High particle uniformity, high photoluminescence quantum yields, narrow and symmetric emission spectral lineshapes and minimal single dot emission intermittency (known as blinking) have been recognized as universal requirements for the successful use of colloidal quantum dots (QDs) in nearly all optical applications. However, synthesizing samples that simultaneously meet all these four criteria has proven challenging. Here, we report the synthesis of such high-quality CdSe/CdS core/shell QDs in an optimized process which maintains a slow growth rate of the shell through the use of octanethiol and cadmium oleate as precursors. In contrast with previous observations, single-QD blinking is significantly suppressed with only a relatively thin shell. In addition, we demonstrate the elimination of the ensemble luminescence photodarkening that is an intrinsic consequence of QD blinking statistical aging. Furthermore, the small size and high photoluminescence quantum yields of these novel QDs render them superior in vivo imaging agents compared to conventional QDs. We anticipate that this new generation of QDs will also result in significant improvement in the performance of QDs in other applications such as solid-state lighting and illumination.

Cancer and stromal cells actively exert physical forces (solid stress) to compress tumour blood vessels, thus reducing vascular perfusion. Tumour interstitial matrix also contributes to solid stress, with hyaluronan implicated as the primary matrix molecule responsible for vessel compression because of its swelling behaviour. Here we show, unexpectedly, that hyaluronan compresses vessels only in collagen-rich tumours, suggesting that collagen and hyaluronan together are critical targets for decompressing tumour vessels. We demonstrate that the angiotensin inhibitor losartan reduces stromal collagen and hyaluronan production, associated with decreased expression of profibrotic signals TGF-β1, CCN2 and ET-1, downstream of angiotensin-II-receptor-1 inhibition. Consequently, losartan reduces solid stress in tumours resulting in increased vascular perfusion. Through this physical mechanism, losartan improves drug and oxygen delivery to tumours, thereby potentiating chemotherapy and reducing hypoxia in breast and pancreatic cancer models. Thus, angiotensin inhibitors —inexpensive drugs with decades of safe use — could be rapidly repurposed as cancer therapeutics.

The presence of growth-induced solid stresses in tumors has been suspected for some time, but these stresses were largely estimated using mathematical models. Solid stresses can deform the surrounding tissues and compress intratumoral lymphatic and blood vessels. Compression of lymphatic vessels elevates interstitial fluid pressure, whereas compression of blood vessels reduces blood flow. Reduced blood flow, in turn, leads to hypoxia, which promotes tumor progression, immunosuppression, inflammation, invasion, and metastasis and lowers the efficacy of chemo-, radio-, and immunotherapies. Thus, strategies designed to alleviate solid stress have the potential to improve cancer treatment. However, a lack of methods for measuring solid stress has hindered the development of solid stress-alleviating drugs. Here, we present a simple technique to estimate the growth-induced solid stress accumulated within animal and human tumors, and we show that this stress can be reduced by depleting cancer cells, fibroblasts, collagen, and/or hyaluronan, resulting in improved tumor perfusion. Furthermore, we show that therapeutic depletion of carcinoma-associated fibroblasts with an inhibitor of the sonic hedgehog pathway reduces solid stress, decompresses blood and lymphatic vessels, and increases perfusion. In addition to providing insights into the mechanopathology of tumors, our approach can serve as a rapid screen for stress-reducing and perfusion-enhancing drugs.tumor microenvironment | desmoplastic tumors | pancreatic ductal adenocarcinoma | mathematical modeling | sonic hedgehog pathway E levated interstitial fluid pressure (IFP) and solid stress are hallmarks of the mechanical microenvironment of solid tumors (1). IFP is the isotropic stress (i.e., applied equally in all directions) exerted by the fluid, whereas solid stress is exerted by the nonfluid components. In 1950, the work by Young et al. (2) provided the first measurements of IFP in tumors growing in rabbits and found it to be elevated compared with IFP in normal testicular tissue. However, the implications of this interstitial hypertension for tumor progression and treatment were not fully revealed for nearly four decades. In 1988, we developed a mathematical model that showed that IFP is uniformly elevated throughout the bulk of a tumor and precipitously drops to normal values in the tumor margin, causing a steep pressure gradient (3,4). Based on the model's results, we predicted that diffusion rather than convection would be the dominant mode of transport within tumors because of nearly uniform pressure within the tumor. Furthermore, we predicted that the steep pressure gradients in the periphery would cause fluid leaking from the blood vessels located in the tumor margin-but not from the vessels in the tumor interiorto ooze into the surrounding normal tissue. This oozing fluid would facilitate transport of growth factors and cancer cells into the surrounding tissue-fueling tumor growth, progression, and lymphatic metastasis. In subsequent years, we confirmed th...

