OPTICAL BIOPSY STAIN PANELS AND METHODS OF USE

Abstract

Optical biopsy staining panels for in vivo or in situ fluorescent staining of optical tissue (or other appropriate tissue), e.g., for the purpose of a direct biopsy such as an optical biopsy. The stain panels may feature a combination of a nuclear stain and a cytoplasmic stain, as a means of functioning as an invivo or in situ hematoxylin and eosin (H&E) stain. Examples of said stains may include anthracyclines such as Daunomcibin, acriflavines like Proflavine, anthracenediones such as Mitoxantrone, phenothiazines like Methylene Blue, and tri- and tetra-heterocyclic dyes like Fluorescein, Phloxine B, Phenol Red, Rose Bengal, Congo Red, and Indigo Carmine.

Description

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to dyes and stains, more particularly to dyes and stains that can be used in vivo or in situ, such as for optical biopsies.

Background Art

A biopsy is where tissue is examined under a microscope in order to obtain a cellular- and molecular-level diagnosis. Traditional biopsies (e.g., a physical biopsy) feature obtaining a piece of a patient's tissue, processing the tissue, and subsequently examining the tissue under the microscope. Unlike traditional biopsies, an optical biopsy involves taking the microscope directly into the patient's tissue. The benefits of a direct optical biopsy may include helping to decrease the rate of false-negative or inconclusive physical biopsy results, obviate the need for a physical biopsy, and provide for faster diagnoses.

The traditional biopsy process requires the tissue to be stained with various dyes to enable visualization of the microscopic architecture or cell type. The most commonly used stain is a hematoxylin and eosin (H&E) stain. Other stains that are commonly used include Gram stain, Cresyl violet, silver nitrate, Gomori Trichrome, Wright's blood, Feulgen reaction, Masson's Trichrome, Toluidine blue, Giemsa, Prussian Blue, etc. However, such dyes are not FDA approved for in vivo use. Optical biopsies are currently limited to what can be seen with visible or near visible wavelengths, limiting its usefulness since hemoglobin dominates the visual spectrum and naturally-fluorescing molecules do not provide sensitive or specific information.

A spectrum of drugs individually is currently FDA-approved for optical/fluorescence imaging, such as indocyanine green, fluorescein, oftasceine, trypan blue, etc. However, no combination of FDA-approved drugs has been developed to provide an adequate optical biopsy stain, such as an H&E equivalent.

BRIEF SUMMARY OF THE INVENTION

One of the unique and inventive technical features of the present invention is the combination of certain drugs or dyes at particular optimal concentrations to create a fluorescent optical biopsy stain panel, such as an H&E equivalent. For example, certain combinations of drugs or dyes allow for emission of two (or more) different wavelengths (colors) upon excitation with one wavelength. Thus, the stain panels of the present invention may allow for multiplexing. None of the presently known prior references or work has the unique inventive technical feature of the present invention.

Furthermore, the prior references teach away from the present invention. For example, it is counterintuitive to use multiple dyes in an optical biopsy stain panel because there is often an overlap of the fluorescent emission signals of the different dyes. However, it was discovered that certain combinations of dyes at specific ratios of concentrations are distinct enough to be used in an optical biopsy stain panel. For example, FIGS. 8-15 show the emission spectra of different combinations of dyes at different concentrations. In the cases where there is a mixture of the dyes, there are distinct emission peaks for each dye.

In some aspects, the present invention features optical biopsy stain panels. In certain embodiments, the stain panels comprise two or more agents, wherein either (or all) of the agents fluorescently stains: nucleic acids; cytoplasm; cell or subcellular membranes; subcellular organelles; extracellular matrix components; or microbes.

In certain embodiments, one or more of the agents are clinical drugs. In certain embodiments, one or more of the agents are therapeutic drugs. In certain embodiments, one or more of the agents are supplements or food additives generally recognized as safe.

In certain embodiments, the agents are existing clinically-used agents. In some embodiments, the agents can be fluorescent nucleic acid stains selected from a group of nucleic acid-binding agents, such as, for example, aminoacridines, anthracyclines, anthracenediones, or phenothiazines. In certain embodiments, the aminoacridines are 9-aminmoacridine or proflavine, or others. In certain embodiments, the anthracyclines are Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Nogalamycin, or Valrubicin, or others. In certain embodiments, the anthracenediones are mitoxantrone or pixantrone, or others. In certain embodiments, the phenothiazine is methylene blue, or others.

In some other embodiments, the agents can be fluorescent cytoplasmic stains selected from a group of protein binding agents, such as heterotetracyclic and heteropentacyclic compounds, xanthylium dyes, azo dyes, indoles, or phthalein dyes. In certain embodiments, the heterotetracyclic and heteropentacyclic compounds are fluorescein or Rose Bengal, or others. In certain embodiments, the xanthylium dye is phloxine B, or others. In certain embodiments, the azo dye is Congo Red, or others. In certain embodiments, the indole is Indigo Carmine, or others. In certain embodiments, the phthalein dye is phenol red, or others.

In certain embodiments, the stains are existing clinically-used agents and fluorescent cell or subcellular membrane staining components, including drugs from Table 3 below. In certain embodiments, the stains are existing clinically-used agents and fluorescent organelle staining components, including drugs from Tables 4 and 5 below. In certain embodiments, the stains are existing clinically-used agents that stain extracellular matrix components. In certain embodiments, the stains are existing clinically-used agents that stain microbes.

