Tumor targetability and site-specific drug release of therapeutic nanoparticles are key factors for effective cancer therapy. In this study, poly(ethylene glycol) (PEG)-conjugated hyaluronic acid nanoparticles (P-HA-NPs) were investigated as carriers for anticancer drugs including doxorubicin and camptothecin (CPT). P-HA-NPs were internalized into cancer cells (SCC7 and MDA-MB-231) via receptor-mediated endocytosis, but were rarely taken up by normal fibroblasts (NIH-3T3). During in vitro drug release tests, P-HA-NPs rapidly released drugs when incubated with cancer cells, extracts of tumor tissues, or the enzyme Hyal-1, which is abundant in the intracellular compartments of cancer cells. CPT-loaded P-HA-NPs (CPT-P-HA-NPs) showed dose-dependent cytotoxicity to cancer cells (MDA-MB-231, SCC7, and HCT 116) and significantly lower cytotoxicity against normal fibroblasts (NIH-3T3) than free CPT. Unexpectedly, high concentrations of CPT-P-HA-NPs demonstrated greater cytotoxicity to cancer cells than free CPT. An in vivo biodistribution study indicated that P-HA-NPs selectively accumulated into tumor sites after systemic administration into tumor-bearing mice, primarily due to prolonged circulation in the blood and binding to a receptor (CD44) that was overexpressed on the cancer cells. In addition, when CPT-P-HA-NPs were systemically administrated into tumor-bearing mice, we saw no significant increases in tumor size for at least 35 days, implying high antitumor activity. Overall, P-HA-NPs showed promising potential as a drug carrier for cancer therapy.

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Herein, we prepared tumor-targeting peptide (AP peptide; CRKRLDRN) conjugated pH-responsive polymeric micelles (pH-PMs) in cancer therapy by active and pH-responsive tumor targeting delivery systems, simultaneously. The active tumor targeting and tumoral pH-responsive polymeric micelles were prepared by mixing AP peptide conjugated PEG-poly(d,l-lactic acid) block copolymer (AP-PEG-PLA) into the pH-responsive micelles of methyl ether poly(ethylene glycol) (MPEG)-poly(beta-amino ester) (PAE) block copolymer (MPEG-PAE). These mixed amphiphilic block copolymers were self-assembled to form stable AP peptide-conjugated and pH-responsive AP-PEG-PLA/MPEG-PAE micelles (AP-pH-PMs) with an average size of 150 nm. The AP-pH-PMs containing 10 wt % of AP-PEG-PLA showed a sharp pH-dependent micellization/demicellization transition at the tumoral acid pH. Also, they presented the pH-dependent drug release profile at the acidic pH of 6.4. The fluorescence dye, TRITC, encapsulated AP-pH-PMs (TRITC-AP-pH-PMs) presented the higher tumor-specific targeting ability in vitro cancer cell culture system and in vivo tumor-bearing mice, compared to control pH-responsive micelles of MPEG-PAE. For the cancer therapy, the anticancer drug, doxorubicin (DOX), was efficiently encapsulated into the AP-pH-PMs (DOX-AP-pH-PMs) with a higher loading efficiency. DOX-AP-pH-PMs efficiently deliver anticancer drugs in MDA-MB231 human breast tumor-bearing mice, resulted in excellent anticancer therapeutic efficacy, compared to free DOX and DOX encapsulated MEG-PAE micelles, indicating the excellent tumor targeting ability of AP-pH-PMs. Therefore, these tumor-targeting peptide-conjugated and pH-responsive polymeric micelles have great potential application in cancer therapy.

IntroductionThe rapid removal of damaged and aged RBCs from the peripheral circulation is important for tissue homeostasis. Based on a life span of 120 days, 170 billion RBCs must be removed daily from the blood circulation by the liver and spleen. Phagocytes need to engulf 2 million RBCs per second. 1 Clearance of aged and damaged RBCs is mediated by the recognition of phosphatidylserine (PS) on the cell surface. 2,3 Kupffer cells in the liver are known to be responsible for engulfing damaged RBCs in a PS-dependent manner. 4 The number of PS-exposed RBCs to be removed is remarkably increased in patients with several hemolytic anemia, including sickle cell disease, ␤-thalassemia, malaria, and chronic renal failure. [5][6][7][8] Furthermore, apoptotic and senescent neutrophils are almost entirely eliminated from the circulation (clearance halftime ϭ 6.7 hours) by Kupffer cells in the liver, but rarely by macrophages in the spleen, lung, and peripheral blood. 9,10 Kupffer cells are also involved in the clearance of macromolecules and pathogens. 11 The many functions of Kupffer cells suggest that an auxiliary mechanism is required for apoptotic and senescent cell clearance in the liver.Stabilin-1 and stabilin-2 are type I transmembrane receptors with multiple functions, including cell adhesion, endocytosis, and phagocytosis. They are expressed in certain populations of macrophages as well as in sinusoidal endothelial cells in the liver, spleen, and lymph nodes. [12][13][14][15] Although stabilin-1 and stabilin-2 have different ligands during endocytosis, 16 they share common functions such as cell-cell adhesion. 17,18 Recently, stabilin-2 was suggested as a novel member of PS-receptor along with Tim-4 and BAI1. 15,19,20 More recently, we showed that stabilin-1 is also involved in apoptotic cell clearance via recognition of PS in alternatively activated macrophages. 21 Although stabilin-2 and its functional homolog stabilin-1 are involved in aged and apoptotic cell clearance in macrophages via PS recognition, 15,21 their role as PS receptors in sinusoidal endothelial cells remains an open question. Hepatic sinusoidal endothelial cells (HSECs) are the major cell population of the hepatic sinusoid and play several important roles in the physiology and pathology of the liver, including Ag presentation and clearance of macromolecules and apoptotic cells. 22,23 Thus, we hypothesized that there is a potential mechanism for the efficient removal of aged or damaged RBCs in the liver, where sinusoidal endothelial cells play a role in facilitating clearance by Kupffer cells. In this study, we present evidence that stabilin-1 and stabilin-2 in HSECs function as receptors in the PS-specific sequestration of damaged RBCs for their effective removal from the blood circulation. Methods Mice, reagents, and AbsSix-to 7-week-old male BALB/c mice were used. These mice were maintained under specific pathogen-free conditions, and the use committee established at the Medical College of Kyungpook National University and Kyungpook National...