Delivering Nanomedicine to Solid Tumors

Rakesh K. Jain; Triantafyllos Stylianopoulos

Abstract and Introduction

Abstract

Recent advances in nanotechnology have offered new hope for cancer detection, prevention, and treatment. While the enhanced permeability and retention effect has served as a key rationale for using nanoparticles to treat solid tumors, it does not enable uniform delivery of these particles to all regions of tumors in sufficient quantities. This heterogeneous distribution of therapeutics is a result of physiological barriers presented by the abnormal tumor vasculature and interstitial matrix. These barriers are likely to be responsible for the modest survival benefit offered by many FDA-approved nanotherapeutics and must be overcome for the promise of nanomedicine in patients to be realized. Here, we review these barriers to the delivery of cancer therapeutics and summarize strategies that have been developed to overcome these barriers. Finally, we discuss design considerations for optimizing the delivery of nanoparticles to tumors.

Introduction

Rapid advances in nanotechnology have permitted the incorporation of multiple therapeutic, sensing and targeting agents into nanoparticles (for example, liposomes, viruses and quantum dots), with a size range of 1–1,000 nm. These agents have offered new hope for detection, prevention, and treatment in oncology. Nanomedicine for cancer therapy is advantageous over conventional medicine because it has the potential to enable the preferential delivery of drugs to tumors owing to the enhanced permeability and retention (EPR) effect, and the delivery of more than one therapeutic agent for combination therapy. Other advantages of nanomedicine include specific binding of drugs to targets in cancer cells or the tumor microenvironment, simultaneous visualization of tumors using innovative imaging techniques, enhanced drug-circulation times, controlled drug-release kinetics, and superior dose scheduling for improved patient compliance.^[1–6] Furthermore, many widely used conventional chemotherapeutics, such as taxanes, include synthetic solvents (for example, castor oil and polysorbate 80) that directly contribute to adverse effects.^[7–9] Finally, many tumor types are inherently resistant to available chemotherapeutics. Nanomedicine has the potential to overcome these problems.^[10,11]

Over 20 nanoparticle therapeutics have been approved by the FDA for clinical use.^[12,13] Nanoparticle formulations for the treatment of solid tumors (Table 1) include liposomes (such as pegylated liposomal doxorubicin and liposomal daunorubicin), albumin-bound paclitaxel, polymeric particles (such as methoxy-PEG-poly[D,L-lactide] taxol) and many more formulations that are in preclinical and/or clinical trials.^[12] Although less toxic than conventional therapies, these agents are still associated with adverse effects, such as stomatitis and palmar–plantar erythrodysesthesia for pegylated liposomal doxorubicin^[14] and sensory neuropathy and nausea for albumin-bound paclitaxel.^[7] Moreover, these agents are expensive, and the increase in overall survival is modest in many cases (Table 1). Therefore, a better understanding of the barriers that prevent efficacy and uniform delivery of nanoparticles into tumors is needed to develop strategies to improve treatment.

Transport of a therapeutic agent from the systemic circulation to cancer cells is a three-step process. First, nanoparticles flow to different regions of tumors via blood vessels. They must then cross the vessel wall, and finally, penetrate through the interstitial space to reach the target cells. Delivery of diagnostic and therapeutic agents differs dramatically between tumor and normal tissues because of differences in their structure. The abnormal organization and structure of the tumor vasculature leads to tortuous and leaky vessels and heterogeneous blood flow.^[15,16] In addition, the lack of functional lymphatic vessels and the vascular hyperpermeability inside tumors results in interstitial hypertension.^[17] This uniformly elevated interstitial fluid pressure (IFP) reduces convective transport, while the dense extracellular matrix hinders diffusion.^[18] In this Review, we discuss the barriers to nanomedicine delivery and present strategies to overcome them. Finally, we propose design considerations to optimize delivery of nanotherapeutics to solid tumors.