In certain embodiments, the fluorescent nucleic acid stain is Daunorucibin and the fluorescent cytoplasmic stain is Fluorescein. In certain embodiments, the fluorescent nucleic acid stain is Methylene Blue and the fluorescent cytoplasmic stain is Fluorescein. In certain embodiments, the fluorescent nucleic acid stain is Methylene Blue and the fluorescent cytoplasmic stain is Phenol Red. In certain embodiments, the fluorescent nucleic acid stain is Methylene Blue and the fluorescent cytoplasmic stain is Phloxine B. In certain embodiments, the fluorescent nucleic acid stain is Methylene Blue and the fluorescent cytoplasmic stain is Rose Bengal. In certain embodiments, the fluorescent nucleic acid stain is Mitoxantrone and the fluorescent cytoplasmic stain is Fluorescein. In certain embodiments, the fluorescent nucleic acid stain is Mitoxantrone and the fluorescent cytoplasmic stain is Phenol Red. In certain embodiments, the fluorescent nucleic acid stain is Mitoxantrone and the fluorescent cytoplasmic stain is Phloxine B. In certain embodiments, the fluorescent nucleic acid stain is Mitoxantrone and the fluorescent cytoplasmic stain is Rose Bengal. In certain embodiments, the fluorescent nucleic acid stain is Proflavine and the fluorescent cytoplasmic stain is Rose Bengal.

In some embodiments, the present invention also features an apparatus where the illumination of an optical biopsy stain panel according to the present invention is about a single wavelength. In certain embodiments, the observation occurs through color filtering means or amplification or conversion of the resultant fluorescence into observable color range.

In other embodiments, the present invention features methods where fluorescence from an optical biopsy stain according to the present invention is observed even indirectly with the human eye.

In some embodiments, the present invention also features optical biopsy stain panels, where the panels comprise two or more agents. In one embodiment of the optical biopsy stain panels, one of the agents is a fluorescent nuclear stain. In another embodiment of the optical biopsy stain panels, one of the agents is a fluorescent cytoplasmic stain. In yet another embodiment of the optical biopsy stain panels, one agent is a fluorescent nuclear stain and another agent is a fluorescent cytoplasmic stain.

Note that while endoscopy, colonoscopy, bronchoscopy, arthroscopy, and other similar procedures may feature applying a microscope directly to tissue, the anatomy can be seen without the aid of fluorescence stains. For example, the procedures may rely on autofluorescence of tissue, or in some cases, the procedures utilize visual dyes for viewing in white lights. Without wishing to limit the present invention to any theory or mechanism, optical biopsies cannot rely on low-sensitivity autofluorescence of tissue, and the visual spectrum is often dominated by hemoglobin, limiting white light or non-fluorescence usefulness.

Any feature or combination of features described herein are included within the scope of the present invention provided that the features included in any such combination are not mutually inconsistent as will be apparent from the context, this specification, and the knowledge of one of ordinary skill in the art. Additional advantages and aspects of the present invention are apparent in the following detailed description and claims.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S)

The features and advantages of the present invention will become apparent from a consideration of the following detailed description presented in connection with the accompanying drawings in which:

FIG. 1 shows proflavine, a topical antiseptic and wound irrigant, after being topically applied to a tissue sample (50 μl at 20 μM concentration) and imaged. Image field is 635.5 μm tall×wide. Inset is the structure of Proflavine.

FIG. 2A shows bovine lung tissue stained with Fluorescein (500 nM) and imaged using confocal microscopy excited with 488 nm wavelengths at various gains. Image field is 635.5 μm tall×wide.

FIG. 2B shows bovine lung tissue stained with Phenol Red (100 μM) and imaged using confocal microscopy excited with 488 nm wavelengths at various gains. Image field is 635.5 μm tall×wide.

FIG. 2C shows bovine lung tissue stained with Phloxine B (10 μM) and imaged using confocal microscopy excited with 488 nm wavelengths at various gains. Image field is 635.5 μm tall×wide.

FIG. 2D shows bovine lung tissue stained with Rose Bengal (100 μM) and imaged using confocal microscopy excited with 488 nm wavelengths at various gains. Image field is 635.5 μm tall×wide.

FIG. 2E shows the inset from FIG. 2A, which shows the fluorescence signal from fibers and variable cellular uptake.

FIG. 2F shows the inset from FIG. 2B, which shows the fluorescence signal from fibers and variable cellular uptake.

FIG. 2G shows the inset from FIG. 2C, which shows the fluorescence signal from fibers and variable cellular uptake.

FIG. 2H shows the inset from FIG. 2D, which shows the fluorescence signal from fibers and variable cellular uptake.

FIG. 2I shows an optimized autofluorescence signal, demonstrating prominent fibers but relative lack of cellular signal. Image field is 635.5 μm tall×wide.

FIG. 3 shows Daunorubicin and Fluorescein as DNA and protein/cytoplasm dyes, respectively. The combination of 25 μM Daunorubicin and 250 nM Fluorescein was added to bovine lung tissue samples and imaged using confocal microscopy with 488 nm excitation and 10 μm thick optical focal plane, with imaged fields being 635.5 μm². Inset shows emission spectra of the combination at 488 nm excitation with the microscope channels indicated along the abscissa.

FIG. 4A shows Methylene Blue as a DNA dye combined with an off-label protein/cytoplasm dye (50 μM Methylene Blue with 250 nM Fluorescein). Imaging was with confocal microscopy, with a bovine lung sample thickness of 10 μm, and an image field of 635.5 μm². Inset shows fluorescence emission spectra of the combination in similar concentration ratios also at 488 nm excitation, with the microscope detector channels along the abscissa.

FIG. 4B shows Methylene Blue as a DNA dye combined with an off-label protein/cytoplasm dye (100 μM Methylene Blue with 100 μM Phenol Red). Imaging was with confocal microscopy, with a bovine lung sample thickness of 10 μm, and an image field of 635.5 μm². Inset shows fluorescence emission spectra of the combination in similar concentration ratios also at 488 nm excitation, with the microscope detector channels along the abscissa.

FIG. 4C shows Methylene Blue as a DNA dye combined with an off-label protein/cytoplasm dye (100 μM Methylene Blue with 10 μM Phloxine B). Imaging was with confocal microscopy, with a bovine lung sample thickness of 10 μm, and an image field of 635.5 μm². Inset shows fluorescence emission spectra of the combination in similar concentration ratios also at 488 nm excitation, with the microscope detector channels along the abscissa.

