Fig.1 Schematic representation of anatomical diffe-rences between normal and tumor tissues[5]^Hyper-permeable tumor vasculature allows preferential extravasation of the circulating macromolecular drug carriers due to enhanced permeability and retention(EPR) effect.

Fig.2 Schematic representation of different mechanisms by which nanocarriers can deliver drugs to tumours[1]^Polymeric nanoparticles are shown as representative nanocarriers(circles). Passive tissue targeting is achieved by extravasation of nanoparticles through increased permeability of the tumour vasculature and ineffective lymphatic drainage(EPR effect). Active cellular targeting(inset) can be achieved by functionalizing the surface of nanoparticles with ligands that promote cell-specific recognition and binding. the nanoparticles can(i) release their contents in close proximity to the target cells;(ii) attach to the membrane of the cell and act as an extracellular sustained-release drug depot; or(iii) internalize into the cell.

Fig.3 Multistep binding and penetration mechanism of iRGD[63]

Fig.4 CDDP/mPEG-b-PLG and a combination with cyclic iRGD applied fornon-small cell lung cancer therapy[65]

Fig.5 Chemical structures of CDDP and PEG-P(Glu)block copolymers and the micellar structures of CDDP-incorporating polymeric micelles(NC-6004)[72]

Fig.6 Schematic illustration of the preparation and the interaction mechanism of DOX-NP[74]

Fig.7 Schematic illustration of drug loading, endocytosisand intracellular drug release of the pH-responsive amphiphile complex[86]

Fig.8 Endosomal pH-sensitive carrier: PEG-PolyA3[88]

Fig.9 Schematic representation oftumor-pHe-triggered charge-reversal CDDP/P(Glu-co-Lys) nanocarriers[89]

Fig.10 pH-sensitive charge-conversion system for doxorubicin delivery[90]

Fig.11 Schematic illustration of DOX loading and targeted intracellular release [97]

Fig.12 Schematic illustration of the formation and stimuli-dependent structural transitions of the pH- and reduction-responsive polyurethane micelles [98]

Fig.13 Schematic illustration of improved cellular internalization and efficient intracellular DOX release of DOX-loaded nanogel, and tumor cellular apoptosis[100]

Fig.14 Schematic illustration of mPEG-P(LL-co-LC) nanogel preparation, DOX derivatives loading and intracellular release[101]

Fig.15 Infiuence of the polymer concentration on the thermosensitive behavior of PPLG112-g-MEO2 in aqueous solution(A), LCST of PPLG112-g-MEO2 solution as a function of its concentration(B) and release profile of doxorubicin from PPLG112-g-MEO2nano-particles(C)[106]

Fig.16 Schematic illustration of self-assembly of “hairy-rod” polypeptides, DOX loading and thermal-responsiveness of micelle and DOX-loaded micelle[107]