Development of the pH Sensitive Drug Delivery System

pH sensitive liposomes contains the such type of the phospholipid bilayer which is sensitive to the change in the pH. Change in the pH influences the release of the drug. pH sensitivity is the important feature of this type of the liposome which gives advantage for the delivery of the drug content at various possible targets. The idea of the development of the pH sensitive drug delivery is coined in 1980 by the Matsuzaki, Hamasaki and Said (Matsuzaki, Hamasaki and Said, 1980). The main objective of this drug delivery system is release liposomal contents in response to a low pH environment especially in case of cancer therapy as well as gene delivery. This system has the capacity to interact as well as enhance the fusion or disruption of the endosomal membrane & perfectly release the encapsulated drug in to the cell cytosol (Paliwal, Paliwal and Vyas, 2014). The development of pH sensitive done by two main strategies; 1) There is use of polymers (polyacids or polybases) with ionisable groups that undergo conformational and/or solubility changes in response to environmental pH variation; 2) The design of polymeric systems with acid-sensitive bonds whose cleavage enables the release of molecules attached at the polymer backbone. (Torchilin, Zhou and Huang, 1993) (Mallick and Choi, 2014) (Mura, Nicolas and Couvreur, 2013).

pH sensitive drug delivery system also designed for the oral delivery for the gastric pH sensitive drugs. Due to the highly acidic environment of the gastric cavity most of the drugs are degraded or less absorb into the systemic circulation. To overcome this problem as well as to increase the absorption in the intestine, the pH sensitive liposomes are the best reliable method (Mura, Nicolas and Couvreur, 2013) (Mallick and Choi, 2014). The selection of the lipid which is pH sensitive as well as surfactant is important parameters for the development of the stable pH sensitive liposomes. These should be regulates the properties of the liposomes such as extent of cellular internalization, the fusogenic ability, pH sensitivity and stability in biological fluids (Paliwal, Paliwal and Vyas, 2014).

The lipid carriers used for the preparation of the pH sensitive liposomes are 1,2-diole-oyl-sn-glycero-3-phoshoethanolamine (DOPE) or 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, which are change at the acidic pH, a lamellar phase to a fusogenic hexagonal phase. There is difference in the pH profile of the tissues due to the variation in diversity of the organs as well as cell environment. The pathological inflammated, infectious as well as cancerous tissue has the different pH profile as compare to the normal tissues. Therefor its gives an opportunity to develop the type of the system which delivers the drug at such type of the diverse area where change in the pH is regularly observed. Such type of the properties helpful for the development of the novel drug delivery system. Therefor the anticancer drugs and gene delivery are principle areas of interest for the development of the such type of the system (Ganta et al., 2008). The applications of the pH sensitive systems are versatile which includes tumour targeted drug delivery, tumour diagnosis, chemotherapy, vaccine delivery as well as gene delivery (Paliwal, Paliwal and Vyas, 2014).

Research Work (Other than Cancer)

Fang & co-workers developed a novel protein delivery system containing a core of magnesium phosphate nanoparticle plus a shell of cationic lipid membranes loaded with the model cargo protein catalase (CAT) which was effectively prepared by micro-emulsion precipitation method. Lipid-coated magnesium phosphate nanoparticles (LPP) of CAT is sensitive to pH which leads to successful delivery of the protein at the targeted site (Fang et al., 2019).

For Cancer

Liposomes are the best system for the targeting the anticancer agents. Among them pH sensitive liposomes are the suitable for the delivery of the anticancer agent at the site specific as well as enhance the bioavailability of the drug. Researchers from throughout the world formulate the pH sensitive liposomes for the increase the bioavailability of drugs, targeted action or site specificity. Such as Yao et al., prepared & evaluate the pH-sensitive carboxymethyl chitosan-modified liposomes with sorafenib (Sf) and Cy3-siRNA co-loaded (CMCS-SiSf-CL delivery system) by using the thin-film hydration method. The formulated system is promising method for the for targeting the hepatocellular carcinoma therapy. (Yao et al., 2019).

Bi et al, works on development of the better method for the preparation of the folate (FA)- targeted liposomes loaded Doxorubicin (DOX). Bi & co-workers first time compare the two methods of preparation of liposomes i.e. conventional chemical synthesis & novel Polydopamine (PDA) method. The developed method can be used as a medium for the conjugating targeted ligands to polymer carriers without reactive chemical groups. The study demonstrated that the PDA method achieve better therapeutic level as compare to traditional method which can be useful for the drug delivery system in the future. (Bi et al., 2019)

One of the effective root for the administration of the chemotherapeutic agent is delivery of the calcium carbonate (CaCO3) encapsulated liposome with pH sensitivity. Chen & co-workers creates an innovative method which includes the benefit of a W/O emulsion to formulate CaCO3 encapsulated liposomes by film dispersion method for the delivery of curcumin. This innovative method successfully reduce the problems related with the delivery of the of curcumin and improved its therapeutic effects on cancer treatment. (Y. Chen et al., 2019)

Multidrug resistance (MDR) is the common problem related with the cancer therapy due to the various factors. Among them overexpression of drug transporters as P-glycoprotein (P-gp) is the one of the factor responsible for the MDR. M. Chen & co-workers developed a novel dual pH-sensitive liposomal system with charge-reversal and Nitric oxide (NO) generation. In this developed system, the pH sensitive polymer i.e monomethoxypoly(ethylene glycol)-poly(L-lysine)-graft-dimethylmaleic anhydride (PEG-PLL-DMA) is modified on the surface of the liposomes for the delivering the NO donor as well as chemotherapeutic drug Paclitaxel (PTX) into the MDR cell to minimise the MDR & increase the therapeutic effect of the chemotherapy. (M. Chen et al., 2019).

To overcome the MDR, Tang & co-workers investigate the dual intracellular delivery approach (mediated by hyaluronic acid (HA) and pH-sensitivity) using hyaluronic acid functionalised pH-sensitive liposomes (HA-pSL). This system demonstrated improved cellular uptake and in vitro cytotoxicity, but fails to completely eliminate the drug-resistant. (Tang et al., 2019)

Development of the long-circulating and pH-sensitive liposome containing paclitaxel (SpHL-PTX) was recently done by Monteiro & group. They establish the molecular & supramolecular interface/interactions between the lipid bilayer and PTX in equivalent biological environment conditions (acidic environment) (Monteiro et al., 2018). For the treatment of the lung cancer, novel drug delivery systems based on cationic (CL) and pH-sensitive liposomes (PSL) for tyrosine kinase inhibitor afatinib (AFT) were developed by Almurshedi and co-workers. The objective of the developed system is to improve tumour target ability against non-small cell lung cancer (NSCLC) cells and therapeutic effect. (Almurshedi et al., 2018)