FIG. 4D shows Methylene Blue as a DNA dye combined with an off-label protein/cytoplasm dye (100 μM Methylene Blue with 100 μM Rose Bengal). Imaging was with confocal microscopy, with a bovine lung sample thickness of 10 μm, and an image field of 635.5 μm². Inset shows fluorescence emission spectra of the combination in similar concentration ratios also at 488 nm excitation, with the microscope detector channels along the abscissa.

FIG. 5A shows Mitoxantrone as a DNA dye combined with a protein/cytoplasm dye (Mitoxantrone 50 μM and Fluorescein 250 nM). Imaging was with confocal microscopy settings at 488 nm excitation after topical application to the bovine lung specimen. Image field is 635.5 μm² at 10 μm thickness. Inset shows fluorescence emission spectra of the combination in similar ratios also at 488 nm excitation.

FIG. 5B shows Mitoxantrone as a DNA dye combined with a protein/cytoplasm dye (Mitoxantrone at 100 μM and Phenol Red 100 μM). Imaging was with confocal microscopy settings at 488 nm excitation after topical application to the bovine lung specimen. Image field is 635.5 μm² at 10 μm thickness. Inset shows fluorescence emission spectra of the combination in similar ratios also at 488 nm excitation.

FIG. 5C shows Mitoxantrone as a DNA dye combined with a protein/cytoplasm dye (Mitoxantrone 50 μM and Phloxine B 50 μM). Imaging was with confocal microscopy settings at 488 nm excitation after topical application to the bovine lung specimen. Image field is 635.5 μm² at 10 μm thickness. Inset shows fluorescence emission spectra of the combination in similar ratios also at 488 nm excitation.

FIG. 5D shows Mitoxantrone as a DNA dye combined with a protein/cytoplasm dye (Mitoxantrone 100 μM and Rose Bengal 100 μM). Imaging was with confocal microscopy settings at 488 nm excitation after topical application to the bovine lung specimen. Image field is 635.5 μm² at 10 μm thickness. Inset shows fluorescence emission spectra of the combination in similar ratios also at 488 nm excitation.

FIG. 6A shows Proflavine as a DNA drug-dye with Rose Bengal as a protein/cytoplasm drug-dye (50 μl of 100 μM Proflavine and 100 μM Rose Bengal). The dyes were pipetted in situ upon bovine tissue ex vivo and examined under confocal microscopy with a 488 nm laser with 10 μm optical thickness and imaged fields being 635.5 μm². Inset shows the fluorescence emission spectrum of the combination at 488 nm excitation.

FIG. 6B shows bovine lung tissue fixed in 10% formalin, paraffin embedded, cut to 5 μm sections and stained with Hematoxylin and Eosin per routine protocol, then imaged at 20×.

FIG. 6C shows an inversion of the colors of FIG. 6B, providing a black background. Image field is 1400×1052 μm.

FIG. 7 shows human breast cancer metastasized to the lung and stained with Rose Bengal and Proflavine to outline the proteins and nucleus, respectively, at concentrations similar to that in FIG. 6A. Image field is 625 μm².

FIG. 8A shows emission spectra of Mitoxantrone as a Hematoxylin-alternative candidate at 10 μM, with Phloxine B at 0.1 μM as an Eosin-alternative candidate drug-dye, excited at 375 nm.

FIG. 8B shows emission spectra of Mitoxantrone as a Hematoxylin-alternative candidate at 10 μM, with Phloxine B at 0.1 μM as an Eosin-alternative candidate drug-dye, excited at 405 nm.

FIG. 8C shows emission spectra of Mitoxantrone as a Hematoxylin-alternative candidate at 10 μM, with Phloxine B at 0.1 μM as an Eosin-alternative candidate drug-dye, excited at 455 nm.

FIG. 8D shows emission spectra of Mitoxantrone as a Hematoxylin-alternative candidate at 10 μM, with Phloxine B at 0.1 μM as an Eosin-alternative candidate drug-dye, excited at 488 nm.

FIG. 8E and FIG. 8F show concentration-dependent fluorescence of Mitoxantrone but not Phloxine B results in various concentration ratios of the two resulting in similar fluorescence intensity peaks, all excited at 455 nm. (Of note, smoothing after normalizing to peak intensity resulted in peaks not reaching exactly 1.0).

FIG. 9 shows an example of fluorescence incompatibility. At 488 nm excitation, increasing concentrations of Phloxine B (a proposed Eosin-like dye) resulted in progressive decrease of fluorescence emission from the Daunorubicin (a proposed Hematoxylin-like dye) fluorescence peak around 590 nm. Additional incompatibility results from overlapping of the component peak emissions.

FIG. 10 shows borderline compatibility of nucleic acid and cytoplasmic dyes. Actual (not normalized) fluorescence intensity of 10 μM Pyrvinium Pamoate decreased in the presence of 1 μM Rose Bengal, but not enough to obscure the Pyrvinium Pamoate component of the combined spectrum at 488 nm excitation.

FIG. 11 shows fluorescence emission spectra compatibility in vitro of the possible protein drug-dye Fluorescein with nucleic acid drug-dye Daunorubicin. Daunorubicin (1 μM), Fluorescein (1 nM) and the combination of the two were excited at 375 nm, with resultant fluorescence emission.

FIG. 12A shows fluorescence emission spectra compatibility in vitro of Methylene Blue as a DNA drug-dye with Fluorescein as a protein/cytoplasmic dye at 455 nm excitation.

FIG. 12B shows fluorescence emission spectra compatibility in vitro of Methylene Blue as a DNA drug-dye with 300 μM Phenol Red at pH 5 and 488 nm excitation.

FIG. 12C shows fluorescence emission spectra compatibility in vitro of Methylene Blue as a DNA drug-dye with Phloxine B at 2 μM at 520 nm excitation.

FIG. 12D shows fluorescence emission spectra compatibility in vitro of Methylene Blue as a DNA drug-dye with 1 μM Rose Bengal at 488 nm excitation.

FIG. 13A shows fluorescence emission spectra compatibility in vitro of the cytoplasmic drug-dye Fluorescein at 0.5 nM with nucleic acid drug-dye Mitoxantrone at 10 μM. The combination was excited at 375 nm, with the resultant emission spectrum shown.

