment. Our interest is in investigating PLGA and PLAbased nanoparticles for intracellular delivery of drugs and genes. The present review discusses the various aspects of our studies and emphasizes the need for understanding of the molecular mechanisms of intracellular trafficking of nanoparticles in order to develop an efficient cytosolic delivery system.

PLGA-Based Nanoparticles as Cancer Drug Delivery Systems

“…The forms of PLGA are usually recognized by the monomers ratio used. For instance, PLGA 50:50 identifies a copolymer whose composition is 50% lactic acid and 50% glycolic acid (Vasir and Labhasetwar, 2007;Danhier et al, 2012). PLGA is a widely used polymer due to biocompatibility, longstanding track record in biomedical functions and welldocumented utility for continued drug release compared to the conventional devices up to days, weeks or months, and ease of parenteral administration via injection (Mundargi et al, 2008;Acharya and Sahoo, 2011).…”

“…PLGAnanoparticles quickly escape the endo-lysosomes and enter the cytoplasm in 10 min of incubation. This facilitates interactions of nanoparticles with the vesicular membranes leading to transient and localized deterioration of the membrane resulting in the escape of nanoparticles into the cytosol (Vasir and Labhasetwar, 2007;Danhier et al, 2012).…”

“…From a broader perspective in medicine, nanoparticle have been used in specific applications such as tissue engineered scaffolds and devices, site specific drug delivery systems, cancer therapy and clinical bioanalytical diagnostics and therapeutics (van Vlerken and Amiji, 2006;Vasir and Labhasetwar, 2007;Liu et al, 2007;Mahapatro and Singh, 2011).…”

Photochemically stimulated drug delivery increases the cytotoxicity and specificity of EGF–saporin

“…These reagents are, however, not optimal for in vivo applications due to lack of selectivity towards target cells and high toxicity. Liposomes (Fretz et al 2005), nanoparticles (Vasir & Labhasetwar 2007), polymers (Neu et al 2005) and viruses (Pouton et al 2007) are today investigated as formulation principles for intracellular delivery of macromolecular drugs. Endo/lysosomal sequestration and subsequent degradation is, however, also shown to be an obstacle for these delivery systems.…”

Multifunctional nanoparticles for cancer immunotherapy

“…8 For example, liposomes, which are the most used for bimolecular delivery, have been equipped with pH-responsive moieties, such as phosphatidylethanolamine (PE) or unsaturated DOPE. 57 In such pH sensitive delivery systems, pH-responsive moieties trigger liposome destabilization after endocytosis and promote lipid membrane fusion under acidic conditions, releasing its content into the cytoplasm and lead to effective MHC class I presentation pathway and therefore improved CTL responses. 58 An alternative approach is surface modification of liposomes with pH-sensitive fusogenic molecules such as pH-sensitive polymers or fusogenic peptides either encapsulated or incorporated in lipid bilayers.…”