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Table 1. Nanoparticle formulations for the treatment of solid tumors*
Generic name	Trade name(s)	Indication	Benefit
Pegylated liposomal doxorubicin	Doxil® and Caelyx®	HIV-related Kaposi's sarcoma	No statistically significant change in overall survival (23 weeks) vs doxorubicin, bleomycin and vincristine treatment (22.3 weeks) for HIV-related Kaposi's sarcoma^[144]
		Metastatic ovarian cancer	Statistically significant overall survival improvement (108 weeks, P = 0.008) vs topotecan treatment (71.1 weeks) for platinum-sensitive patients with ovarian cancer^[14]
		Metastatic breast cancer	No statistically significant overall survival change (84 weeks) vs conventional doxorubicin (88 weeks) for breast cancer patients receiving first-line therapy¹⁴⁵
Liposomal daunorubicin	DaunoXome®	HIV-related Kaposi's sarcoma	No statistically significant overall survival change (52.7 weeks) vs doxorubicin, bleomycin and vincristine treatment (48.9 weeks)¹⁴⁶
Albumin-bound paclitaxel	Abraxane®	Metastatic breast cancer	Statistically significant overall survival change (56.4 weeks, P = 0.024) vs polyethylated castor oil-based paclitaxel treatment (46.7 weeks) for patients receiving second-line treatment⁷

*The polymeric platform methoxy-PEG-poly(D,L-lactide) taxol with the trade name Genexol-PM (Samyang Co., Seoul, Korea) has been approved in Korea for the treatment of metastatic breast cancer.^147,148

Box 1. Determinants of blood flow
Tumor blood flow, Q, is equal to the pressure difference between arterial and venous ends, ΔP, divided by the flow resistance (FR). This is defined in the following equation:²² FR = ηZ, where η is the apparent viscosity (viscous resistance), and Z is the geometrical resistance. Abnormalities in tumor vasculature increase both the geometric and viscous resistance to blood flow.^22,149–151 Geometric resistance is elevated because of the peculiar branching patterns of tumor vessels,^152–154 and their deformation due to compression by cancer cells.^28,30 viscous resistance is elevated because tumors lose 5–10% of plasma as the blood flows from the arterial to venous side. This results in the increase of red blood cell concentration (hemoconcentration) that in turn increases the apparent viscosity.^151,154,155

Box 2. Determinants of transvascular transport
Extravasation of materials from the blood vessels can occur by diffusion and convection and is described by the following equation:²⁴ J is the flux (mass per unit volume) of materials crossing the vessel wall, P is the vascular permeability, S is the vessels' surface area, C _p–C _i is the concentration difference of the material between the plasma and the interstitial space, L _p is the hydraulic conductivity of the vessel wall, p _v–p _i is the difference between microvascular and interstitial fluid pressure, σ is the osmotic reflection coefficient, and π_v–π_i is the osmotic pressure difference across the wall. The vascular permeability depends on the properties of the particle (size, charge and configuration) and the vessel wall (pore size, charge and arrangement). it decreases as the particle size increases and becomes zero when the particle size is larger than the pore cutoff size. The hydraulic conductivity is a property of the morphology of the wall and depends on the fraction of the wall surface occupied by pores. More comprehensive models for transvascular models exist but they are beyond the scope of this Review.

Box 3. Determinants of interstitial transport
Transport of nanoparticles through the interstitial matrix is governed by diffusion and convection:¹⁸ C _i is the nanoparticle concentration, v the interstitial fluid velocity, D the diffusion coefficient of the nanoparticles and R a term that accounts for binding or degradation of the nanoparticles. The fluid velocity depends on changes in the interstitial fluid pressure and because the latter is uniform in the center of the tumor, it is negligible except at the tumor margin. The diffusion coefficient depends on the properties of the nanoparticles (size, charge and configuration) and the structure of the interstitial matrix.

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Delivering Nanomedicine to Solid Tumors

Abstract and Introduction

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