FIG. 13B shows fluorescence emission spectra compatibility in vitro of the cytoplasmic drug-dye Phloxine B at 10 μM with nucleic acid drug-dye Mitoxantrone at 10 μM. The combination was excited at 405 nm, and the resultant spectrum displayed.

FIG. 13C shows fluorescence emission spectra compatibility in vitro of the cytoplasmic drug-dye Phenol Red at 100 μM with nucleic acid drug-dye Mitoxantrone at 10 μM. The combination of 10 μM Mitoxantrone and 10 μM Phenol Red at pH 5 was excited at 455 nm; the resultant spectrum is shown.

FIG. 13D shows fluorescence emission spectra compatibility in vitro of the cytoplasmic drug-dye Rose Bengal at 1 μM with nucleic acid drug-dye Mitoxantrone at 10 μM. The combination was excited at 455 nm and the resultant spectrum displayed.

FIG. 14 shows fluorescence emission spectra compatibility in vitro of Rose Bengal as a cytoplasmic drug-dye candidate with the nucleic acid drug-dye Proflavine. With 405 nm excitation, Proflavine at 0.25 μM, Rose Bengal at 10 μM, and the combination result in roughly the same order of magnitude peaks resulting from their respective fluorescence.

FIG. 15A shows fluorescence emission spectra compatibility in vitro of the cytoplasm-dye Fluorescein at 5 nM with nucleic acid drug-dye Pyrvinium Pamoate at 10 μM. The combination emission spectrum is shown with 455 nm excitation.

FIG. 15B shows fluorescence emission spectra compatibility in vitro of the cytoplasm-dye Phloxine B at 100 nM with nucleic acid drug-dye Pyrvinium Pamoate at 10 μM. The combination emission spectrum is shown with 455 nm excitation.

FIG. 15C shows fluorescence emission spectra compatibility in vitro of the cytoplasm-dye Phenol Red at 100 μM with nucleic acid drug-dye Pyrvinium Pamoate at 10 μM. The combination emission spectrum is shown with 488 nm excitation at approximately pH 5.

FIG. 15D shows fluorescence emission spectra compatibility in vitro of the cytoplasm-dye Rose Bengal at 1 μM with nucleic acid drug-dye Pyrvinium Pamoate at 10 μM. The combination emission spectrum is shown with 488 nm excitation.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which a disclosed invention belongs. The singular terms “a,” “an,” and “the” include plural referents unless context clearly indicates otherwise. Similarly, the word “or” is intended to include “and” unless the context clearly indicates otherwise. The term “comprising” means that other elements can also be present in addition to the defined elements presented. The use of “comprising” indicates inclusion rather than limitation. Stated another way, the term “comprising” means “including principally, but not necessary solely”. Furthermore, variation of the word “comprising”, such as “comprise” and “comprises”, have correspondingly the same meanings. In one respect, the technology described herein related to the herein described compositions, methods, and respective component(s) thereof, as essential to the invention, yet open to the inclusion of unspecified elements, essential or not (“comprising”).

All embodiments disclosed herein can be combined with other embodiments unless the context clearly dictates otherwise.

Suitable methods and materials for the practice and/or testing of embodiments of the disclosure are described below. Such methods and materials are illustrative only and are not intended to be limiting. Other methods and materials similar or equivalent to those described herein can be used. For example, conventional methods well known in the art to which the disclosure pertains are described in various general and more specific references.

All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety for all purposes. In case of conflict, the present specification, including explanations of terms, will control.

The present invention features optical biopsy staining panels for in vivo or in situ staining of tissue, e.g., for the purpose of a direct biopsy such as an optical biopsy, or in conjunction with a physical biopsy followed by optical biopsy of the harvested tissue. While the compounds used in the optical biopsy staining panels may be FDA-approved chromogenic or fluorescent drugs, none have been used for fluorescent optical staining. Further, it was surprisingly discovered that combinations of said drugs at specific concentrations could be used as fluorescent stain panels.

Table 1 below shows examples of FDA-approved chromogenic/fluorescent drugs and their current uses

Chromogenic/fluorescent drug     General in vivo Use/Treatment
Brilliant Blue G (Acid Blue, Coomassie Ophthalmic contrast
Brilliant Blue)
Brilliant Green                  Topical antiseptic additive
Congo Red                        Chromoendoscopy contrast agent
Crystal/Gentian Violet           Topical antiseptic additive, ophthalmic contrast
Fluorescein                      Ophthalmic contrast, fluorescence angiography
Indigo Carmine                   Neurosurgical, Gastrointestinal and Urological contrast
Indocyanine Green                Fluorescence angiography, lymphangiography
Isosulfan Blue                   Lymphangiography
Lugol's Iodine Solution          Topical antiseptic, Stain for Schiller's Test
Methylene Blue                   Antidote for methemoglobinemia, ophthalmic contrast
Oftasceine                       Ophthalmic contrast
Patent Blue (Sulfan Blue)        Lymphangiography
Phenol Red                       Chromoendoscopy
Phloxine B                       Dental disclosing agent
Porphyrinoids/Porphyrin precursors Neurosurgical and Urological surgery contrast
(Hexview/Cysview, 5-ALA)
Prussian Blue                    Antidote for cesium and thallium poisoning
Rose Bengal Free Acid            Ophthalmic contrast
Toluidine Blue                   Visual diagnostic aid on mucosal lesions
Trypan Blue                      Ophthalmic contrast

Table 2 below shows non-limiting examples of optical biopsy stain panels according to the present invention. The biopsy stain panels may, for example, be equivalent to a traditional H&E stain. For example, in certain embodiments, the compound in the “Dye 1” category represents a nuclear/DNA stain and the compounds in the “Dye 2” category represent a protein/cytoplasm stain.

