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Previously reported amphiphilic diblock copolymer with pendant dendron moieties (P 71 D 3 ) has been further evaluated in tumor-bearing mice as a potential drug carrier. This P 71 D 3 -based micelle of an average diameter of 100nm was found to be biocompatible, non-toxic and physically stable in colloidal system up to 15days. It enhanced the in vitro potency of doxorubicin (DOX) in 4T1 breast tumor cells by increasing its uptake, by 3-fold, compared to free DOX. In 4T1 tumor-bearing mice, the tumor growth rate of P 71 D 3 /DOX (2mg/kg DOX equivalent) treated group was significantly delayed and their tumor volume was significantly reduced by 1.5-fold compared to those treated with free DOX. The biodistribution studies indicated that P 71 D 3 /DOX enhanced accumulation of DOX in tumor by 5- and 2-fold higher than free DOX treated mice at 15min and 1h post-administration, respectively. These results suggest that P 71 D 3 micelle is a promising nanocarrier for chemotherapeutic agents., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Conjugation of Doxorubicin (DOX) to N-(2-hydroxypropyl) methylacrylamide copolymer (HPMA) has significantly reduced the DOX-associated cardiotoxicity. However, the reports on the impact of HPMA-DOX conjugates on the cardiovascular system such as blood pressure (BP) and heart rate (HR) were in restrained animals using tail cuff and/or other methods that lacked the resolution and sensitivity. Herein, we employed radiotelemetric-spectral-echocardiography approach to further understand the in vivo cardiovascular hemodynamics and variability post administration of free DOX and HPMA-DOX. Rats implanted with radio-telemetry device were administered intravenously with DOX (5 mg/kg), HPMA-DOX (5 mg DOX equivalent/kg) and HPMA copolymer and subjected to continuous cardiovascular monitoring and echocardiography for 140 days. We found that DOX-treated rats had ruffled fur, reduced body weight (BW) and a low survival rate. Although BP and HR were normal, spectral analysis indicated that their BP and HR variabilities were reduced. All rats exhibited typical signs of cardiotoxicity at histopathology. In contrast, HPMA-DOX rats gained weight over time and survived. Although BP, HR and related variabilities were unaffected, the left ventricular end diastolic volume (EDV) of these rats, as well as of the HPMA copolymer-treated rats, was found increased at the end of observation period. Additionally, HPMA copolymer caused microscopic injury of the heart tissue. All of these suggest the necessity of caution when employing HPMA as carrier for prolonged drug delivery. The current study also indicates the potential of radiotelemetric-spectral-echocardiography approach for improved preclinical cardiovascular risk assessment of polymer-drug conjugate and other nano-sized-drug constructs.

Previously synthesized amphiphilic diblock copolymers with pendant dendron moieties have been investigated for their potential use as drug carriers to improve the delivery of an anticancer drug to human breast cancer cells. Diblock copolymer (P71 D3 )-based micelles effectively encapsulate the doxorubicin (DOX) with a high drug-loading capacity (≈95%, 104 DOX molecules per micelle), which is approximately double the amount of drug loaded into the diblock copolymer (P296 D1 ) vesicles. DOX released from the resultant P71 D3 /DOX micelles is approximately 1.3-fold more abundant, at a tumoral acidic pH of 5.5 compared with a pH of 7.4. The P71 D3 /DOX micelles also enhance drug potency in breast cancer MDA-MB-231 cells due to their higher intracellular uptake, by approximately twofold, compared with the vesicular nanocarrier, and free DOX. Micellar nanocarriers are taken up by lysosomes via energy-dependent processes, followed by the release of DOX into the cytoplasm and subsequent translocation into the nucleus, where it exert its cytotoxic effect., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We synthesized a dextrin (DEX)-conjugated graphene oxide (GO) nanocarrier (GO 100 -DEX) as a potential drug delivery system to respond to a tumor-associated stimulus, α-amylase, that has high permeability through the fenestrated endothelial barrier to the tumor site. At acidic pH and in the presence of α-amylase to simulate tumor conditions, GO 100 -DEX released a 1.5-fold higher amount of doxorubicin (DOX) than of GO 100 . Under the same conditions, the cytotoxic effects of GO 100 -DEX/DOX were 2-fold greater than those of free DOX and 2.9-fold greater than those of GO 100 /DOX. Employing an in vitro biomimetic microfluidic blood vessel model lined with human umbilical vein endothelial cells, we evaluated the tumor vasculature endothelial permeation of GO 100 -DEX and GO 100 using dextrans of 10 and 70 kDa for comparison and as standards to validate the microfluidic blood vessel model. The results showed that the permeabilities of GO 100 -DEX and GO 100 were 4.3- and 4.9-fold greater than that of 70 kDa dextran and 2.7- and 3.1-fold higher than that of 10 kDa dextran, thus demonstrating the good permeability of the GO-based nanocarrier through the fenestrated endothelial barrier. [ABSTRACT FROM AUTHOR]

Hybrid carriers were successfully synthesized by chemically binding OH-terminated fourth generation poly(amido amine) dendrimer and folic acid on graphene oxide (GO) with a size of 100 nm, and their drug carrier ability was compared with hybrids of 1500 nm GO. The small hybrid carriers possessed a 1.3 times lower loading capacity (1.43 g/g(GO)) for doxorubicin (DOX) than the large hybrid carriers. However, the amount (86%) of DOX released at pH 5.5 from the small hybrids after 72 h was 1.14 times larger than from the large hybrids. This difference could be due to the extent of π–π interaction between DOX and the graphitic domain on GO. In vitro MTT assays revealed that the small hybrids led to higher cell viability than 63% at 0.75 μg/ml in HeLa human cervical cancer cells. An investigation of the intracellular uptake of hybrid carriers revealed the efficient internalization of small hybrids in the HeLa cells (97% at 62.5 mg/ml). Taken together, these results indicate that the small hybrids consisting of 100 nm GO carrier can successfully load and deliver the anticancer drug DOX into HeLa cells. In the carriers, dendrimer had a role of stable suspension of the hybrids in water, and folic acid acted as an effective anchoring of the hybrids on HeLa cells. The present investigation highlights the potential use of these hybrid materials as nanocarriers with high loading and releasing efficiency for the delivery of anticancer drugs to tumor cells. [ABSTRACT FROM AUTHOR]