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The blood vessels of cancerous tumours are leaky1–3 and poorly organized4–7. This can increase the interstitial fluid pressure (IFP) inside tumours and reduce blood supply to them, which impairs drug delivery8–9. Anti-angiogenic therapies – which “normalize” the abnormal blood vessels in tumours by making them less leaky – have been shown to improve the delivery and effectiveness of chemotherapeutics with low molecular-weights10, but it remains unclear whether normalizing tumour vessels can improve the delivery of nanomedicines. Here we show that repairing the abnormal vessels in mammary tumours, by blocking vascular endothelial growth factor (VEGF) receptor-2, improves the delivery of small nanoparticles (12nm diameter) while hindering the delivery of large nanoparticles (125nm diameter). We utilize a mathematical model to show that reducing vessel wall pore sizes through normalization decreases IFP in tumours, allowing small nanoparticles to enter them more rapidly. However, increased steric and hydrodynamic hindrances, also associated with smaller pores, make it more difficult for large nanoparticles to enter tumours. Our results further suggest that smaller (~12nm) nanomedicines are ideal for cancer therapy, owing to superior tumour penetration.

The dense collagen network in tumors significantly reduces the penetration and efficacy of nanotherapeutics. We tested whether losartan-a clinically approved angiotensin II receptor antagonist with noted antifibrotic activity-can enhance the penetration and efficacy of nanomedicine. We found that losartan inhibited collagen I production by carcinoma-associated fibroblasts isolated from breast cancer biopsies. Additionally, it led to a dose-dependent reduction in stromal collagen in desmoplastic models of human breast, pancreatic, and skin tumors in mice. Furthermore, losartan improved the distribution and therapeutic efficacy of intratumorally injected oncolytic herpes simplex viruses. Finally, it also enhanced the efficacy of i.v. injected pegylated liposomal doxorubicin (Doxil). Thus, losartan has the potential to enhance the efficacy of nanotherapeutics in patients with desmoplastic tumors. drug delivery | matrix modifier | thrombospondin-1 | transforming growth factor β | transport A lthough nanotherapeutics have offered new hope for cancer treatment, their clinical efficacy is modest (1-4). This is partly because their penetration is hindered, especially in fibrotic tumors, where the small interfibrillar spacing in the interstitium retards the movement of particles larger than 10 nm (5-8). Pegylated liposomal doxorubicin (Doxil), approved by the Food and Drug Administration, and oncolytic viruses, currently in multiple clinical trials, represent two nanotherapeutics whose size (∼100 nm) hinders their intratumoral distribution and therapeutic effectiveness (9). Matrix modifiers such as bacterial collagenase, relaxin, and matrix metalloproteinase-1 and -8 have been used to modify the collagen or proteoglycan network in tumors and have improved the efficacy of intratumorally (i.t.) injected oncolytic viruses (8,(10)(11)(12)(13). However, these agents may produce normal tissue toxicity (e.g., bacterial collagenase) or increase the risk of tumor progression (e.g., relaxin, matrix metalloproteinases).Losartan (14)-approved to control hypertension in patients -does not have many of these safety risks. Furthermore, in addition to its antihypertensive properties, losartan is also an antifibrotic agent that has been shown to reduce the incidence of cardiac and renal fibrosis (15, 16). The antifibrotic effects of losartan are caused, in part, by the suppression of active transforming growth factor-β1 (TGF-β1) levels via an angiotensin II type I receptor (AGTR1)-mediated down-regulation of TGF-β1 activators such as thrombospondin-1 (TSP-1) (15-19). Using a dose that has minimal effects on mean arterial blood pressure (MABP), we show that losartan reduces collagen I levels in four tumor models-a spontaneous mouse mammary carcinoma (FVB MMTV PyVT), an orthotopic pancreatic adenocarcinoma (L3.6pl), and s.c. implanted fibrosarcoma (HSTS26T) and melanoma (Mu89). Losartan also improves the intratumoral penetration of nanoparticles injected i.t. or i.v.Based on these results, we tested how losartan would affect the distributi...

Cancer nanomedicines approved so far minimize toxicity, but their efficacy is often limited by physiological barriers posed by the tumour microenvironment. Here, we discuss how these barriers can be overcome through innovative nanomedicine design and through creative manipulation of the tumour microenvironment.

Tumors are similar to organs, with unique physiology giving rise to an unusual set of transport barriers to drug delivery. Cancer therapy is limited by nonuniform drug delivery via blood vessels, inhomogeneous drug transport into tumor interstitium from the vascular compartment, and hindered transport through tumor interstitium to the target cells. Four major abnormal physical and physiological properties contribute to these transport barriers. Accumulated solid stress compresses blood vessels to diminish the drug supply to many tumor regions. Immature vasculature with high viscous and geometric resistances and reduced pressure gradients leads to sluggish and heterogeneous blood flow in tumors to further limit drug supply. Nonfunctional lymphatics coupled with highly permeable blood vessels result in elevated hydrostatic pressure in tumors to abrogate convective drug transport from blood vessels into and throughout most of the tumor tissue. Finally, a dense structure of interstitial matrix and cells serves as a tortuous, viscous, and steric barrier to diffusion of therapeutic agents. In this review, we discuss the origins and implications of these barriers. We then highlight strategies for overcoming these barriers by modulating either drug properties or the tumor microenvironment itself to enhance the delivery and effectiveness of drugs in tumors.