Example	Dye 1	Dye 2
1	Daunorucibin	Fluorescein
2	Methylene Blue	Fluorescein
3	Proflavine	Fluorescein
4	Acridine Orange	Fluorescein
5	Mitoxantrone	Fluorescein
6	Pyrvinium Pamoate	Fluorescein
7	Daunorucibin	Phloxine B
8	Methylene Blue	Phloxine B
9	Proflavine	Phloxine B
10	Acridine Orange	Phloxine B
11	Mitoxantrone	Phloxine B
12	Pyrvinium Pamoate	Phloxine B
13	Daunorucibin	Phenol Red
14	Methylene Blue	Phenol Red
15	Proflavine	Phenol Red
16	Acridine Orange	Phenol Red
17	Mitoxantrone	Phenol Red
18	Pyrvinium Pamoate	Phenol Red
19	Daunorucibin	Rose Bengal
20	Methylene Blue	Rose Bengal
21	Proflavine	Rose Bengal
22	Acridine Orange	Rose Bengal
23	Mitoxantrone	Rose Bengal
24	Pyrvinium Pamoate	Rose Bengal
25	Daunorucibin	Congo Red
26	Methylene Blue	Congo Red
27	Proflavine	Congo Red
28	Acridine Orange	Congo Red
29	Mitoxantrone	Congo Red
30	Pyrvinium Pamoate	Congo Red
31	Daunorucibin	Indigo Carmine
32	Methylene Blue	Indigo Carmine
33	Proflavine	Indigo Carmine
34	Acridine Orange	Indigo Carmine
35	Mitoxantrone	Indigo Carmine
36	Pyrvinium Pamoate	Indigo Carmine

Table 3 below shows non-limiting examples of clinically-used agents also working as lipid membrane stains based on similarity to membrane bilayer research dyes.

	Research membrane dyes	Specific Drugs with similarity to
				Heptamethine	research dyes (>0.45
Drug Class	Cy5	CY7	DiO/I	cyanine dye-1	DrugBank.ca similarity score)
(Proto)Porphyrins	X	X	X	X	Hydroxocobalamin,
					Cyanocobalamin, Verteporfin
Ace inhibitor	X				Benazepril
Adrenergics/	X		X	X	Ergotamine, Silodosin, Yohimbine
dopaminergics
Antihyperglycemic	X				Repaglinide
Antineoplastic	X	X	X	X	Vindesine, Bleomycin, Vinblastine
Bacitracin		X			Bacitracin A
Carbapenems	X	X	X	X	Ertapenem
Cefalosporins			X	X	Cefpirome, Cefpiramide
Cyclooxygenase		X			Meloxicam, Piroxicam
inhibitor
Indigotindisulfonic			X		Indigotindisulonic Acid
acid
Kinase inhibitors	X	X	X		Nintedanib
Na+ channel blockers		X	X		Ajmaline
Non-dihydropyridine		X			Diltiazem
calcium channel
blockers
Opioids		X			Codeine, Morphine
Phosphodiesterase		X			Vardenafil, Sildenafil
inhibitor
Rifamycins	X	X	X	X	Rifabutin, Rifapentine, Rifaximin
Ristocetins		X	X		Vancomycin, Oritovancin
Tetracyclines	X	X	X	X	Tigecycline

Table 4 below shows non-limiting examples of clinically-used agents with localization to mitochondria as the prototypical subcellular organelle.

	Mitochondrial Dyes
	Mitotracker	Mitotracker	Mitotracker	Mitotracker
Drugs with similarity score >0.45	Orange	Deep Red	Red	Green
Antimitotic: Vinorelbine, Vinblasine,	X	X
Vincristine, Vinflunine, Bleomycin
Opioids: Pholcodine,	X
Benzhydrocodone, Oxycodone,
Morphine, Codeine, Hydrocodone,
Naltrexone, Methylnaltrexone,
Naloxone, Oxymorphone
Restocins: Vancomycin, Telavancin	X
Rifamycins: Rifaximin, Rifapentine	X
Porphyrins: Cyanocobalamin,	X	X
Cobamamide
Atypical Antihistamine: Tritoqualine	X
Cephalosporins: Ceftolozane,		X
Ceftaroline Fosamil, Ceftriaxone,
Cefpirome
Anti-Insomnia: Suvorexant		X
Anti-inflammatory: Benoxaprofen		X
Antineoplastic: Trabectedin		X

Table 5 below shows non-limiting examples of clinically-used agents with localization to lysosomes and related organelles similar to research dyes.

	Lysosome Dyes
	Lysotracker	Lysotracker	Lysotracker	Lysotracker	Lysosensor	Lysosensor	Lysosensor
Drugs with similarity score >0.5	Red	Yellow	Green	Blue	Blue	Yellow	Green
Antifungal: Butenafine, Naftifine,				X	X
Terbinafine
Hematopoietic Stem Cell Mobilizer:				X	X
Plerixafor
H1 Antagonist: Cyclizine, Hydroxyzine				X	X
Maoi: Pargyline				X
Class 1 Antiarrythmics: Procainamide				X
Porphyrins: Cobamamide,	X
Methylcobalamin, Hydroxocobalamin,
Cyanocobalamin
Antimitotics: Vinorelbine, Vinflunine,	X
Vindesine, Vinblastine, Bleomycin
Antiviral: Voxilaprevir, Grazoprevir,	X
Glecaprevir, Elbasvir, Simeprevir
Topoisomerase Inhibitor: Irinotecan	X
Cephalosporins: Cefpirome, Cefpiramide,	X
Ceftriaxone, Ceftazidime, Cefixime,
Cefotaxime, Cefmenoxime
Dopaminergic/Adrenergic: Bromocriptine,	X
Ergotamine, Dihydroergotamine,
Reserpine, Deserpine
Rifamycins: Rifapentine,	X
Rifabutin, Rifampicin
Opioid: Naldemedine	X
Non-Steroidal Antiinflammatory:						X
Oxaprozin
Broad-Spectrum Antimicrobial:					X
Benzethonium

The present invention is not limited to the aforementioned examples of optical biopsy stain panels.

