Strategies of Overcoming the Physiological Barriers for Tumo(2)

Overcoming Physiological Barriers of Tumor-targeted Nanomedicines Current Pharmaceutical Design, 2015, Vol. 21, No. 42 6241

(Table 1) Contd….

Delivery barriers 7)

Drug response

1)

Physiological basis Based on summarized pathophysiological basis

1) 2) 3)

Strategies Directly target and kill CSCs

Synergistic combination of two or more drugs Multi-functional targeted delivery

3) 1)

Examples

NPDAC combined with NPDOX, SAL-SWNTCHI-HA complexes, phenformin-loaded polymeric micelles

Combination of different chemotherapy and combination of chemotherapy and gene therapy

Liposome system functionalized with PEG, RGD and TAT, DGlueNP/PTX nanoparticles, octa-functional PLGA nanoparticles

2)

endosomal escape and enhance the biological response of various drugs [82, 98-101]. Besides, based on the fusion process occurring between the viral envelope and the endosomal membrane of host cell, some influenza-derived fusogenic peptides such as HA2 and diINF-7 have been used to increase the endosomal escape of siRNA and further the gene silencing efficiency [84]. Other synthetic fu-sogenic peptides such as KALA and GALA, capable of forming ??-helical structure for destabilization of endosomal membrane, have also been used to increase the endosomal escape of NDDSs [102, 103].

The Proton Sponge Effect

Unlike fusion systems that relied on the fusogenic property of the lipid or peptide to mediate endosomal escape, some nanocarri-ers, usually composed of cationic polymers and drugs, are supposed to use the so-called “proton sponge” effect to enhance the endoso-mal escape. Proton sponge effect is mainly caused by cationic polymers coated on the NDDSs that promote endosome osmotic swelling, rupture of the endosome membrane and intracellular re-lease of loaded drugs. Based on the mechanism, the cationic poly-mers with ‘proton-sponge’ nature such as polyethylenimine(PEI) and Polyamidoamine(PAMAM) dendrimers have been extensively studied as plasmid DNA (pDNA) delivery vehicles [104]. Cationic polymers containing NDDSs, such as PEI-coated and siRNA-loaded mesoporous silica nanoparticles and PAMAM dendrimer-siRNA complexation, were proved to possess the capability of initi-ating effectively endosomal escape before the degradation of the packaged siRNA in endolysosomes [95, 105]. Other chemical agents such as poly(amido amine)s (PAAs) and poly(propylacrylic acid) (PPAA) also have the function of endosomal escape and have been proved to improve the transfection efficiency of genetic drugs [97, 106]. Therefore, “proton sponge” agents are a promising can-didate for cytosolic drug delivery.

Drugs Release

As the last line of defense, an optimal drug release profile can be realized through biological stimuli-responsive NDDSs based on the acidic environment and specific enzymes present in tumor tissue or endolysosomes, thereby enhancing the killing effect on tumor cells [107].

pH-sensitive materials are more and more used to promote drug release in tumor stroma or tumor cells based on the low pH in tu-mor tissues(~6.5) or endolysosomes (4.5-6.5) compared with nor-mal tissues (pH7.4) [108, 109]. Thus various pH-responsive nano-carriers such as liposomes, nanoparticles, nanogels, polymer-drug conjugates and micelles have been extensively designed and re-ported [110]. As the conformational change can be exploited to trigger the drug release, a pH-sensitive charge-conversion system including micelles and polycarboxylates nanospheres was recently designed and the drug could be released in a pH-dependent manner

[109, 110]. Beside, both inorganic nanoscale materials like chitosan enclosed mesoporous silica nanoparticles and hybrid organic nano-materials such as P(St-co-DMAEMA) complexes(poly(styrene-co-N,N'-dimethylaminoethyl methacrylate) nanoparticles) and MPEG-b-PMaIPG(methoxy-polyethylene glycols (PEG)-b-poly (d-galactopyranose)nanoparticles have been proved to show a sensitive response to narrow pH changes and a good drug release behavior, exhibiting a high antitumor activity [109, 111-113].

Enzyme-responsive NDDSs were another effective system de-veloped to promote the drug release based on the specific enzymes present in tumor. For example, gelatin can be easily hydrolyzed into its sub-compounds by gelatinase, which is an endogenous prote-olytic enzyme and usually over-expressed in tumor tissues but not in normal tissues [114]. Gelatin-DOX (gelatin-doxorubicin) conju-gates or cationic gelatin/polyGC-DOX complexes can be specifi-cally digested when exposed to gelatinase and release doxorubicin [114, 115]. Some lysosomal cysteine proteases such as cathepsin B and cathepsin D, which play important roles in tumor progression and metastasis, also provided the possibility of designing enzyme-responsive drug delivery vehicles [116, 117]. Appropriate substrate which effectively degraded upon exposure to these cysteine prote-ases had been used as the linker of bioconjugates of antitumor drugs and polymers, permitting intra-lysosomal drug release after endocy-tosis [116, 117]. Nowadays, some esterases are found to be highly expressed in the intracellular compartments, and their substrates have been used as responsive self-immolative linkers in polymeric drug conjugates to trigger the drug release once taken up by tumor cells. For example, cholesterol esterase is highly expressed in en-dosome and lysosome, and the poly(ethylene carbonate), which can be degraded when exposed to cholesterol esterase, enabled release of bovine serum albumin (BSA) in an enzyme-responsive manner [118, 119].

Drug Response

Synergistic Antitumor Effect of Two or More Drugs

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