Referring to FIG. 1, 50 μl at 20 μM of Proflavine was topically applied directly to ex vivo bovine lung tissue in situ and imaged immediately with confocal microscopy. The drug-dye Proflavin showed staining like those typical of a fluorescent DNA dye. Likewise, Fluorescein, Phenol Red, Phloxine B, and Rose Bengal were each added to ex vivo bovine lung tissue and imaged under confocal microscopy (see FIGS. 2A-2I). Each drug-dye resulted in variable staining of the proteinaceous connective tissue and cellular cytoplasm, granules or vesicles. Qualitatively at these concentrations, Fluorescein, Phloxine B and Rose Bengal drug-dyes appeared to localize to cell cytoplasm in addition to the connective tissue fibers, which fibers also demonstrated autofluorescence. Fluorescein was the only protein/cytoplasm dye without excessive overlap with the resultant fluorescence signal from Daunorubicin as a DNA-dye. This combination was then added topically to bovine lung tissue and imaged using confocal microscopy (FIG. 3).

Methylene Blue was tested as a fluorescent DNA drug-dye in combination with several protein/cytoplasm dyes. These combinations were applied topically to bovine lung samples and imaged using confocal microscopy at 488nm excitation (see FIGS. 4A-4D). Also, mitoxantrone was tested as a DNA dye in combination with several protein/cytoplasm drug-dyes. Again, the combinations were topically applied to bovine lung and examined with confocal microscopy at 488 nm excitation (see FIGS. 5A-5D).

Lastly, a combination of Proflavine and Rose Bengal was tested on bovine lung samples and evaluated with confocal microscopy (see FIG. 6A). Since H&E is the gold-standard to which these new optical stain panels are compared, bovine lung tissue was fixed in formalin, embedded in paraffin and sectioned at 5 μm thickness and finally stained with Hematoxylin and Eosin per routine protocol (see FIG. 6B). To provide a more intuitive comparison in making the background black, the color was inverted (see FIG. 6C).

FIGS. 8A-8F show emission spectra of various drug dye candidates. FIGS. 8A-8D show Mitoxantrone as a Hematoxylin-alternative candidate at 10 μM, with Phloxine B at 0.1 μM as an Eosin-alternative candidate drug-dye, and a combination of the two excited at different wavelengths: (FIG. 8A) 375 nm, (FIG. 8B) 405 nm, (FIG. 80) 455 nm, and (FIG. 8D) 488 nm. FIGS. 8E-8F show concentration-dependent fluorescence of Mitoxantrone but not Phloxine B results in various concentration ratios of the two resulting in similar fluorescence intensity peaks, all excited at 455 nm. The molar ratios varied primarily based on excitation wavelength, although some dyes demonstrated concentration-dependent change in fluorescence which resulted in unexpected changes in the molar ratio required for similar peak emission intensity. Specifically, Mitoxantrone as a DNA dye mixed with Phloxine B as a non-specific protein dye at 100:1 molar ratio resulted in primarily Mitoxantrone from the resultant fluorescence emission signal at 375 nm excitation (FIG. 8A), but nearly all the fluorescence emission signal from Phloxine B at 488 nm excitation (FIG. 8D). Additionally, there was overlap of emission spectra (FIG. 9) and the combination of certain DNA and protein dyes decreased the emission intensity relative to the same concentration of the component dye alone (FIG. 9 and FIG. 10).

FIGS. 11-15 demonstrate individual and combined fluorescence emission spectra of particular DNA dyes and protein/cytoplasm dyes. Of note, Pyrvinium Pamoate was not further evaluated based on substantial overlap of the emission spectra of all the protein/cytoplasm dyes.

The present invention also features methods of use of the optical biopsy stain panels of the present invention. In certain embodiments, the methods feature injecting one or a combination of stains (e.g., in series, at the same time) into the target tissue, introducing the microscope (e.g., microendocsope) to the tissue, and viewing the stain. In certain embodiments, the methods herein provide for a provisional diagnosis and allow for determining whether or not to proceed with a physical biopsy.

The present invention also features kits comprising one or a combination of dyes disclosed herein, e.g., the combinations disclosed in Table 2. For example, in certain embodiments, the kit comprises Daunorucibin and Fluorescein; in certain embodiments, the kit comprises Proflavine and Rose Bengal; etc.

Table 6 below shows non-limiting examples of optical biopsy stain panels and the parts of the cell that are fluorescently labeled.

	9-	Profla-	Dauno-	Doxo-
	aminoacridine	vine	rubicin	rubicin	Epirubicin	Idarubicin
Fluorecein	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	cytoplasm	cytoplasm	cytoplasm	cytoplasm	cytoplasm	cytoplasm
Rose	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
Bengal	acids +	acids +	acids +	acids +	acids +	acids +
	cytoplasm	cytoplasm	cytoplasm	cytoplasm	cytoplasm	cytoplasm
Phloxine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
B	acids +	acids +	acids +	acids +	acids +	acids +
	cytoplasm	cytoplasm	cytoplasm	cytoplasm	cytoplasm	cytoplasm
Congo	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
Red	acids +	acids +	acids +	acids +	acids +	acids +
	cytoplasm	cytoplasm	cytoplasm	cytoplasm	cytoplasm	cytoplasm
Indigo	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
Carmine	acids +	acids +	acids +	acids +	acids +	acids +
	cytoplasm	cytoplasm	cytoplasm	cytoplasm	cytoplasm	cytoplasm
Phenol	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
Red	acids +	acids +	acids +	acids +	acids +	acids +
	cytoplasm	cytoplasm	cytoplasm	cytoplasm	cytoplasm	cytoplasm
Hydroxycobalamin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Cyanocobalamin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Verteporfin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Benazepril	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Ergotamine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Siiodosin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Yohimbine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Repaglinide	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Vindesine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Bleomycin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Vinblastine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Bacitracin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
A	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Ertapenem	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Cefpirome	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Cefpiramide	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Meloxicam	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Piroxicam	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Indigotindisulonic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
Acid	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Nintedanib	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Ajmaline	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Diltiazem	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Codeine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
	or	or	or	or	or	or
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
Morphine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
	or	or	or	or	or	or
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
Vardenafil	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Slidenafil	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Rifabutin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Rifapentine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
	or	or	or	or	or	or
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
Rifaximin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
	or	or	or	or	or	or
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
Vaneomycin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Oritovancin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Tigecycline	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lipid	lipid	lipid	lipid	lipid	lipid
	membranes	membranes	membranes	membranes	membranes	membranes
Vinorelbine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	or	or	or	or	or	or
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Vinblastine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	or	or	or	or	or	or
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Vincristine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	or	or	or	or	or	or
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Vinflunine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	or	or	or	or	or	or
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Bieomycin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	or	or	or	or	or	or
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Pholcodine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
Benzhydrocodone	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
Oxycodone	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
Hydrocodone	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
Naltrexone	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
Methylnaltrexone	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
Naloxone	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
Oxymorphone	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
Telavancin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
Cyanocobalamin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	or	or	or	or	or	or
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Cobamamide	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	or	or	or	or	or	or
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Tritoqualine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
Ceftoiozane	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	or	or	or	or	or	or
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Ceftaroline	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	or	or	or	or	or	or
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Fosamil	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
Ceftriaxone	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	or	or	or	or	or	or
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Cefpirome	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	or	or	or	or	or	or
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Suvorexant	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
Benoxaprofen	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
Trabectedin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
Butenafine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Naftifine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Terbinafine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Plerixafor	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Pargyline	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Procainamide	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Methylcobalamin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Hydroxo-	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
cobalamin	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Voxilaprevir	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Grazoprevir	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Glecaprevir	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Elbasvir	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Simeprevir	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Irinotecan	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Cefpiramide	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Ceftazidime	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Cefixime	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Cefotaxime	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Cefmenoxime	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Bromocriptine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Ergotamine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Dihydroer-	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
gotamine	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Reserpine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Deserpine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Rifabutin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Naldemedine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Oxaprozin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Benzethonium	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Rescinnamine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Lymecycline	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Moxifloxacin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Dactinomycin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
Ertapenem	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	acids +	acids +	acids +	acids +	acids +	acids +
	lysosome	lysosome	lysosome	lysosome	lysosome	lysosome
				Mitoxan-		Methylene
		Nogalamycin	Valrubicin	trone	Pixantrone	Blue
	Fluorecein	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		cytoplasm	cytoplasm	cytoplasm	cytoplasm	cytoplasm
	Rose	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	Bengal	acids +	acids +	acids +	acids +	acids +
		cytoplasm	cytoplasm	cytoplasm	cytoplasm	cytoplasm
	Phloxine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	B	acids +	acids +	acids +	acids +	acids +
		cytoplasm	cytoplasm	cytoplasm	cytoplasm	cytoplasm
	Congo	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	Red	acids +	acids +	acids +	acids +	acids +
		cytoplasm	cytoplasm	cytoplasm	cytoplasm	cytoplasm
	Indigo	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	Carmine	acids +	acids +	acids +	acids +	acids +
		cytoplasm	cytoplasm	cytoplasm	cytoplasm	cytoplasm
	Phenol	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	Red	acids +	acids +	acids +	acids +	acids +
		cytoplasm	cytoplasm	cytoplasm	cytoplasm	cytoplasm
	Hydroxycobalamin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Cyanocobalamin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Verteporfin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Benazepril	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Ergotamine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Siiodosin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Yohimbine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Repaglinide	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Vindesine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Bleomycin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Vinblastine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Bacitracin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	A	acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Ertapenem	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Cefpirome	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Cefpiramide	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Meloxicam	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Piroxicam	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Indigotindisulonic	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	Acid	acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Nintedanib	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Ajmaline	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Diltiazem	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Codeine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
		or	or	or	or	or
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	Morphine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
		or	or	or	or	or
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	Vardenafil	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Slidenafil	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Rifabutin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Rifapentine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
		or	or	or	or	or
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	Rifaximin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
		or	or	or	or	or
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	Vaneomycin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Oritovancin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Tigecycline	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lipid	lipid	lipid	lipid	lipid
		membranes	membranes	membranes	membranes	membranes
	Vinorelbine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
		or	or	or	or	or
		lysosome	lysosome	lysosome	lysosome	lysosome
	Vinblastine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
		or	or	or	or	or
		lysosome	lysosome	lysosome	lysosome	lysosome
	Vincristine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
		or	or	or	or	or
		lysosome	lysosome	lysosome	lysosome	lysosome
	Vinflunine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
		or	or	or	or	or
		lysosome	lysosome	lysosome	lysosome	lysosome
	Bieomycin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
		or	or	or	or	or
		lysosome	lysosome	lysosome	lysosome	lysosome
	Pholcodine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	Benzhydrocodone	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	Oxycodone	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	Hydrocodone	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	Naltrexone	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	Methylnaltrexone	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	Naloxone	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	Oxymorphone	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	Telavancin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	Cyanocobalamin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
		or	or	or	or	or
		lysosome	lysosome	lysosome	lysosome	lysosome
	Cobamamide	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
		or	or	or	or	or
		lysosome	lysosome	lysosome	lysosome	lysosome
	Tritoqualine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	Ceftoiozane	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
		or	or	or	or	or
		lysosome	lysosome	lysosome	lysosome	lysosome
	Ceftaroline	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
		or	or	or	or	or
		lysosome	lysosome	lysosome	lysosome	lysosome
	Fosamil	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	Ceftriaxone	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
		or	or	or	or	or
		lysosome	lysosome	lysosome	lysosome	lysosome
	Cefpirome	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
		or	or	or	or	or
		lysosome	lysosome	lysosome	lysosome	lysosome
	Suvorexant	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	Benoxaprofen	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	Trabectedin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		mitochondria	mitochondria	mitochondria	mitochondria	mitochondria
	Butenafine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Naftifine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Terbinafine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Plerixafor	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Pargyline	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Procainamide	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Methylcobalamin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Hydroxo-	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	cobalamin	acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Voxilaprevir	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Grazoprevir	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Glecaprevir	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Elbasvir	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Simeprevir	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Irinotecan	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Cefpiramide	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Ceftazidime	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Cefixime	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Cefotaxime	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Cefmenoxime	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Bromocriptine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Ergotamine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Dihydroer-	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
	gotamine	acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Reserpine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Deserpine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Rifabutin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Naldemedine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Oxaprozin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Benzethonium	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Rescinnamine	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Lymecycline	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Moxifloxacin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Dactinomycin	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome
	Ertapenem	Nucleic	Nucleic	Nucleic	Nucleic	Nucleic
		acids +	acids +	acids +	acids +	acids +
		lysosome	lysosome	lysosome	lysosome	lysosome

Table 7 below shows non-limiting examples of optical biopsy stain panels according to the present invention. The stain panels listed below use a combination of nucleus dyes and protein/cytoplasm dyes that have been optimized for their compatibility.

	Approximate	Nucleus dyes
	peak		Methylene			Pyrvinium
	fluorescence	Daunorubicin	Blue	Mitoxantrone	Proflavine	Pamoate
	(nm)	550, 590	695	685	508	700
Protein/	Fluorescein	505	X	X	X		X
cytoplasm	Indigo	400, 450	X	X	X	X	X
dyes	Carmine
	Phloxine B	550		X	X		X
	Phenol Red	535		X	X		X
	Rose Bengal	565		X	X	X	X
	Congo Red	425	X	X	X	X	X

Although there has been shown and described the preferred embodiment of the present invention, it will be readily apparent to those skilled in the art that modifications may be made thereto which do not exceed the scope of the appended claims. Therefore, the scope of the invention is only to be limited by the following claims. In some embodiments, the figures presented in this patent application are drawn to scale, including the angles, ratios of dimensions, etc. In some embodiments, the figures are representative only and the claims are not limited by the dimensions of the figures. In some embodiments, descriptions of the inventions described herein using the phrase “comprising” includes embodiments that could be described as “consisting essentially of” or “consisting of”, and as such the written description requirement for claiming one or more embodiments of the present invention using the phrase “consisting essentially of” or “consisting of” is met.

Claims

1. An optical biopsy stain panel comprising two or more agents, either of which fluorescently stains: a. nucleic acids;b. cytoplasm;c. cell or subcellular membranes;d. subcellular organelles;e. extracellular matrix components; orf. microbes.

2. The stain panel of claim 1, wherein one or more of the agents are clinical drugs or therapeutic drugs.

3.-4. (canceled)

5. The stain panel of claim 1, wherein the two or more agents are existing clinically-used agents, wherein at least one agent is a fluorescent nucleic acid stain selected from a group of nucleic acid-binding agents consisting of: aminoacridines, anthracyclines, anthracenediones, or phenothiazines.

6. The stain panel of claim 5, wherein the aminoacridines are 9-aminmoacridine or proflavine.

7. The stain panel of claim 5, wherein the anthracyclines are Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Nogalamycin, or Valrubicin.

8. The stain panel of claim 5, wherein the anthracenediones are Mitoxantrone or Pixantrone.

9. The stain panel of claim 5, wherein the phenothiazine is Methylene Blue.

10. The stain panel of claim 1, wherein the two or more agents are existing clinically-used agents, wherein at least one agent is a fluorescent cytoplasmic stain selected from a group of non-specific protein binding agents consisting of: heterotetracyclic and heteropentacyclic compounds; xanthylium dyes; azo dyes; indoles, or phthalein dyes.

11. The stain panel of claim 10, wherein the heterotetracyclic and heteropentacyclic compounds are fluorescein or Rose Bengal.

12. The stain panel of claim 10, wherein the xanthylium dye is phloxine B.

13. The stain panel of claim 10, wherein the azo dye is Congo Red.

14. The stain panel of claim 10, wherein the indole is Indigo Carmine.

15. The stain panel of claim 10, wherein the phthalein dye is phenol red.

16. The stain panel of claim 1, wherein the two or more agents are existing clinically-used agents, wherein at least one of the agents is a fluorescent cell stain or subcellular membrane stain selected from a group of lipid-binding agents consisting of (proto)porphyrins, ace inhibitors, adrenergics/dopaminergics, antihyperglycemics, antineoplastics, bacitracins, carbapenems, cefalosporins, cyclooxygenase inhibitors, indigotindisulfonic acid, kinase inhibitors, Na+ channel blockers, non-dihydropyridine calcium channel blockers, opioids, phosphodiesterase inhibitors, rifamycins, ristocetins, and tetracyclines.

17. The stain panel of claim 1, wherein the two or more agents are existing clinically-used agents, wherein at least one of the agents is a fluorescent organelle stain selected from a group of organelle binding agents consisting of antimitotics, opioids, restocins, rifamycins, porphyrins, atypical antihistamines, cephalosporins, anti-insomnia agents, anti-inflammatory agents, antineoplastics, antifungal agents, hematopoietic stem cell mobilizers, H1 antagonists, MAOIs, class 1 antiarrythmics, antiviral agents, topoisomerase inhibitors, cephalosporins, dopaminergics/adrenergics, non-steroidal anti-inflammatory agents, and broad-spectrum antimicrobial agents.

18. The stain panel of claim 1, wherein the two or more agents are existing clinically-used agents, wherein at least one of the agents is an extracellular matrix stain.

19. The stain panel of claim 1, wherein the two or more agents are existing clinically-used agents, wherein at least one of the agents is a microbial stain.

20. The stain panel of claim 1, wherein the two or more agents comprise a fluorescent nucleic acid stain and a fluorescent cytoplasmic stain, wherein the fluorescent nucleic acid stain is Daunorucibin Methylene Blue, Mitoxantrone, or Proflavine, and the fluorescent cytoplasmic stain is Fluorescein, Phenol Red, Phloxine B, or Rose Bengal.

21.-29. (canceled)

30. An apparatus where the illumination of an optical biopsy stain panel according to claim 1 is about a single wavelength, wherein observation occurs through color filtering means or amplification or conversion of the resultant fluorescence into observable color range.

31.-34. (canceled)